Understanding the neurocognitive impact of outdoor PM10 and PM2.5 exposure: an in silico dosimetric modeling study using MPPD

Title: Unders t anding the neurocog ni tiv e impac t of outdoor PM 1 0 and PM2.5 ex posure : an in s ili co dosimetric model ing study us i ng MPP D A uthors: D i ego Ru iz-S obrem a z a s 1, 2 ; Blanc a Ca t iv iel a -Ca mpo s 1 ; Ma r í a C ada l s o 3 ; A ngel Ba r ra s a 1 ; P i l a r Cat alá n- Ed o 4 ; Cri s tian P e re z -F ern a ndez 5 ; Be atri z F errer 6 ; F e rnando S ánch e z -S a nte d 3 ; Tere sa C olomi na 7, 8, 9 ; Ca r i dad L ópez-G ra nero 1 * 1 Un ive r si ty o f Za ragoza , Depar tment o f P s ycholo gy and S o c i o logy , T eruel, S p a i n . 2 Current: De p a rtme n t of H uman Anat omy a nd P s y cho b iol o g y, U n iversi ty of M urcia , Murcia, S pai n . 3 D e p a rtme n t of Psyc hology an d CI BIS , Un iver s i ty of Alme ria, A lme ri a 0 4 120, S pa i n 4 E s c u el a Uni v e r si t ar i a d e En f er m er í a d e Te r u e l ( U N I ZA R ) , Te r u e l , S p ain . 5 D ep ar t m en t o f H ea l th S ci en ce s , U n i v er s i t y o f Bu r go s , B u r g o s 0 90 01 , Sp ai n. 6 Al bert Einstein Co l leg e o f Medi c i ne, Molecular Pharm aco lo g y Departm ent, Bronx, NY, 104 61, US A 7 Un ive r si ta t R ovira I Virgil i , R e s e arch Group in Neuro b e h a vio r a n d He alth (NEUROLA B ), Ta rrag o na, Spai n 8 Un ive r si ta t R ovira I Virgil i , Departm ent of P sy ch ol o g y an d Rese arch Ce nter fo r Behavi or Ass es sme nt ( C RA MC ), Ta r r a g o n a, S p ai n 9 Un ive r si ta r Rovira I V irgil i , Cen ter o f Envir on m en tal, F o o d a nd T o x i c o l o g ical Te ch n ology (T ECNA T O X ), R e u s , Spa i n. * Corre spo n d ing a u t ho r: cg ranero@ u niza r.es Graphic al Abstrac t: Ab s t ra c t : Air pollu tion h a s be en incr ea s ing l y l inked to adv erse neur odevel op mental and neurod ege ne r a tive outcome s . Whil e ex periment al and p recli nical s t ud ie s sugge st tha t exposur e to p artic ul at e matt er ( PM ), particul a rly during ge sta tion, may di srup t c ogni t iv e devel opmen t, the imp ac t o f sh ort- term PM exp os u re on c ognitive and behav ior al func tion in g in healthy y oung popula tio ns r emai n s insu ffici e ntly expl or e d i n Spain. Mor eov e r , f ew s tud ie s have incorpo rat ed i ndividu ali zed do sim e try mode l s to e stimat e e xpo sur e mor e ac curately . This s tu dy inclu ded 186 h e al thy y oung ad ults (mea n ag e = 20.4 y ear s) rec r ui t e d f r om thre e Sp ani sh citie s (Te ruel, Almería , and Tala ve ra ) cha r a ct erize d by dif fer ent po llution l ev el s. Ambient fin e and c oar s e PM conc en tra tion s wer e r eco r de d 8, 15, a nd 30 days pri or to psychol ogic al asse s s me nt . In s te a d of r elyi ng sol el y on raw in situ envi r on me ntal m ea s urem en ts, indivi dualized PM d epo siti on w as e s t ima ted u s ing t h e Mul tiple -P ath P a r tic l e Do s i metr y M o del (M P PD), al lowing a more bi ologic all y meaning ful exposu re ap proxi mation . Psychol ogic al outcome s we r e a sse s s ed u s ing val ida ted que sti onnai re s: DASS -21 (d epre ssion , a n xiety, s tr e s s ) , BIS-11 (imp ul s iv ity) , UCLA L onelin e ss Sca le, a n d SWLS ( l if e s a t i sfac tion) . Beh av iora l .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint perf or ma nce wa s ev alua ted u s i ng c omputeri z e d ve rsion s o f the A t te ntion a l Netwo rk Task (A NT ) and t he S troop Ta s k . B lood NRF 2 conc entr ation s w e re an al yz e d a s a bi omarke r poten tially re lat ed to oxida t i ve stre s s me chani s ms . I n s i t u da ta indic a ted that Talav era pr e s en ted t he hig he st po llutio n le vel s, foll owed by Almerí a and Teru el. L ine ar reg re ssi on analy se s s how ed tha t co ars e PM e xpo s ur e ac ro ss 8 - , 15- , and 30-day w indows s ig ni fica n t l y pr e dict ed po o r e r Ex ecu t i ve Cont rol Inde x perfo r m ance in th e A N T . Ad dition ally , 15-day coa r s e PM and 30 -day fin e PM expo sure we r e a ssocia te d wi th gr eat er co gnitive i nt e r f er enc e . O x idative s t re ss marke rs wer e signi fican tly as soc iat ed wi t h P M e xposu re l eve l s . T hes e fin ding s s upp o r t emergi ng evi dence tha t sho rt-t e rm PM ex po s ure ma y nega t i vely a ff ect e xe cutive and atte ntio nal proc ess e s eve n in h ea lthy y o ung ad ults. F u r th er l ongitu dina l r esea r c h inc orpor a t i ng indivi dualized e xpo sure modelin g is w arran ted t o c larify cau sal pa th way s a n d underlyi ng biologi cal mecha ni s m s. Keywords: Environme ntal To xic ology; Pa r tic ul at e Mat t e r ; M PP D model; Atten t io n al functio ning ; Men tal he alth ; Oxida t i ve S tr es s 1. Introduc ti on Air p olluti on is wid e ly rec ognized a s on e of the l e ading environm ent al r i s k f a ct or s c ont r i but i ng t o global morbidity a nd morta lity ( Pozz e r e t a l., 202 3; Fora s tier e et al. , 2024). D e s pite it s broa d r e cogni t i on , th ere i s no singl e, univ e r s al ly a cce p t e d d ef inition of air poll u t i on due t o i ts intr i n s ic compl e xity. Th e W o rld H ealt h Or g aniza tion (WHO, 2025) de fine s air p ollution a s the contami na tion o f i ndoor o r outd oor e nvironme nts by ch emica l, phy sica l, o r bio l ogic al age nts t h at alt er th e na tural c harac teri s t i cs of the atmo s p h ere . Amo ng the d iv er s e c om ponen ts of air pollution , p ar t ic ulat e m at t e r ( PM ) has rec eived par t i cular a t t enti on be cau se of i ts physicoc hemic al pr oper tie s an d it s c a pac ity to pen et rat e biolog ical sys tem s ( Onive f u & Imarhiag be , 2024 ; N a t i onal In sti tute of Env ironmental H ea lth Sci ence s, 20 25) . PM i s typic ally c las s i f i ed acc ording to a erodyna mic dia me te r int o c oar se pa rtic l es ( PM₁ ₀; ≤10 µm), fin e pa rticl es ( PM ₂ .₅ ; ≤2 .5 µm), a n d ultr afi ne p articl e s (≤0.1 µm ) . Inc r e a s i ng ev idenc e s ug ge sts th at s ma ller pa rtic le s may exe r t grea te r biol ogica l da mage, a s th eir reduc ed s iz e facil ita te s de e per pen etr ation into th e re spi rat or y trac t and po ten tial t ra n sloc a tion in to s y stemic circ ul ation (Sc h r a u fnagel , 2020 ; Wya tt et al., 2 020; Garcia e t a l. , 2023) . A sub sta nt i a l body of ep idemiolo gica l r e s e a r c h has ex amined the impac t o f PM e xpo sure on res p i r a tory and cardiov a scular outc om es . Long - t erm c oh ort s tudie s hav e con si ste ntly lin ke d PM₂ . ₅ expo sur e t o an incre a sed r isk of chronic o bs truc tive pul monary di se a se, lower re s p ira t o ry i nfe cti on s, a nd lung c ance r (Ky ung & Jeong , 2020). More rec e nt l y, a s s oc ia tion s have bee n esta bli she d betwee n PM ex po s ure an d c ardi ova sc ular morbidity (C handa e t al ., 2024) , as well a s neurod ege ne r a tive di sord er s (C r i s taldi e t al ., 20 22; Ca tiv iela -C amp o s e t a l ., 2025 ). The s e finding s have progr e ssiv ely s h i fted at te ntion towa rd t h e c ent r a l ne r v ous sy s t e m (CNS ) a s a critica l ta rget o f P M- rela ted t ox ici t y . Early mec hani stic hypot he se s p ropo se d t h at in h aled p ar ticle s trig ger sys temic infla mmat ory r e s pon se s thr ough t h e r elea s e o f p ro-in flamma t ory medi a t o r s (S e at on e t a l. , 1 995) . Subs equen t r e s e a rch ha s i den tifi e d mult iple pa t hw ays thro ugh whi ch PM may a f fect th e CNS , inclu ding neuroi nfl amma t i on, ox idativ e s tr e s s, di srup tion o f the ne urov ascul a r unit, bl ood – br a in bar r i er (BB B) d y s fun c tion, and ne uronal ap opto si s (Cal d er ó n-Garc idu ena s et al . , 20 02, 2021; Co r y - S l ec ht a et al. , 2 023). Neve rth ele ss, the ex te nt to whic h the s e mecha ni sm s tran sl at e into direc t fun c tional impai rment s in hu ma ns rema in s unde r ac t i ve de b ate . .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint Two primary, non-mutu all y e xcl us iv e p athway s hav e b ee n prop o sed to ex plain PM-in duc ed CN S alt era tion s. T he first involv e s a di r e c t route , w hereby ultr afin e part ic le s ma y t ran s l oc at e fr om the n a s a l ep ithel i um to the br a in via t h e ol fac tory b u lb (Elder e t a l., 2006; Oberd öste r e t al., 2 004; G r a ham e t a l., 2025 ). Addi tion ally , fine pa r tic le s d epo sit ed in th e alveo l ar r e gion ma y ente r sys temic c ircul a t io n , fa cili ta t in g t h e tr an spor t o f s o l uble par ticl e compon e nts t h a t ma y compromis e BB B in tegri ty ( G u na s i ngam et al. , 202 4; C a lder ón- Garcid ue na s et a l., 20 08) . Th e s ec on d, indi rec t pa thwa y sugge s t s tha t P M expo s ur e promo te s s ys temic in fla mmation a nd oxida t i ve st r e s s, whic h in t urn di s rupt CN S home os ta s i s thro ugh i mmune a c tivation and periphe ral–c ent ral signa ling c asc ade s (S e r a fini et al ., 2022; Ren t s c hler & Kodav ant i, 2024 ) . Preclin ical evi denc e la rgel y suppo rt s t h e se mech a ni st ic mod e l s . Expe r i ment al stu die s h av e d e m o n s t r a t e d t h a t P M e x p o s u r e i n c r e a s e s o x i d a t i v e s t r e s s m a r k e r s a n d n e u r o i n f l a m m a t o r y r e s pon se s (Zh ang e t a l. , 2 023), i nduce s apopto si s in C NS c ell s (C hang et a l., 2 019), r e duce s neurogen e si s in a nim al mo del s (Wood w ard e t al ., 2018) , and is a s s oc iat ed w ith struc t u ral bra in alter atio ns (N ephew e t al ., 2021 ; Eh san i f a r et al ., 2019) . Howev er , a s highli ght ed by r e cen t s y stema tic review s ( Ruiz -Sobr emaza s et al ., 20 23; Rodul fo - Card ena s e t al. , 2 023), the re r e m a i n s n o c l e a r c o n s e n s u s r e g a r d i n g t h e m a g n i t u d e a n d s p e c i f i c i t y o f P M e f f e c t s o n neurod eve lopmen t, be h avioral al ter atio ns, an d g lobal cogni t i ve f unc tioning . Cognitiv e func tioni ng enc ompa s s e s a br o ad s et of ment al p roc e sse s es senti a l f or adaptiv e dai ly behav ior. Acco r din g to th e America n P s y chia t ric A ssoci ati on (A PA, 2018 ), c ognitiv e functio ni ng r e fe rs to the pe r fo rmanc e o f ment al proces s e s such a s pe rce p t i on, le arni ng, me mory, r e a s on ing, judg men t, and l anguag e. A gr owing number o f pr ecl inica l s t udi e s ha v e inv e s tig a ted t h e e ff ect s o f PM expo s ur e on sp ec ific c ognitiv e doma i n s , i ncludi n g memory (Rui z -Sob rema z a s et a l. , 2025a ; Hou et al ., 20 23; Fonk en et a l. , 2012), lea r ni ng (Ruiz-S ob remaz as et al. , 20 25b; Pat ten e t al . , 2020), and soci a l beha vior ( Weit ekam p & Ho fman n, 2021; B erg e t al. , 2020). A similar tre nd i s emergin g in human re s e a r c h. Longi tudi nal co hor t st u di e s h av e ex plore d assoc ia tion s be t w een ch r oni c PM expos ure a nd cog nitive ag ing ( Q i et al., 20 24; W a ng et a l. , 2024; Lóp ez - Gran ero e t al ., 2023), a s w ell as c ognitiv e devel o pment i n sch o ol - aged c hildren (Sunye r e t al., 2015; L e t t e t al. , 2017). Neve rth ele s s, mo st h uman evide nce remain s obse r v ati onal in na tu r e. T o da te, expe r i ment al re s e arch dir ec t l y manipul ating P M conc entra tion s to e valua t e acu t e beh avi or a l or cog nitive e f f e c t s in huma ns is ex t rem e ly limited. Not ably , Fahe rty et al. (20 25 ) c onduc ted o ne o f th e fir st cont rolle d s tu dies modi fyi ng PM expo sur e leve l s and r epor ted that h ighe r PM co nc entr ation s impai red sel ec t iv e at ten tion perf or ma nce and redu ce d acc uracy in emotion rec ogni tion t a s k s. D e spi te t he s e adva nce s , s ig nific a nt ga p s remain rega r di ng t h e c aus al rela tion ship be twee n PM ex po s u r e and speci fic cogn it i ve domain s in h umans , a s well as t h e me chani s ms un d erlying the se po t e n t i a l alter atio ns . Fur ther e xperimen ta l r e s ear c h is the re for e requi red t o cla r i fy th e extent to whic h acute or shor t- term P M ex po s u r e dire ctly influ enc e s cog nitive func tionin g a nd beh av ioral outcome s. O ne o f the ma jo r c halle nge s in e nv iron mental t oxic ology is t he ac cu rat e a s s e s smen t of the exposom e. Thi s requi re s th e integr atio n of in si t u ex po s ur e mea sur ement s, whi ch c aptur e s ho rt -t er m a nd i ndivid ual varia bility (S t einl e e t a l ., 2015 ), with i n silic o m odeli ng a ppr o ach e s capa ble o f s imu la ting ke y environmen t a l a nd expo sur e -rel ate d varia bl e s (T sir o s et al . , 2 022 ). The c ombination o f th e se app roac he s improves expo sur e e stim ation a nd f a cilita te s th e identi fic ati on o f a ddi tional fa c tor s tha t ma y be in fluenc ed by varyi ng PM c once nt r atio n s (H ouw eling e t al., 2024 ). .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint Base d o n p rev iou s ex perimen tal and ep i demiolog ica l e videnc e, we hy po t h e s iz e d tha t high er PM expo sure in th r e e di ff ere nt e xpo sure window s (8 -, 15-, an d 3 0 -day ex pos u r e time) w ould be a s s oc ia ted with p oore r p er for m anc e in a tten tion a nd cogni t i ve in ter fe rence c ontr ol ta sk s. Addition all y, we incorpo rat ed s y s t emi c biologic al mark er s to expl or e w heth er the ob s e r v ed assoc ia tion s ar e more con si s t e n t w ith direc t tr a n s l o cation me ch ani sms or i ndirec t inflamma tory pathway s . 2. M e thodol ogy 2.1. Par t ic ipants O ne -hu ndre dt h an d ei gh ty- six Spani s h - s peak ing par ticipa nts from thr ee ci tie s ( n = 120 f rom T e r u e l ; n = 4 3 f r o m T a l a v e r a ; n = 2 3 f r o m A l m e r í a ) , a g e d 1 8 - 3 9 ( m e a n o f 2 0 . 5 y e a r s o l d ) . T a b l e 1 p r o vi d es a s u m m a r y of th e de m o gr a p h i c c h ar ac te r is t ics of t he s a m p le us e d. N one of t he c i t i e s a r e l o c a t e d c l o s e t o e a c h o t h e r , a n d a r e l o c a t e d a t d i f f e r e n t r e g i o n s o f S p a i n : T e r u e l ( i n Ar a gón; 40 °20,κ4837,κ48 N 1°06,κ4826 ,κ48O), Al mería (in Andal ucí a; ~3 6 ° 5 0,κ4830,κ48N 2°2 7,κ4850,κ48O) and Tala vera de la Re ina (Tole do ; 39°58,κ48 00,κ48N, 4°50,κ480 0,κ48O). Excl us ion c rit er i a were: (i ) not s pe a king Spani s h, and (ii) di agno si s o f int elle ctu al di sab ility or o the r psyc hia try is sue s. Table 1 S a m p le c h ar act e r is t i cs Ch ara cte ris t i c s T eruel ( n = 120) Al mería ( n = 23) T alav era ( n = 43) Total Comp ari s o ns 1 Woman, n (%) 82 (68 .3) 1 8 (78.3) 27 (62.8) 127 (68.3 ) p = .441 A g e, m ea n ( S D ) 19 .9 (2.4 ) 22.6 ( 4 .9 ) 21.0 (2 .4 ) 20. 4 (2.9 ) p = .005 Wei ght, me an (S D) 65 .3 (14.9 ) 67.0 (1 9.3 ) 64.7 (12 .9 ) 65.3 (14.4 ) p = .832 Height, me an (SD ) 165 .1 (23.4) 163.2 (7.7 ) 169.3 (1 0.0) 167. 6 (9.6 ) p = .021 BMI, me a n (S D) 23 .5 (6.5 ) 24.8 ( 6 .1 ) 22.5 (3 .6 ) 23. 7 (6.4 ) p = .315 Tid ial Volu me (SD ) 497 .9 (71.3) 466.8 (5 4.6) 494.8 (5 9.1) 493.3 (67.2) p = .125 Func tional Re s idu al Capac i ty 2 (SD) 2 .7 (0.5 ) 2.5 (0 .4 ) 2.8 (0. 5 ) 2.7 (0.5 ) p = .073 S moking , n (%) 14 (11 .7) 4 (17.4) 7 (16.3) 25 (13.4 ) p = .632 1 Du e to t h e v iolat ion o f Le ven e’s te st, a l l c omp ari so ns we re p e rfo rmed w i t h W e l c h correc ti on . 2 T h e fu n c t i o na l re sid ual ca pac i ty wa s calc ula te d wit h the onl i ne Gl obal L u ng Fu nct ion I nitia ti v e fro m t he E u ro p e an R e sp ira t o ry So c i et y Bef ore a ss es s m ent, p artici p ant s gav e w ritte n i nfo r me d c on se nt; pa rtic ipant s di d not rec eiv e any m onet ary c ompen s ation . The projec t w a s p erformed unde r t he Decl a rat ion o f Hel si nki an d approved by th e loc al in s ti tuti ona l ethi c s commi tte es ( re fer enc e num ber P I21 -213 ) and i n acc ordance with Regul a tion (EU ) 2 016/6 79, the Gene ral Dat a Pr ot ection R eg ulat ion, a nd wit h O rga nic L aw 3/ 2 018 on t he Prot ectio n of Per s o na l Da ta an d Gua ran tee o f Dig it a l Rig hts (r e fe r en ce R AT 2023-284) . 2.2. Real and phys i cal da ta acqui s ition The pre sen t cro s s- sectio na l s tudy wa s c o nducted b e t w ee n Ma r c h 2024 and May 2025. All dat a fr om pa r tic ipa nt s ( phy s i o logic al, qu es tio nnai r e, a nd n eurocog ni tive outco m e s ) we r e ob ta ine d within only one s e ssion. Fir st, p art i cip an ts w e r e w e ighed and m ea s ure d, af t er that , eac h participa n t c ompl ete d a ll que sti onnair es , and a f t e r fini shing t h o s e, they co mpl eted tw o computati on al t e s t s (At ten tiona l N etw o rk Task and Str oop ). A ft er fin i s hi ng the c omputa t i on al t a s k s, pa rtic ipant s wer e a s k ed i f they wa nted to give blood fo r bi ochemi cal an aly sis. 2.3. Ma te ri a l s .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint 2.3.1. A sses s ment of mental hea lth variables S e v er al q ues t i on na i res w er e us e d t o s cr e e n d iff e re n t c o g ni t iv e an d m e nt a l hea lt h va r i ab l es . F i r s t , w e u s e d a s u b j e c t i v e m e a s u r e o f p e r c e i v e d h e a l t h t h a t c o n s i s t s o f a L i k e r t s c a l e w h e r e participa n ts must r e sp ond wheth er t h e y c onsider ed t ha t th eir ow n he al th i s eithe r ba d or exc ellent . Al s o, we u s ed th e S pani sh ve r sion o f Sa ti sf action w ith Liv e Sc ale (SWL S ; P on s e t a l. , 2000). The fi r s t va ria ble analy zed i s d epr e ssion , a nxiety a nd s tre ss . We u se d th e Sp an i s h ve rsion of t h e De pr e ssio n Anxi ety and S t r e ss S cal e- 21 (DA S S -21; L ovibond & Lo vibond, 1 99 5). This t e s t i s compose d of 21 i tem s tha t s c re ened t hr e e sub -dimen sio ns : str e ss, anxie t y a n d de pr e s sion . Fons eca - P e dre r o et al . (201 0) s ho wed g o od ps y chome tric prope rti e s reg arding C r onba ch al pha for tot al s ym pt om s ( α = .9 0) , f or de pre ss ion ( α = . 80), fo r anxi ety (α = .73 ), a nd stre ss ( α = .81) . In a dditi on, th e Spa ni s h DA S S -21 ver s i on al s o achi eved good punctu ati ons in o the r ps y chome tric outcom es . The s ec ond va r i abl e a na lyzed i s impul sivity. Thi s va r i abl e w a s s c re ened with the Spa nis h versio n o f t he Ba rra tt Impul sive ne ss S cal e ( BIS -11 ; Pa tt on, S tan for d & B arr at t , 1995 ) . Thi s que st i onn aire i s c ompo s ed o f 3 0 i te ms that sc r e e ned to t a l imp ulsive ne ss a nd three type s of impulsivity : at t e n t i onal , mot or and no n -pl anned im puls i vi ty. T he Span i s h v ersion of th e B I S-1 1 was t es t e d by Oqu endo e t al. (20 01), rev ea ling a good Cronb ach a lph a ( α = .81 ). The last e mo t i on al varia ble analy zed is loneline ss . This v ariable wa s scr een ed wi t h the brie f Spani sh ve rsio n o f the UCLA lon e line s s s cal e. Thi s que s t i onnai re i s compo sed o f 10 i t e m s tha t s c r e ened lone li ne s s . Th e que s t io nn air e wa s t es t e d by V elard e- May ol e t al . (201 5 ), an d obtain ed a good C r onb ach alp ha ( α = .95 ). 2.3.2. A sses s ment of neurocog niti ve va ria bles All ta sk s w e re programm e d a nd adm in is t ere d u s i ng P s yc hopy (ver sio n 2 023.2 .3), an o pen - s ou rc e s o ftwa re pa cka ge for th e c r e ation a nd pr ese nta tion of b ehavi o r a l e xperime n t s . Ps y chopy allow s pr eci se c ontrol ov er s ti mulus pr ese nta tio n and re s pons e r e c o r d in g , e n su r in g millisec ond a ccu r a cy in re a ction t i me me as u reme n ts. The e xperimen t wa s c o nduc t e d on a s t anda rd de s k top compu t e r a nd pa rticip a nt s ’ re spon s e s we re reco rded via keybo ard inpu t. W e us e d a c omput eriz ed ver si on o f th e A tt ention al Netwo rks Ta sk ( AN T ) d ev elope d orig inally by Fan et al . (2002 ). Thi s t a sk invol ves pa rtic ipan ts re s pon ding t o t he di rec tion of bo th c ue d (spati a lly or no t) a nd unc ued c ent er a r r ow ta r g e t s tha t ar e flank ed by c ongru en t, inc ongru ent o r n e u t r a l s t i m u l i ( s e e f i g u r e 1 ) . T h e c u e t y p e s m e a s u r e h o w a l e r t i n g o r o r i e n t i n g a t t e n t i o n network s a re employ ed a nd the fl ank e r type s me a s ur e the a bility to re solve confli ct fr om visual s timuli. Pa r tic ipa nt s, th er e fo r e , ha ve to re sp ond u sing th e k eyboa rd a r row s (ei the r righ t or l ef t ) to th e direc t i on of t h e c entr al ar row that might be c ongruen t or incon gru ent with the s ur rounding ar rows . Furth ermor e, a co ntrol condit ion, whe re blac k squa re s we r e us ed a s s ur rounding s t i muli, was inc luded withi n th e proc edur e. W e f ollow ed th e sa me p r oc edur e expla ined i n Fa n e t a l. (2002) to c alc ula t e the da ta and the rati os fo r th e ori ent at ion, a le rt , and cogn it i ve fu nctioning at ten tional ne two rks u s ing th e fol lowing formula e : Or i e nt a t i on I nde x [( T Rinva lid - TRv alid )*10 00 ], Al ert Index [ (TRab sen t - TRp re se nt )*1000 ], a nd Ex ecu tiv e Func tion [( T Rinco ng r - TRc o ngr) *1000] . All ratio s were pr e sen ted a s rea c tion time in mill i s e con ds ( m s ) as de pend en t varia ble s to fur ther ana ly si s . A com pute r i zed ver s i on o f the St roop Ta s k , ba se d o n th e o rig inal p aradigm de scribe d by Stroop (1935) , wa s a dmini ste r ed . In t h i s ta sk, pa rtic ipan t s a r e r e qui red to re spo nd to th e font .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint color o f visu al ly pre s ent ed word s wh ile i gnoring t heir s emantic con ten t, whic h ca n be cong r ue nt or inc ongrue nt wi th r e s pe ct to th e ink col or. Co ngruen t t rial s p r e se nt col or w o r d s whose meani n g matche s t h e d i s pl ayed c olor (e. g ., RED prin ted in red) , whe r e a s inc ongruen t t ria l s int roduce a c on flic t be tw een th e word meaning a nd t he i nk color ( e.g., R ED printe d in blue), ther eby el iciting i nte rfe renc e an d eng aging inhibitory co ntrol mec hani sm s. Par t i cipa n t s r e s pond vi a keybo ard in put , se lec ting th e k ey corre spond ing to th e i nk color as qui ckl y and acc urate ly as p o s s ibl e. Str oop re actio n t ime w as u sed to c a lcul at e cog nitive in te rfe renc e wi th t h e f ollow ing formul a: [( RT incon gr/RTc o ngr)*100 ] This p rocedu re enabl es th e q u anti fica tio n o f co gnitive int erfe ren ce a nd the ef fic ienc y o f exec utive c ontrol pr oce s s e s in volve d in s elec t i ve at ten tion . All t he t a s k s w ere per for m ed u s i ng t h e sa me s c reen s with th e sa me cha r a ct eri st i c s ( r e soluti on of 14 40 x 900 , r e f re s hment ra te o f 59.89 h z a nd 8-bi t s ) . (In s e rt Fig ure 1 here ) Figure 1. Grap h ica l re p re s e n ta ti o n of A NT proced ure (s ec ti ons a , b an d c) . I n ea ch tria l, p a rtic ip a n ts sta rt by l o oki ng to a f ixa tion p oint wi th a varia ble a nd ran dom d u ra ti on (40 0 -1 6 0 0 m s) u n til o n e o f t he cues d e p i cte d in im age a) a ppea rs. Aft er th e cue , a fixa tio n p o i nt rea p pe ars and , a fter 4 0 0 m s, t h e ta rge t appea rs on th e sc r e e n . E ac h partic ipa nt ne eds t o answe r as soo n as p o ss i b le wit h i n 150 0 m s or th e tri a l is con s idere d a s an omission. The dow n part of th e figure r e p r e s e n ts the ST R OOP p roce d ure. Particip a n ts sta rt th e task w i th a fi x ati on poi n t w it h a r andom durat i o n betwe en 2 2 0 -1 495ms. After that, the t a rg e t appears (o ne of t he ta rge t s that a p pea rs in i ma ge d ) an d partic ipa nts n e ed t o answer a s s o o n as possible t o t he co l or o f t he wo r d p re s ent (i m ag e e). 2.3.3. In s i t u air pollution data Air pol lu t i on in for m a tion wa s ta ken fr o m thre e dif fe ren t dat a se t s . Tho se d ata s et s ar e op en- acc es s fr om t he Min i stry f o r th e Ec olo gi cal Transi tion and the Demogr aphi c C halleng e ( for Almería ), Regio na l Mi ni stry of S u stain a bility, Env ironment and Blu e Econom y (fo r Tala ver a) , and the D epar tment of Enviro nmen t an d T ouris m (f or Te ruel ). Thr ee d i ffe re nt ti mel ine s w ere us e d to de te r mi ne th e number of mol ec ule s that wer e pre sen t i n the air . S pecifi call y, w e s e l e c t e d 8 - , 1 5 - , a n d 3 0 - d a y s p r i o r t o c o l l e c t i n g a l l t h e d a t a . W e s e l e c t e d t h e s e t i m e l i n e s beca u s e we w ant ed to di ff er entia t e b et ween “ac ute” a nd “ chronic ” ex pos u r e t o air pollut an ts . There for e, the ai r pollutio n data wa s t ak en from th r e e di f fer ent colle c tor s : Al mería ( Code : ES139 3A; 36.8 4133 a l titu de, -2 .44 672 l on gitude, 5 1 el e vation above se a) , Ta l avera (Cod e: ES213 6A; 39.9638 al t i t ud e , - 4 .8257 l ong itude, 380 ele vat ion abov e sea ); T eruel ( Code : ES142 1A; 40.336 39 alti tude , -1.10667 lo ngitude , 915 e l eva t i on ab ov e se a ). To obta in th e f i nal in situ PM c once nt r a t io n , ea ch subjec t’ s te s t da y w as co ns id e r e d . P M conc entra tion s from th e monitori ng s t a tion s loca te d in eac h c ity were ca lcula te d using th e o ff i c i al d at a pr o v id e d b y g o v er n m e n ta l ag e n ci e s. F ina l l y , P M c o n ce nt r a t io ns wer e a ve r ag e d f or eac h expo sure p eriod (8- , 15-, a n d 30-da y s ) . 2.3.4. In s i lico a ir pathway si mulation (MPPD) To obtai n a m or e a cc ur a t e and indiv idu ali z ed e stima te of ex po s ur e to ai r bor ne c ontamina n ts, we employ ed t he M PP D -v3.04 ( Applied Re sea rch A ssoci a te s , 2025 ), mode l to simula t e th e depo sitio n of in hal ed p articl e s ac r o s s t h e human re spi rat or y trac t ( A n jilvel & A s gharian, 1 995 ; Miller et al ., 2016 ). Tr adi t io n al ex po s ur e me t ric s ba sed solel y on ambi en t conc en tra tion s ( e. g. , µg/m³ mea s u red a t f i xed - sit e mo nito r i ng s t ation s ) prov ide valua bl e inf or mation abou t environme n t a l polluti on le vel s but d o n ot c aptur e t h e s ub st antial in terindi vidu a l v ariabil ity in inhala t i o n, d epo siti on, a nd c lea ranc e pr o ce s s e s. A s a re sul t, relyin g exc lu si vely on r a w .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint conc entra tion dat a can lead t o mis c la s s i f i c ation o f pe r s ona l ex po s ure and a n inco mplet e under s t and ing of the biol ogic al d o s e t h a t ultimately re ache s t arge t ti s s u e s . The M PP D mod el o f fer s a m ec hani st i c f r amework t h a t in teg r a te s p a r tic l e cha r a c teri stic s ( e. g. , s ize di st rib ution , de n s i ty, hy gro s c opic i t y ) w ith phy siologic al p aram e t e r s suc h a s airwa y geometry, b rea thing pa tte r n s, a nd ve nt i lation r at es (A njilv el & A sgha rian, 19 95 ; M i ller et a l ., 2016; Mori , I to & Sek ine , 202 4; Bui et a l., 2020; Man oj kumar e t al ., 2019 ) . By s i mul ating t he t ran spo rt and depo si t i on of pa rtic le s th r oug hout th e ex tr a thor ac ic, t r a che ob ronc hial, and alve olar r eg io ns , the mod el provi de s a biol ogica lly mea ningful e s t i mate o f th e intern al do se t h at i s m ore c lo s e ly al ign ed w ith tox ico lo gica l rel e vanc e t ha n a mbient conc en t r a t io n al on e. This i s pa rt ic ula rly importa nt for c o ntam inan ts who se h e al th e ff ect s d epend on the f r a ction o f particle s that p en e t ra te de eply into the l ung s o r a cc umula te i n s pe ci fic ana tomic a l reg ion s . Furthe rmor e , the u s e of M PP D all ow s u s to i nco rpora te indivi duali zed or p o pul ation - speci fic physiologi cal in pu ts, ther eby improvi ng the ecol o gica l vali dity o f e xpo sure e s ti mate s. F ac tor s s uc h a s age , sex, body siz e, a nd b rea t h i ng mode (na s a l v s . oral ) can sub s t anti al ly influ enc e depo sitio n e f fic iency , and t h e mod el enable s the s e sou rce s o f va r i ability t o be ex plic itly r e pre sent ed. Th i s l ev el o f pe rsonal iza t io n i s no t achi e vable w hen usi ng e nvi r onme ntal conc entra tion da ta a l one, whic h a ssum es uni fo r m ex pos u re ac r o s s indi vidual s r e gardl es s o f t h eir phy siolog ical o r behav ior al c harac t eri st i c s. By integrati ng e nvironmen tal m ea su r e m ent s wi t h do sime tric mod eling, ou r app roa ch bridge s t h e ga p b e t w een e xt ernal ex po s ur e a nd int ernal do se . T hi s i s e s s e n tial fo r inte rpre t i ng poten tial h ea l t h e ffe ct s , a s the bi olog ica l re spon s e t o a irb or ne c ont amina nts i s driv en no t by t h e c once n t r ation pre se nt in th e e nvir onment bu t by th e amoun t o f ma teri al that actual l y depo sit s in th e r e s pi ra tory sy s t em. Th e MPP D model ther e fore p rovide s a mor e r e fi ned an d mecha nistic ally g r o un ded e stimate o f e x posur e , enh ancin g the ac curac y of ri sk as s e s sm ent and streng t he ning the link b e tween env ironment al poll uti on and indiv idual h e al th outcome s . Table 2 summari z e d th e speci fi c va r i able s to c alcul ate indiv idu al dat a. Table 2 . Va ria b l es re quire d f or th e MPP D m o de l an d s pe c i f i c s e t t in gs us ed f or t he calcu la t io ns Do ma in s i mu la t ed Va r i a bles re qu i r e d D ata us ed i n t he MP P D mo d e l A i r w a y m or ph o me t r y Spec i es Hu ma n-like Mode l Ye h - Schu m 5-Lob e Func tio nal Res i du a l Ca pa c i t y (F R C) C a lcul a t e d wit h G LI c al c u l at or Up pe r Res p ira t o r y T r a c t (URT ) De f aul t s ett ings ( 50. 0 ml ) Pa rt i c l e Pro p ert ies De ns it y D e f ault se tti ngs ( 1 g/c m 3 ) As pe c t R at io Def au l t se tti ng s ( 1 µ m) Diame te r Mult imo d a l M MA D w it h d i ffer en t s e t tin gs fo r PM 10 ( MMF = 1; D ia meter = 5; G SD = 2.2; Dens it y = 1. 5 ) and PM 2.5 (M MF = 1 ; Di am e t e r = 2 . 5; G S D = 2; Dens it y = 1 . 5 ) Ex po sure co ndit io n (cons ta nt ex pos ure) Accelera t io n of G r a vi t y De f aul t s ett ings ( 98 1.0 c m/ s 2 ) Bod y o ri en ta ti on U p r i gh t po s it i o n (h e a d po s it i o n : α (3 0º ) , β (0º ) , γ ( 0º ) Aer os ol conce n t rati o In di vid ua l a e ros ol con c e n trat io n f or t hree d iff ere n t pe r iod s ( 8 - , 1 5 - , a nd 3 0- d a y s p ri o r d a t a c o ll e cti on ) .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint n Br ea t h in g fr e q uenc y Def au l t se tti ng s ( 1 2 per m in ut e ) Ti d a l v o l u m e I ndi vid u all y ca lcul a t ed w it h heigh t In s pi ra tor y F r a c t i on De f ault s etti ngs ( 0. 5) Pa u s e F r a c t i on Def a ul t set tings ( 0) Br ea t h in g Scen a r i o Nasa l 2.3.5. Biochemic al a nalysis Blood s amp l es wer e col lec ted by spe ci ali z ed nu r s i ng sta f f a t t h e s ame facil iti es whe r e th e r e s ea r c h proc edu res we r e conduc t ed. D ue to fu nding con st r a int s, bi ologic al sam ples c ould n ot be c ollec ted from par t i cipan ts i n Tal avera; th er efo r e , onl y bi ologic al dat a fro m Teruel and Almería ar e inclu ded in t hi s study . Who le bl ood w as c ollec t ed us i ng Va cut aine r® saf ety -loc k blood col lec tion sys t e m s ( Vacu ta in er; R e f: 36 8652 ). Pla sma sampl es w ere obtai ned in EDTA - coated tube s (Fi sh er Sc ien ti fic; Re f: 12 987666), w hile se rum s a mple s we re col l e cted in se rum t u be s ( F i s h er Sci en tif ic; BD Vac u taine r S S T II A d vanc e; R ef : 10 829270). For plasm a proc e ssing , EDTA -t r ea t e d blo od sample s w er e store d a t 4 °C and proc e ss ed wi t hi n 1 hour o f col l ection . Sampl e s w ere ce ntrif ug ed at 170 0 × g f o r 1 0 minut e s a t 6° C in a re fr i g era te d centri fuge. The pl a s ma was al iquo ted af t er ce n t ri fug atio n. Fo r se rum proc e ssing, sampl es w ere s t ored a t 4° C unde r the s a m e pre -pr oce ssing condi t i on s a s pla s ma sample s . S ample s wer e centri fuged at 1.700 × g for 10 minu te s a t ro om t emper atur e. No st a nd ardiz ed cl o t ting t i me at r oo m temp era ture wa s a ppli ed, a s sampl es wer e not c entr i fuged im medi at ely aft er coll ecti on. Follow ing c ent rifuga tion , bo th pl a s ma a nd serum s a mple s w ere al iquo ted and st or e d at −80 ° C until ana ly si s . Sampl es we re subjec te d to a max imum of t w o fre ez e –thaw cyc le s. 2.3.5.1. ELISA s Pla sma and se rum sam ple s w ere a naly zed u s ing e nz y me-link e d immuno sor b ent a ssay (EL IS A) kits fo r t he q ua nti fica tion of the fol lo wing bioma r k er s : int erle ukin-6 (IL -6; In vitrogen, Re f: EH2IL6), tumo r necr osi s fac tor al pha (TN F -α ; In vitr ogen, R ef : KA C1751), nuc lear facto r erythroi d 2–re la ted fac tor 2 ( NRF2; Abc a m, Ref: a b277397 ) , and Klo tho p rotein (T hermo Fi sher Sci enti fic, Re f: EE L200) . All a ssay s w er e pe rfo rmed a cc o r di ng to the manufac tur e rs’ instruc t io n s. All sample s we re a naly z ed i n du plica t e . O nly mea surem ent s w ith a coe ffic ien t of variation b elow 15% b etween duplic a te s w ere inc luded i n the fi nal anal y s i s. Standa rd c ur v e s w er e gen era ted f or eac h pl at e ac cording to the manufac tur e r ’ s r e commen da tion s , a nd co ncen tra tion s w er e c alc ula ted u s ing a fou r-p ara meter l ogis t i c r e g r e s s i o n m o d e l . T h e l o w e r l i m i t o f d e t e c t i o n ( L L O D ) f o r e a c h a s s a y w a s a s s p e c i f i e d b y t h e manufac t u r e r. A p i l o t a n a l y s i s p e r f o r m e d i n ED T A - p l a s m a s a m p l e s y i e l d e d c y t o k i n e c o n c e n t r a t i o n s b e l o w t h e LL O D for all a nalyt e s. Con se quen tly, all sub se quen t ELIS A me as u reme nts were condu cted in s e rum sample s . G iven th at the st u dy p o pulation d id no t p r e sen t cl inica lly ov er t infla mmat ory conditio n s , low circul ating lev el s o f pro - infla mmat or y cytok ine s w ere an tic ipat e d, in line with pr e viou s lit era tur e (Kl ein er et a l ., 2013 ). All EL ISA s w er e re ad u s in g In fini te® F5 0 a bsorbanc e r e ade r (TEC AN, R ef : 30 190077) fol lowing eac h EL ISA’ s in st ruc t i on . 2.4. Dat a A n aly s is .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint Two di ffe ren t s ta tistic al a naly se s we re p e r f ormed w ith the obtai ne d dat a. F i rst, e nvi r onm enta l and MP P D simul at ed da ta we re comp ared u s i ng two-w ay ANO VAs w he re P M a nd M PP D s imu la ted ou tc ome s b etwee n citie s a re c ompared . P rev iou sly pe rforming thi s a na lysis , equ a lity of v arianc e s w as te s t e d wit h Lev ene’ s tes t. If the te s t s hows n o equ al v arianc e s , ther ef ore a W e lch ANOV A will be perfo rmed beca u s e it work s per f e c tly wi t h uneq ual varia nc es ( Welc h , 1951; Z immerman, 2004) a nd diff er ent s ample s i z e s (Zim merman , 20 04). Spe a rman correla tion s ar e pe rfo rmed w ith th e da ta t o det ermine the rel ati on s h ip be twee n v aria ble s . To exa mine the a s socia t i on be tween e n vironmental poll ution a nd t he b ehavi ora l outcome s of inter e s t, lin e ar r eg r e s sion mod el s were fit t e d with s imu la ted pa rticl e a b s orp tio n (perc en t a g e abso r be d s imu lat ed by the M PP D mod el multipli ed by t he real PM conc en tr a t i on ) a s the ma in pr e dicto r. PM a bsorp tion wa s de rive d f rom the M P P D mode l a nd wa s u sed a s a continu ou s indic ator o f cont ex t u al environm en t a l po llution load , re flec t i ng di ffe r e nce s i n a mbient exposur e acro s s ar ea s with va r y ing leve ls o f air pollu tion ra the r t ha n p rec i se in divid ual-lev el exposur e. B ec au s e th e prima r y variabi li t y in s i mulated ab so rptio n occ urs b etwe en area s with diff er ent polluti on lo ad s, and n ot w i thin ea ch spec i fic a r ea , ci t y wa s no t inc lude d a s a cov ari at e neithe r a s a fac t or in t h e ma in regr e ssi on mode l s , in o r de r to av oid over -adj ustm ent tha t would remove the con tex t u al vari abil it y of inter e st . Acc ordingly , reg res si on c oef fic ien t s ar e interp r e t e d a s a ssocia t i on s a t t he e nviro nmental -c on textual level , and not a s ind ivi dual c ausa l ef fect s . S am e an al ys i s i s per form ed wit h the 8- , 1 5 - , a n d 30 -e xpo sure pe r i od t ime. S ex wa s inclu ded a s c ovariabl e in a ll the r egre s s i o n anal ys es. G i ven th e m ode ra te s a mpl e size and the s ub tle ef fec t siz e s typi call y ob served i n e nvi r onm enta l neuro toxic ology s t u die s, regr e s s io n mo de ls were int ention al ly kept par s imon i ous to reduc e t h e ri sk of o ver fit t i ng an d uns t a ble p a r a met er e stima te s. There for e, t he pri mary analy s e s focu sed on the a ssoc ia tion b etw ee n c ont e xtua l P M ab s o r pti on e s tima t e s an d behav iora l outcome s, ra t h e r th an at t e mp t i ng t o a djust for a l arge numb er o f pot enti al e nvi r onm enta l cova r i ate s. Sepa r a te r egre ssion model s w ere es ti mated for each beha vio ral outcom e. A ssumpti on s of linea r i ty, homo sceda s tici t y , and no r ma lit y of re sidual s we r e a sse s sed t hr oug h vis ual i ns p ec tio n of r es idual p lo ts and summary s t a t i stic s , wi t h no ma jor v iol ation s d et ect ed. S ta t i stic al s i g n i f i c a n c e w a s s e t a t p < . 0 5 . A l l a n a l y s e s w e r e c o n d u c t e d u s i n g J A S P 0 . 1 9 . 3 . 0 an d G r a p hP a d Pri s m 8 . 3. Res ults 3.1. Sample charac te ristics and sociode mogr aphic informa tion All part i cipa nts were r ecrui ted f rom the Unive r si ty of Zarago z a a t th e campu s of Teru el, th e U ni ver s i t y of Alme ría, a nd pe opl e livi ng in the city of Talav era . No dif fe renc e s w e re det ec t e d in t h e perc entag e of women tha t par tic ipa ted in the stu dy, nev er th e le ss, femal es c or re spo nd to 68.3% of t he to tal s a mpl e; f u rthe rmor e, o ther va r i abl es li nked to the MP PD model an d to other d e mographic a s pe c t s we r e no t s i gnific ant . W e f ound signific an t dif fe renc es in age ( F (2, 47.119) = 6.072 ; p = .0 05; η 2 p = .098 ). Bon fe rr on i po s t - hoc ana ly si s r ev eale d s ig ni fica nt dif fe renc e s betwee n T er u el and Alme ría ( t = -4 .246 ; p < .001) , whi le th e r e s t compa r i son s d id not r eac h s ig nific a nt l e vel s (p ≈ .083 ). Al so, a signi ficant dif fe rence w a s det ec te d in h eigh t (F (2, 56.868) = 4.165; p = .0 21; η 2 p = . 0 3 4 ) . P o s t - h o c c o m p a r i s o n s r e v e a l e d t h a t A l m e r í a a n d T a l a v e r a h a d diff er ent height s (t = -2.4 89 ; p = .041), w hile the re st d id not rea ch signi fic ant d iff ere nc e s . N o other comp a r i son s r evea led signi fic ant di ff ere nc e s (Tabl e 1). .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint 3.2. In s i t u PM 10 and PM 2.5 con c entration a n d MPP D s imula tion outc omes PM10 a nd PM2.5 c once n t ra tion s we re a n alyzed in th ree di ff eren t time perio ds pr e viou s da ta colle ction (8- , 1 5- , an d 30 -da y s). Re sult s sh ow tha t w e, the re fore , selec ted di ff er en t participa n ts whi ch a re ex pose d to d i ffe re nt c onc e nt r atio ns (p < .001 ) a cr o s s all exposur e time window s . Ne verth ele s s , t he ai r pollu ti on d ynamic s was no t stable ac ro ss all compa r i s on s , r e veal ing dif f eren t dy namic s i n PM10 a n d PM 2.5 c onc en tr a tio n s a cro ss t he c iti es (Table 2) . In t e r m s of P M2. 5 c onc ent r a tio n s , Tal a vera ac hiev ed higher conc en tra tion s th an Te r ue l, and Teruel highe r f r om Almerí a [8 -day s , (T ala vera, M = 21.88 5 µg/m 3 , S D = 7 . 0 0 5 ; T e r u e l , M = 9.927, S D = 6.930; A l m ería , M = 5.7 51, S D = 0. 168) ; 15-day s (T alav e r a , M = 15.53 1 µg/m 3 , SD = 3.209; Te r u e l, M = 9 .899 µg /m 3 , SD = 5. 485; Almerí a, M = 5.6 96 µg/ m 3 , S D = 0. 1 21); 30 -day s (Talav era , M = 16.054 µg / m 3 , SD = 0.46 5; Teruel, M = 9.036 µg / m 3 , S D = 2 . 0 3 9 ; A l m e r í a , M = 6.181 µg/ m 3 , SD = 0. 084) ]. Howev e r, in term s of PM10 conc en tr a t i on s c ha ng ed the c ity distribut ion, being the mo s t pol lut ed ci t y Tala vera f oll owed by Alme ría a nd then Te r ue l [8 -day s (Talav era , M = 36.47 µg/m 3 , SD = 11.67 4; A l mería, M = 21.46 µg / m 3 , SD = 0.85 8 ; Teruel, M = 14.20 µg / m 3 , S D = 10.90 1 ), 15 -day s (T al a ve r a , M = 25 .88 µg/m 3 , S D = 5.349; Alme r í a, M = 2 1.15 µg/m 3 , S D = 0.844; T eruel , M = 14 . 41 µg /m 3 , SD = 8 .61 7), 30-d ays (Tal ave ra, M = 2 6.76 µg /m 3 , SD = 0. 775; Almería , M = 24. 54 µg /m 3 , SD = 0.496; T e r u el, M = 13.61 µg / m 3 , S D = 3.197 ) . Resu lts show t h a t th ose PM c once ntr ation s di f fer be t w een ci tie s in all o f th e pe rfo rmed compa r is on s ( p < 0 .001) . N ever thel es s, the air p ollutio n dynami c s w a s no t s t a ble ac ro ss a ll compa r is on s. Table 2 summa r i ze s all th e comp arison s regarding tim e pe riod s a n d c ities in air pollution me as ur e s a nd Fig u r e 2 s hows g raphic ally tha t dyna mic. As de scrib ed earli er, th e M PP D model wa s d eve lop ed t o impr ov e the rep re s e nt a t i on o f air pollution ex pos u r e a nd t o a s se ss i t s e ff ec ts ac r o s s d i ffe r e n t med ical e ndpoin t s . Nev erthel e ss , t h is mo d el p er sonaliz e s t h e air poll u t i o n expo sur e. The re f o re, t h e t o t a l alv eolar dep osi t fr a c tion was u se d to ca lcula te in vitro PM expo sure s . Tho se expos ure s f ollow ed the s a me dynami cs t h an in situ outcom es . Ab sorb e d PM acc ording t o MP PD model i s depi cted in F igure 2. M PP D’ s in silico’s s imul atio n expo sur e al so di ff er betwe en c i tie s a s c an be se en in Ta ble 2 . T a l ve r a ’s s u b j ect s abs or b e d m o r e PM 2 .5 t ha n T e r ue l and t he n A l m e r ía [ 8 - day s , ( Ta l a ve r a , M = 2.186 µg / m 3 , S D = 0.700; T eru el, M = 0 .9 82 µg/m 3 , S D = 0 .671; Alme r ía , M = 0.57 9 µg/m 3 , S D = 0.026), F igure 2a ; 15-d ay s (Ta lave r a , M = 1.55 1 µg/m 3 , S D = 0 . 321; Te rue l , M = 0. 97 5 µg/m 3 , SD = 0.526 ; Almerí a, M = 0.573 µg / m 3 , S D = 0.023), Figure 2 c; 30- da ys (Talav era , M = 1. 604 µg/m 3 , SD = 0 .0 46; Te ruel , M = 0.8 96 µg/m 3 , S D = 0 .187; Alme r í a , M = 0.6 22 µg /m 3 , SD = 0 .023), F igu re 2 e ] . S a m e a s b e f o r e , t h e p a t t e r n c h a n g e d , b e i n g t h e s u b j e c t s f r o m T a l a v e r a t h o s e t h a t abso r be d mor e PM10 than Alme ría and then Te r u el [8- days , (Tala ver a, M = 3. 64 4 µg/m 3 , S D = 1.166; T eru el, M = 1 .4 02 µg/m 3 , S D = 1.0 5 8; Almería , M = 2.159 µg/m 3 , S D = 0 . 1 1 2 ) , F i g u r e 2 b ; 15-day s (Ta lave ra, M = 2.586 µg/ m 3 , S D = 0.534 ; Te ruel, M = 1.417 µg / m 3 , S D = 0 .828; Al me r í a, M = 2.128 µg / m 3 , SD = 0. 114 ), Figure 2d; 30-day s (Tala ver a, M = 2.67 3 µg / m 3 , SD = 0. 077; Teruel, M = 1.349 µg/m 3 , S D = 0.2 94; Al mería, M = 2 .46 9 µg/m 3 , SD = 0 .101) , F igure 2f ]. Table 2. ANO V A’s c om p ari so ns fro m in s it u an d i n s ilic o PM 2.5 a nd PM 10 m e as ures a c ros s diff e ren t ex pos u re t ime w in dow s Com pa r i s on ANO V A’s outc omes 1 Po s t - H o c 2 Cities’ d yna m ics P M 2.5 – 8 days In s itu F (2, 83.043) = 13 4.4 0; p < . 0 01; /g2020/g3043 /g2870/g3404 0.419 T er uel - Al me r ía ( t = 2.81 4; p = . 0 1 6 ) T e ru e l - Ta l ave r a (t = -10 . 321 ; p < . 0 01 ) Almería - T al a vera ( t = - 9.58 0; p T e r uel > Al m ería PM2.5 – 1 5 days In s itu F (2, 83.217) = 23 4.2 1; p < . 0 01; /g2020/g3043 /g2870/g3404 0.292 T er uel - Al me r ía ( t = 3.94 4; p < . 0 0 1 ) T er uel - T al a vera ( t = - 6.76 6; p T e r uel > Al m ería .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint Almería - T al a vera ( t = - 8.13 0; p < . 0 0 1 ) PM2.5 – 3 0 days In s itu F (2, 90.011) = 9 146 ; p < . 0 01; /g2020/g3043 /g2870/g3404 0.799 T er uel - Al me r ía ( t = 7.55 8; p < . 0 0 1 ) T e ru e l - Ta l ave r a (t = -23 . 797 ; p < . 0 01 ) Al m ería - T al a v e ra ( t = - 2 3 .0 3 2 ; p T e r uel > Al m ería PM 10 – 8 d a ys In s itu F (2, 85.115) = 61. 56; p < . 0 01; /g2020/g3043 /g2870 /g3404 0.442 Ter u el- Al m erí a ( t = - 3. 057; p = .0 08 ) T e ru e l - Ta l ave r a (t = -12 . 022 ; p < . 0 01 ) Almería - T al a vera ( t = - 5.57 8; p A lmería > T er uel PM 10 – 15 da ys In s itu F (2, 89.367) = 52. 99; p < . 0 01; /g2020/g3043 /g2870/g3404 0.307 Ter u el- Al m erí a ( t = - 3. 996; p < .0 01 ) T er uel - T al a vera ( t = - 8.71 3; p A lmería > T er uel PM 10 – 30 da ys In s itu F (2, 83.043) = 3 296 . 894 ; p < . 0 01; /g2020/g3043 /g2870/g3404 0.841 Ter ue l- Al m erí a ( t = - 18.40 1; p < . 00 1 ) T e ru e l - Ta l ave r a (t = -28 . 339 ; p A lmería > T er uel P M 2.5 – 8 days In s i lico F (2, 83.424) = 13 3.1 9; p < . 0 01; /g2020/g3043 /g2870/g3404 0.432 T er uel - Al me r ía ( t = 2.78 3; p = . 0 1 6 ) T e ru e l - Ta l ave r a (t = -10 . 646 ; p < . 0 01 ) Almería - T al a vera ( t = - 9.77 7; p T e r uel > Al m ería PM2.5 – 1 5 days In s i lico F (2, 84.343) = 22 9.5 8; p < . 0 01; /g2020/g3043 /g2870 /g3404 0.310 T er uel - Al me r ía ( t = 3.91 2; p < . 0 0 1 ) T er uel - T al a vera ( t = - 7.19 5; p < . 001) Almería - T al a vera ( t = - 8.39 7; p T e r uel > Al m ería PM2.5 – 3 0 days In s i lico F (2, 107.356) = 6 58 9. 8 ; p < . 0 01; /g2020/g3043 /g2870/g3404 0.825 T er uel - Al me r ía ( t = 7.88 1; p < . 0 0 1 ) T e ru e l - Ta l ave r a (t = -26 . 092 ; p < . 0 01 ) Al m ería - T al a v e ra ( t = - 2 4 .8 9 5 ; p T e r uel > Al m ería PM 10 – 8 d a ys In s i lico F (2, 86.619) = 64. 76; p < . 0 01; /g2020/g3043 /g2870/g3404 0.456 Ter u el- Al m erí a ( t = - 3. 258; p = .0 04 ) T e ru e l - Ta l ave r a (t = -12 . 359 ; p < . 0 01 ) Almería - T al a vera ( t = - 5.63 3; p A lmería > T er uel PM 10 – 15 da ys In s i lico F (2, 93.069) = 58. 79; p < . 0 01; /g2020/g3043 /g2870/g3404 0.331 Ter u el- Al m erí a ( t = - 4. 357; p < .0 01 ) T er uel - T al a vera ( t = - 9.17 7; p A lmería > T er uel PM 10 – 30 da ys In s i lico F (2, 71.089) = 10 1 0 . 1; p < . 0 01; /g2020/g3043 /g2870 /g3404 0.862 Ter ue l- Al m erí a ( t = - 20.29 8; p < . 00 1 ) T e ru e l - Ta l ave r a (t = -30 . 719 ; p A lmería > T er uel 1 AN O V A ’s c ompari sons w er e c o r r ect ed u sing We l ch H omo gen ei ty C o r r e ctio n due t o L e v e n e’ s si gnif ic anc e. 2 Post-hoc compar is o n s w e r e co rr e c t ed w i th Bonf e r r o ni m ethod. (In s e rt Fig ure 2 here ) Figure 2. Gra ph i c al repres e ntation o f t he PM 2 .5 (gra p hs a, c, e ) a n d PM10 (gra p hs b , d, f). Gra phs a ) and d) sho w PM co n c entrati on in 8 d a ys; g raph s c) a nd d) sho w P M c o n c entrati on i n 15 day s; gra p hs e) a nd f) sh ow PM c o nce n tra t i o n in 30 d a ys. T h e left Y a xis corresp o nds t o in si tu air p o l l u ti on o u tc o m es, w h i le the ri g h t Y a xis c o r r e s p o n d s t o a b s o r b e d P M a c c o r d i n g t o t h e M P P D s i m u l a t i o n ( in vitro ). E ach gra ph depi c ts in div i du a l da ta . *** c o rrespo n d s t o p < 0 . 001. T eruel ( n = 12 0 ), Al m erí a (n = 2 3 ) , Ta l a vera (n = 43). Furthe rmor e , the M P PD model c alcul a t es seve ral v ariabl e s r e la ted t o a ir pol lu t ion exposu re. H ow eve r , w e only s ele c ted tho s e varia bl es th a t a re d ir e ctly rela t e d with th e mai n objec t iv e of t h e pr ese nt work . Be tw een t ho se va r i a ble s, we s el ec ted de po s it frac ti on s a cross a ll the r e s pira tory tr act ( alve olar , conduc ting ai rwa ys, and h ead) . In ter e st i ngly, th e AN O VA revea l ed diff er ence s in tota l alv eola r dep o sit f rac tion [F (2, 57.142) = 7.698 , p = .001; /g2020/g3043 /g2870/g34040 . 1 1 6 , F i gu r e 3 a] , where Ta lave ra ac hiev ed l owe r tot al alv eolar depo si t fr a c tion than Almerí a and Te r u el [po st- hoc c ompari son s: T eru el -Almerí a (t = -0. 632 , p bonf = 1) ; Te ruel -T alav era (t = 4.620 , p bonf < .001 ) ; Almería -Tal ave ra ( t = 3 .735; p bonf < .00 1 ). I n a ddi tion , the to tal pe rcen tag e d epo sit fr ac tion in t h e conduc ting airwa y s a l s o rev eal ed di f fer enc e s b e t w e en c it i e s [F (2, 59.002) = 16.695, p < . 001 ; /g2020/g3043 /g2870/g3404 0.195 , F i gure 3 b] . Howev er, T alav era subje c ts had hig her pe r c en tage dep o sit fr a ct ion in t h e conduc ting airwa y s tha n A l me ría an d Teruel [po st-h oc: Te r ue l -Tala ve ra (t = -1. 706; p bonf = .269), Ter uel - T alav era (t = -6 .65 5; p bonf < . 001), Alm ería -Ta laver a ( t = -3.075; p bonf = .007 ). T h e .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint las t va r i able ana lyz ed is th e tot al head depo sitio n, reve aling no dif f erenc es (p = .128, F igure 3c). (In s e rt Fig ure 3 here ) Figure 3. Grap hica l re p re s entatio n of m a in MP PD- o u tcomes r e lated to t he ob jec ti v e o f the p re s e n t work. The u p per v io l in g r a p h s de pi c t t o t a l a l v e ol a r d e p os it f r a c t i o n ( % , i m a g e a ) , t o t a l c o n du c t i n g a i r w a y s de po s i t f r a c t i o n ( % , im a g e b ) , a n d t o t a l h e a d d e p os i t f r a c t i o n ( % , im a g e c ) . I m a g e d s h ow s g r a ph ic a l s i m u la t i o n s of a 5- l o b e no n- s y m m e t r i c lu n g i n Teruel (orange), Al m ería (b l a ck ) a nd Ta la vera (b lue). The l o we r lu n g gra p h in Ta l a vera (b lue) also de picts 1 0 lu n g ra mif i c ati ons. ** * p < . 001 3.3. Correla tions between in si lico PM10 and PM2 .5 conc entra tions and cognitiv e /behavioral var iables Prior c alc ulating li n ear r e gre ssi on, c orrel a t i on an aly se s were per form ed be twee n variabl e s t o dete rmine t h e pre s ent rel a tion s h ip s. O nly the signi f i cant corr ela tion s a re sh o wn, the re for e, t h o s e co rrela tio n s th at w er e no t inc lud ed did not a chi ev e s ig ni fica n t lev el s. D ue to th e no - normality o f our da ta, non -pa r a me tr i c Sp e arman c orrel a tion s wer e c alcu lat ed. As c a n be see n in Figur e 4, the c o r rel a t i on matr i x r evea le d di ff eren t vari able dy namic s . F ir s t , s ev e ral ne ga tive cor rela tion s we re d etec ted b e t w ee n P M 2 . 5 exp o s ur e f or 15 -, an d 30-da y s an d emotion al ou tc ome s. Be ing ex po s e d to PM2.5 fo r 15 day s i s n egativ ely r elat ed w ith D AS S -21 s c ore s (dep re s s i on, p = .020, ρ = - . 171; anx iety, p = .03 3, ρ = -.157; st r e ss, p = . 005, ρ = - . 208; and t otal punc tuati on, p = .0 06 , ρ = - .20 3 ) . Th e ex pos u re w indow o f 3 0 -day s al s o reve al ed th e s a me nega t i ve c orrela t i on s w ith D A S S-21 (de p r e s sion, p = .007, ρ = - .196; an xie ty, p = .015, ρ = -.179; s tre ss, p < .0 01, ρ = -.2 47; an d total pu nc tua tion, p = .001, ρ = -.23 5). H ig her PM conc entra tion s a r e r elat ed w ith lowe r pu nctuatio ns in t he p s y cholo gica l t e st p e r f o rmed. Sec ond, po si tive c orrela t i on s we re d et ected b etwe en PM2.5 exposu re for all t im e pe riod s a n a l y z e d w i t h b e h a v i o r a l o u t c o m e s [ 8 - d a y s , S t r o o p ( p = . 0 5 , ρ = . 1 4 5 ) ; A N T , A l e r t I n d e x ( p < .001, ρ = . 475) ; 1 5 -days , St r oop (p = .0 17, ρ = .17 6); ANT, Ale rt Index (p < .001, ρ = .363) , Exec utive Function ing (p = .069, ρ = .135); 3 0-day s, St roop (p = .028, ρ = .162) ; ANT, Ale rt Inde x (p < .001 , ρ = .55 6) ]. Fu rth ermore , po sit i ve c or rel a tion s were p re se nt in P M2.5 e xposure for 3 0 days wi t h li fe sati sfa ct ion (p = .004; ρ = .2 10 ). T h i r d , P M 1 0 e x p o s u r e w i n d o w s d i d n o t a c h i e v e t h e s a m e c o r r e l a t i o n s a s P M 2 . 5 . O n l y P M 1 0 exposur e time fo r 15 -day s ac hi eve anec d ot a l corr elati on s with stre s s ( p = .055 , ρ = - .14 1) and s ig nific a nt c o rr e l ation with t otal punc tu ation (p = .046, ρ = -. 147 ). O n th e c on tra r y , and sam e as wit h PM2 .5, p o s i tiv e c orrela t i on s w ere d ete cted wi th be h avioral o utcome s f o r 15 -day s [St r oo p (p = .045, ρ = .148 ) ; ANT, Ale rt In de x (p < .0 01, ρ = . 373 ), Ex ecutiv e Fu nc ti on Ind ex (p = .021, ρ = .171 )]. Highe r PM c oncen tra t ions a r e rel ate d with s lo we r reac tion t ime (ANT ) or higher in t e r f er enc e (S tro op) Lastly, reg ard ing bi ochemi cal o ut c ome s, we fou nd sever al nega tiv e corr ela ti ons b etw e en PM10 expos ure window s and NRF2 co nc entr a t i on s ( all p’ s = .00 4, ρ = -.685 ), whi le 15-days .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint exposur e of P M 2 .5 i s als o nega t i vely c orr el a ted (p = .0 25 , ρ = -. 565) . H i gher P M ex posure i s r e lat ed to l ow er NRF2 c onc entr atio ns . There for e, i t i s no tew orthy th e di f f e ren c e in th e numb er o f co rrel ation s be twe en P M2. 5 a nd P M 1 0 w i t h o u r o u t c o m e s . P M 2 . 5 i s m o r e r e l a t e d w i t h o u r v a r i a b l e s , a c h i e v i n g m o r e correla tion s with high er expo su re tim e . Als o, s ee m s impo rtan t t he r elati on ship betwe e n a ll exposur e wi ndows a nd all mol ecule s w it h the Ale rt I ndex in the ANT ta sk. (In s e rt Fig ure 4 here ) Figure 4. Hea tmap re p res entati o n of S p e arma n correlation s betw ee n m o lec u le s and exposu re times with s o m e v ariables. Onl y signif ica n t co m p a risons a nd tend ency c o rr e lations a re depicted. On l y signi fica n t c o rre l a tio ns a re depicted. The number i n e ach qua drant repre s e n ts the ca lcu la t ed R ho n u mber. Sign ifi c a nce levels a re depicted wit h the fo l l ow i ng sy mbo ls: ** * p < .00 1 , ** p < . 01, * p < .05, # p < . 0 7 . 3.4. Relations hip between i n s ili co MPPD si mulated absorpti on PM10 and PM2.5 conc e ntration and emotional v ariables. All t h e li near regr e s si on ana ly se s w e re performed w it h M P P D - simula ted a b s or bed dat a f rom t h r e e t i me -pe riod wind ows expo su re: 8-, 15-, 30 -da ys p r io r da t a colle cti o n and a ll the cogn it i ve/b ehav ioral d ata . Star ting with cog nitive /emo tiona l vari a ble s, PM2 .5 did no t pr edict li fe sa ti s f ac tion ou tcome s [8- days , p = .149; 15 - d ay s (F (2, 185) = 2.4 44; p = .090; R 2 = . 0 2 6) ; 3 0- d ays (F (2, 185) = 2.736 , p = . 068; R 2 = .029) ]. Howev er, in both t i me exp osu re, P M c oe ffici en t ac hi eve d signifi ca nt leve l s [15 - days, t = 2 .200, p = .029 , R 2 = .020 ; 3 0-da y s, t = 2 .32 9, p = .021, R 2 = . 0 2 4 ; F i g u r e 5 d - 5 f ] pr e dicting li fe sa ti s f a ction . H i gher P M2 . 5 e xposure pr edic t s be tte r life qua li ty p unctuati on s. Regarding PM10, non e o f the a nalyz ed w indow s ac hi eve d n eith er s i gni fica nt level s no r anec dot al. The same m od el s were c alc ul ate d fo r DA SS-21 to tal punct uati on and it s s ub sec t io ns . All PM2 .5 exposur e wi ndows ach ieved sign ifica n t l e vels for t o ta l punctu a t io n [8 -day s (F (2, 184) = 5 . 3 6 1 , p = .005, R 2 = .04 5; 15-day s (F (2, 184) = 6.04 9, p = .003 , R 2 = .062); 30-d a ys (F (2, 184) = 5. 315, p = .0 06, R 2 = .045); F igur e 5a -5c ]. S e x reac hed sig nific ant l ev el s at 8 -day s (t = 2. 014, p = .0 45) an d at 30 - days ( t = 2 .126, p = .035 ). PM2.5 c onc e n t ra tion s we re signi fican t in a ll exp osure w indows (p < .05). All P M 1 0 mod el s ana lyze d w ere a ble to predi c t t otal DA SS-21 punc t ua t i o ns , but in a ll models , only s ex ac hieve d sig nifica n t lev els while PM10 c once n t ra tion s re mained no t - s i gn i f i can t [ 8 - day s ( F (2, 184) = 3.2 89, p = . 040, R 2 = .0 24); 15 -day s (F (2, 184) = 2.991, p = . 053, R 2 = .021); 30 -da y s (F (2, 184) = .025 , p = .037, R 2 = .036 ); D ata n o t shown] . High er e xp osu r e t o PM i s r e lat ed wi t h lower pun ctua tion s in tot al DASS - 2 1 punc t ua t i on. The dep re ssion su bscal e follow s t h e an aly s i s . Fir st, rega r di ng PM2 .5 exp osu re, o nly 15 -day ex po s ur e r eac hed s i g nifica nce (F (2, 184) = 3. 111, p = .0 47 , R 2 = .033 ) , whi l e th e 8 -, a nd 30 -day s did not p r e dic t the s ub sca l e punctuati on s (Fi gu re 6a -6c ) . Higher PM2 .5 e xpo sure i s li nke d to lower d ep re ssi on scor e s in th e D AS S -21 sub s c al e. Nei the r o f the P M10 expo s ur e wi ndow s pr e dic ted th e DASS - 21 de pre ss ion s u b s c a l e o u t c o m e s . I n t e r m s o f a n x i e t y s u b s c a l e , 8 - , a n d 3 0 - d a y s p r e d i c t a n x i e t y o u t c o m e s , w h i l e t h e 1 5 - d a y s r e m ai n at a t r e n d le v e l. O n l y s e x r e a ch ed s i g n if ic a n ce i n t h os e m o d el s [ 8 -d ay (F (2, 184) = 4.74 0, p = .010, R 2 = .050 ); 15 -d ays (F (2, 184) = 4. 194, p = .017, R 2 = .044) ; 3 0-day s (F (2, 184) = 4.21 6, p = .0 16, R 2 = .0 44 ); Fig ur e 6d-6 f ]] . S ame pat ter n wa s foun d for PM10 [8 -da ys (F (2, 184) = 3.277, p = .040 , R 2 = .035 ); 15 -day s (F (2, 184) = 2 .794, p = .064, R 2 = .030) ; 3 0 -day s (F (2, 184) = 3.2 53, p = .041, R 2 = .035 ) ; data not shown ]. La s tly , in term s of th e stre s s s ub sca le , all exposur e window s a chi e ved signi fic ant lev el s f o r P M2.5 [ 8 - d a ys (F (2, 184) = 6.802, p = .001, R 2 = . 0 7 0 ) ; 1 5 - .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint days (F (2, 184) = 8 . 6 0 9 p < . 0 0 1 , R 2 = . 0 76) ; 30- d a ys ( F (2, 184) = 8.039 , p < .00 1, R 2 = .07 1) . I n a ll models sex a nd P M ex po su r e time reac hed s ig nific a nt le vel s [ 8 - da y s (PM2 .5 ; t = -1.982, p = .049; s ex; t = 2.749, p = .00 7 ); 15 -days (P M2.5; t = -2.714, p = .007 ; sex ; t = 2.31 3, p = .0 22); 30 - days ( PM2.5 ; t = -2. 506, p = .0 13; sex; t = 2. 811, p = . 005); Fig ure 6g-i ]. S ame pa t tern a s be for e was d et ec t e d f or P M 1 0 [8 -day ( F (2, 184) = 5.067, p = .007 , R 2 = . 0 5 3) ; 1 5- d ays ( F (2, 184) = 5.184, p = .006, R 2 = .054 ); 30 - d a ys (F (2, 184) = 4.8 53, p = . 009, R 2 = . 051) ; da ta n ot show n] . S ex was th e on ly s i gn i f i can t v ar i a b le i n a ll e x p os u re w in d ow s ( p < . 0 5) . L i n ear r e gr e s s i o n s h o w e d th at hi g he r P M exposur e lea ds to low e r str ess punc tua ti on in the DASS - 2 1 s ub sc ale ; fu rthe rmore , women had higher pun ctua tion s in t his sub s c al e. The same ana ly se s we re p erform ed wi th lon eline ss. N o mode l ac hiev e d signi fic ant le vel s, neithe r t h os e with PM2.5 no r w ith P M1 0 a nd lonelin e s s (a ll p’ s > .05 ) The s a me r e sult wa s found fo r P M10. L a stly , in t erm s o f impu lsivity, no time ex po s u re n ei the r molec ul e w as a ble t o pr e dict e i t he r of t h e B IS-11 o ut c ome s ( to t a l, non -pl an ned, mo t or a nd cog ni tive i mpulsivity) . ( I ns er t Fi g u re 5 h e r e) Figure 5. Li n e ar r elatio n shi p s b e twee n PM2 .5 Absorb e d d e ri v ed from the MPP D m o del a n d d i f ferent cogniti v e o u t c om e s . I m a g e s a -c de pi c t s i t s r e la t io n s hi p w it h DA S S - 21 t o t a l s c or e . I m a g e s d- f s h ow s i t s r e l a t i o ns hi p w i t h S WL S (life satisfa ction). ( Ins er t F ig u re 6 h e r e) Figure 6. Li n e ar r e lationships betw een PM 2.5 A bso rbed derive d f rom th e M PPD mod e l and DA SS -2 1 subsc ales. F i g u re a-c r e p r e s ent d e p re s sion, fi g u re s d -f corr esp o nd t o a nxiety and figures g-I corr e s p ond to stre ss sub sc ales. Al l g raph s dep ict in d ivi d u a l data . 3.5. Relations hi p between i n s ili co MPPD si mulated absorption PM10 and PM2.5 a nd cognitiv e variabl es . Regarding the Or i e nta tion I nd ex ( time s pe n t shi fti ng s pa t i a l a tten t i o n) c alcu lat ed fr om va li d and inva lid cue s in the AN T , n e ith er PM mole cule s nei the r expo sur e time wind o ws a chi ev ed s ig nific a nce a s predic t or s of or ie n ta tion index ( p > . 05 ). S ame r e sult s w e re d et ected from th e Aler t Ind ex (tim e s pe n t incr ea sing al ert re adine s s) calc ula ted wit h th e a l erted cue and non -c ue . N one o f th e mode ls te sted a chi e ved sig nific ant l ev el s (p > .05 ). Howe ve r, t he r e s u lts foun d fo r Exec utive I ndex ( time sp ent re solving stimulu s co n f l ict) ar e dif f eren t from the p reviou s index es. Ne ith er o f the expos ure w ind ows for PM 2.5 achi eved s i gni fic ance (p > .05 ). P M 10 exposur e wi ndow for 8-d ay s d id not ac hieve s ig ni fica nce (p = .192 ); ne ve rth ele s s , P M 10 exposur e f or 15 -da ys a chiev ed mod era t e fit (F (1, 181) = 4.573; p = .034; R 2 = .025). Al s o , PM 10 exposur e windo w for 30-d a ys a chiev ed s i gnific a nt l evel s (F (1, 181) = 4. 153; p = .0 43; R 2 = . 0 2 3 ; Figure 7 a -c). Th e be st p redi c tor i s t he 1 5 -day pe riod , whic h expl ain ed 1 .9% of th e v ariance . In t e r m s o f 15 -da y ex po sur e , no signi fic anc e was d et ec ted fo r C ongruen t- (p = .360) , Inc ongru ent - (p = .572) nor Ne utr al- tr ia l s (p = .326). F or th e 30 - d ay pe riod, no s ig ni fica nce w a s d et ected fo r Congrue nt - (p = . 764), Inc ongruen t - (p = . 149), nor N eut ral -tr i a l s ( p = .527 ) . Regarding S t ro op- outc om es, no signific ant o ut c ome s w er e p re sen t for P M10, whi le 15-d ay s PM10 exposu re remain e d a necdo ta l (F (1, 183) = 3.533 ; p = .0 62 ; R 2 = .0 19) . In t e rms o f PM2 .5, t h e 15-d ay ex pos u re w indow ac hiev ed sig nifica nt l evel s ( F (1, 183) = 4.43 0; p = . 037; R 2 = . 024), while the o ther ex pos u re w indow s di d not ac hieve s ig nific a nt leve l s (F igure 7d -e ) . (In se rt Fig ure 7 here ) .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint Figure 7. Gra p h ica l re p re s entatio n of l inea r re g r e s sion betwe en ti m e ex p osure p e ri o ds an d cog ni t ive variables. Upper ro w (ima ges a t o c) repres e n ts ANT E x ec u tive Con tro l I nde x, wh il e t h e l ower row im age s r epr es e nt S troop ou tco m es. 3.6. Relations hip between i n s ili co MPPD si mulated absorption PM10 and PM2.5 conc e ntration and EL ISA outc omes D ue t o t h e p r ese n ce of he te r os c e da s t i c i t y a n d de v i at io ns f ro m n or m al it y i n t he r es i d ua ls , a logarithmic t r an sf ormati on was ap plie d to the ELI S As va r i able s pr i o r to reg r e ssi on modeli ng. Regarding IL-6 da ta , no model r ea ched e videnc e (p > .05 ) . S ame re sul ts w er e fou nd fo r Klo tho pr o t e i n conc ent rati on (p > .05), a nd fo r TN F - α conc en tra tion (p > . 05) . O n t h e co ntrary, s e ver al m odel s re ac hed signi fic ant l e vels r ega r di ng N RF2a prot ein conc entra tion . In t erm s of P M2.5 e xpo s ur e p eri od s , on ly the 15 -day exposu re p eriod re ac hed s ig nific a nt leve l s [8 -day s (p > .05) ; 15-d a y s (F (2, 15) = 7.527; p = .007; R 2 = .465) ; 30 - d ay s (F (2, 15) = 1.017; p = .389 ; R 2 = .002 ); F igure 8a-c ]. On the cont rary, all the e xpo sure w ind ow s o f PM1 0 exposur e reac h ed signi fic an t lev els [8 -da ys (F (2, 15) = 5. 832; p = .0 16; R 2 = .3 92); 15 -day s (F (2, 15) = 5.709; p = .017 ; R 2 = .4 68) ; 30-day s (F (2, 15) = 6.034; p = .014; R 2 = .48 1); F igure 8d-f ] . PM and N RF 2a dyna mics a re com plex, sh owi ng that being e xpo sed to PM fo r hig her con c entr a t i on s i s link with low er N RF 2a, b u t t hi s dy namic i s no t pre s e n t for P M2. 5. (In se rt Figur e 8 here ) Figure 8 . Grap hica l repre sentati on of the L i nea r Regr es s i on a nalysis b e twe e n P M2 . 5 an d P M10 e xpo sure wi t h NRF2a protei n conce n tra ti on ana lyz ed wit h ELIS A. Up p e r g ra p hs (a -c) corr e s p ond t o i n s i l ico PM2 . 5 a bsorp t io n c alcu l a tio n; lo w er gra p hs (d -f) corr e spond t o in silico P M 1 0 a b s o rp ti o n c a lcu l a t i o n. E ach graph re pres e n ts in divi dual d a t a. 4. Discussion The obje ctive of the pr e sent s tu dy was t o exa mine the e f f e c ts o f s h ort - t e r m ( 8 d ays) , mid-t erm (15 day s ), a nd long -t erm (30 days ) exp o sure t o in s il ico PM10 and PM2 .5 expo sur e on cogni t i v e functio ning , w ith a part i cul ar focu s on a tt e n t i on and cog nitive in ter f e ren ce contr ol. Addition all y, system ic bi ol ogic al mark e r s were i ncorpo rat ed to ex plore pot e ntial i ndi rect inflamma tory and oxi dative s tre ss pat hwa ys a ssoc ia ted wi t h the s e be havio r al outcom e s. Indivi dual PM ex po s ure c oncen tra tion s were e stima ted u sing th e MP PD model , allow ing fo r a per s ona lize d a s s essm ent o f inh ale d pa rtic le d e po s iti on . To our kno wledg e, t h is i s the fir st s tu dy to u se the MP PD mod el t o simula te P M e xposu re in hum an subjec t s an d to a pply the s e data to pr edict cog ni tive and e motion al ou tcome s. Fur t h er m o r e , no pr e viou s s tudie s ha v e exam ined th e se ef f e c ts in he althy you n g indiv iduals in thre e di f fere nt c itie s, whic h r ep re sen t markedly dis tinct envir onmen t s a nd th ere for e c aptu re th e he tero genei ty of c ontempo rary W e s t ern c onte xt s . W e ob s erve d t ha t P M 1 0 and PM2.5 ex pos u re a cro ss 8- , 15-, an d 30 -day period s wa s assoc ia ted with low er score s in t ot al p s yc hologi cal sympt oms a nd higher r epor t e d q uality o f life . In add i t i on, ex po sure to PM10 over 15 a nd 30 day s w a s rela ted to poo rer ex ecu t i v e control and g r e a te r i nte rfer enc e ef fec ts i n beh av ioral p er formanc e . Fur the r more, PM10 exposur e wa s signi f i cantly as s ocia ted wi t h serum NRF2 l ev el s, supp orti n g a p ote nt i al r e lati on ship be twe en pa rtic ul ate ma tt er ex pos ur e a nd ox ida tive stre ss r egul ati on. A k ey meth odolog ical st r en g th o f thi s s tudy lie s i n the u s e o f t he M PP D mod e l to e s timat e indivi dualized in hal ed pa rtic le de po s i tion (Juna idi e t al . , 2025). U nli ke pr ev iou s ep idemiol ogic al .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint s tu die s th at r ely pr i marily on ambie nt c o nce nt ra tion me a sur e s , the M P P D a p proa ch prov ides a biologi call y grounded e s tim ation o f de p os i ted do se w ithi n the re s pira tory tr act (Juna idi et a l ., 2025; Ch oi e t al ., 2025) . Ambien t c once ntra tion s d o no t n ece s sar ily re flec t i n t e rna l expo sur e, as ac tual depo si ted do se d epen d s on mu ltiple phy siolog ical and p artic l e- s p e ci fic f ac tors . By modeling particle d e po s i t i o n, thi s a pp r oa ch ap pr ox imat e s the biolog ical ly e ff ec t i ve do se r e achi ng the low e r re s p ira t o ry tract , whic h ma y be more directly as socia ted with s y stemi c r e s pon se s (Alex i s et a l., 2 006) . M or eov er, t raditi ona l ex po s u re met rics ba sed on area -l ev el pollution m ay intr o du ce n o n-di f fere nti al e xpo sur e miscla ssi fica t i on, p oten tial l y a t te nu atin g obse r v ed a s s oc ia tion s (Yu e t a l. , 2024). In dividu alized depo si tion mod e ling ma y partial ly mitigate thi s l imit ation and e nha n ce ex pos ur e prec i s io n . T his imp r ov ed exposu re charac te riz a tio n may h el p ex plain th e de t e c tion o f sub tle a ssocia ti on s be twe e n par tic ula te matte r expo sure and at t e n t i onal func ti o ning o bs e rve d in th e p r e se nt study. Most evid ence in en vironmen tal toxi col og y r e mains groun ded in pr ecl inica l models ( rod e nts , fi s h, or n ema tode s ) . In hum a n popul a ti ons , the ma jo r i t y of s tudie s h a ve rel i ed on coho rt design s to e xami ne the r elati on ship betw een pa rtic ula te ma tte r expo s u re a nd c ogni t iv e functio ning . Fo r exam ple, Q i e t a l . ( 2 02 4) anal yze d th ree fol l ow-up wav e s w i thi n the Chin es e H e alth an d Reti remen t Lon gitudin al S tu dy (CHA RL S; 200 0–2018 ) and r epor ted t hat long- te rm exposur e to high e r c once n t ra tion s of P M2.5 was a s s oc ia ted w it h an inc r e a s e d risk o f c ogni tiv e impairment (Haz ard Ra tio [H R ] = 1 .19) . Howev er , t h a t s tudy foc u sed o n indivi du als ol der than 65 yea rs, a pop ulati on a l r e ady wi thi n t he ag e r a nge a t r i s k for age -r ela te d c og nitiv e decl in e. O ur fin dings e xtend thi s li ter atu re by s ugg es ti ng that p ollution -r ela ted co gniti ve alter ation s may a ls o be d etec tabl e ou tsid e a dvanc e d a ging p opulation s . Addition al a naly se s using th e CHA RLS databa s e (Y ao, Wang, & Xia ng, 20 22) repor t e d tha t PM1 , PM2.5, and PM10 w e r e a ssocia t e d w ith cogni t i ve dec lin e in middl e - aged adu l ts , with e f fec ts modera ted by sex, r egion , a nd l if esty le facto r s . T h e s e findi ng s hi ghligh t the po t ential rol e o f s oc iod emog r a phic an d b e havio r a l varia ble s in shaping v ulner abil ity t o a i r pol lu tion expo sure , an is s u e tha t wa r ran t s fu r th e r e xplora tio n. A g r o wing bod y of r e sea r c h ha s al so exa mi ned cog nitive ou t c ome s in chil dr e n . Ja laludi n et al . (2022) r epor t e d a s ma ll po si tive a s socia tion b e t w een PM2 .5 e xpo sure and cog n itive score s i n Indone si an region s af fec ted by for e st fi re s, where a s Suk umar an et al . (2024) f ound nega t i v e assoc ia tion s b etwe en PM2 .5 c ompone n t s and multipl e neu rocog nitive d oma ins (ge ne ra l ability , me mo r y , exec u tive function ) in U.S. chil dr e n ag ed 9–10 ye a rs. Th e se h ete r o gene ou s finding s s ugges t th at th e impa ct o f pa rtic ul ate ma tt er may v ary ac cording to expo s ur e c ont ext, devel opmen tal s tage , a nd pollut ant c om pos i t i on. A s y stem atic r e view by Donz ell i et al . (2019 ) r e p o r t e d i n c o n s i s t e n t e v i d e n c e l i n k i n g p a r t i c u l a t e m a t t e r t o A D H D b u t n o t e d a c l e a r e r assoc ia tion wi t h a t t entio n al and be h avioral pr ob lem s. Simila r l y, Sa en en e t al. (2 0 16) obs er v e d impaired se lec tive a tten tion i n Belgia n c hild r en , and Sid di que et al . (20 10) re ported a po s i t i v e assoc ia tion be t w een PM10 ex po sure a nd ADHD symptom s in I ndia n yout h. S ame a s wit h epidemi ologic al dat a, F ahe rty e t a l . (2 025) p erforme d an exp er i me nt w h ere the P M conc entra tion s we re modi fied u sing ca ndl e s ; th ey fou nd a n in cr ea sed rea c tio n t im e in th e exec utive contr ol netw o r k af ter b eing expos ed to P M for 1 hour . In Spa in, S unyer e t al . (20 15) rep ort e d that c hildren a t te ndi ng hig hly polluted sc hool s in Barcelo n a ex hibit ed r educ ed c ogni tive d evel opmen t growth compa red t o p eer s i n les s po llut ed s c hool s . In contr as t , Gignac e t al. (202 1) fou nd no s ig nific an t improve men t s in a t ten t io na l outcome s fol lowing ai r fil tr a t i on in terv e ntion s in adole sc e nts. To our know le dge, howe ver , .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint limited evi denc e ha s e xami ned the s e a ssoc ia tion s in you t h popula t i on s u s i ng i ndividu alized exposur e e stim ation a ppr o ach e s. Collec tively , the s e fin ding s in dicat e t ha t PM expo sur e i s a s s oc iat ed with me a sura ble behav io ral and cogn itive al te rati on s. Our re sult s a re bro adly c on s i st ent w ith prev iou s li te ratur e linki ng particula t e m at t e r ex po sure to imp a ired cog nitive p e rformanc e. To ou r kno wled g e, thi s i s th e first s tudy to d et ect a l tere d c ognitive perf ormance in you th u sing indiv iduali zed expo sur e estima t i on w ithou t ex perim ent ally ma nipulating amb ie nt PM conc en tra tion s. Fah erty et al . (2025) w ere th e fir st to expe r ime n ta lly modify PM c oncen t ra tion s a nd dem on s tr ate atte ntio nal al ter ation s follow ing sho rt -te r m expo sure . Ou r fi ndi ngs extend th eir re sul t s by s ug ge st i ng t h at simila r c ognitive e ffe cts may be d et ectabl e u nde r re a l-w orld expo sur e conditio n s . Howev er , s ev e ral m ethod olo g ical c onsid era tion s w arran t fur the r di sc us s ion . F ir st, neithe r study com preh en s i vely ad ju s t e d for p ote ntia l c on fou nding va r i abl es , wherea s la rge- s c ale epi demiol og ical i nves tigati on s typi ca lly inc orpora te ext en sive c ova r ia te c o ntrol . Sec ond, Fahe rty et al. (202 5) e mploye d c ontrol l ed expo s u re manip ul ation , whi le our de s ig n r el i ed on natur ally oc curring ex posu r e v ari abil ity, whic h limits c au sal in fe r en ce . Thi r d, bo t h ap pr o a che s are unable to c harac te r i ze the spec i fic c hemic al com pos i tion o f p a r tic ula te ma tt er, wh ich ma y critica lly infl uenc e biologi cal a nd cog nitive ou tcome s. N e u r oi maging r es ea rch provide s addition a l c ontext for the se finding s. P r ev iou s s t u die s hav e r epor ted al te rati o ns in de faul t mode netwo rk func t i o ning in chi ldre n e xposed to hi gher p ollutio n lev el s ( Pujo l e t al . , 2 016), with mo r e re cent e videnc e i n dica t i ng disru pted netw o r k dyna mics a ssocia t e d with PM2 .5 exposur e (Zundel e t al ., 20 24 ). Take n t oge t h e r , the s e da ta s u gge st tha t the co g nitive e f fec ts obse r v ed in th e p re s e n t stu dy may re fl ect s ub tle p oll ut i on- r e la ted alt era tion s in large -sca l e br a in ne tw or k organiza tion . The influ e nce o f se x as a cov aria te app e a r s only in the DASS -21 a nxie t y a nd s tr e s s sub s c ale s, w h i l e t h e r e m a i n i n g v a r i a b l e s a r e m i n i m a l l y o r n o t a f f e c t e d a t a l l . T h i s p a t t e r n i s c o n s i s t e n t with t h e w ell -e s t a bli sh ed l i tera t u re sh owing multipl e sex- rela t e d di ff erenc es in stre s s r e s p o n s e s . S t r e s s r e a c t i v i t y i s o n e o f t h e d o m a i n s w i t h t h e c l e a r e s t s e x d i f f e r e n c e s ( V e r m a e t al., 2 011 ). The DASS -21 i s a s elf -r epor t i n s t rumen t, and women ty pical ly repo rt hi ghe r l evel s of s ubj ective di stre s s i n re s pon s e to s tre ss o r s ( Child s e t a l., 2010 ; Kelly et al., 2008) , w herea s men t e nd to sh ow strong er physi ologi cal stre ss reac t i vity. M ore ov er, m en a n d women ofte n enga ge in qual ita tively dif fer ent co ping st r a te gie s whe n f acin g s t re s s (Nol en - H oek s ma , 20 12). Regarding bi ochemi cal pa thwa ys , ev ide nc e l inking a ir pollu t io n, sy stemic in fla mm ation, and cogn it i ve func t i oning in human s r e m a ins limit ed. M os t mecha ni stic insigh t s d er i ve f rom pr e clin ical m od el s (Eh s a ni fa r e t a l ., 2022 ; Ruiz -Sobr ema z a s et al., 202 3). Some h uma n studie s s ug ge st a ssocia t i on s b e t w e en p ollu t a nt e xposure and in fla mma tor y ma rker s. Fo r in s ta n ce, D u et al . (2022 ), u s in g CH ARLS da ta, r epo rt e d tha t solid f u el u se w as a ssoc iat e d with h igher depre ssion ri sk, poo rer cog ni tive func t i o ning, an d eleva t e d whi te blo od c ell c ou nts. How eve r, controll ed e xposu re studie s in h eal thy a dult s ha ve not c on s i st ently d emon stra ted a cut e chan ges in c la s s ic al p ro -infl amma t o r y ma r k er s follow ing die sel exh au s t ex po s ur e (Cli f f e t a l. , 2016). In line wi t h the s e fi n dings , o ur r esul ts did n ot show signif ic ant ass oci ati ons b etw e en particula t e ma tte r expo sure and t r adi t i o nal infl amma tory ma r k er s. N otab l y, howe ve r, we ob se r v ed a s ig nif ica nt a s soci atio n be t w een PM10 expo s ure a nd NRF2 leve ls. NRF 2 i s pr i ma rily involv ed in ox idative stre s s r egula t i on ra the r t han cl a ssic al inflamma tory s i gn ali ng. P rec linic al evid en ce indic at e s t h a t P M2.5 expo sur e c a n a lter NRF2 activ ity (Mei et al ., 2024 ) , a n d inte ractio ns be twee n NRF2 a nd N F -κB pa thwa ys a r e k nown t o modulate ox ida tive st r e ss and infl amma t o r y re spon s es (Zha ng et al., 2021 ; G ao et al. , 2 022) . .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint The i nte r pl ay be t w een the s e p a thway s i s c omplex , a s NF -κB a ctivi t y may sup pr e s s NRF2 s i gn a l i n g, w h i le N R F 2 d ef i ci e n cy ca n e n han c e N F - κB– m e d i a t ed i nf l a m m at o r y r es po n ses . F u t ur e s tu die s should simul tan e ou s l y a s s e ss N RF 2 and N F - κ B ac t i vity t o be tte r c h aract erize the oxida t i ve–in fl ammat ory ba lanc e a s socia ted with p artic ulat e mat t e r expo sure . T here i s no t enough inf ormati on ab ou t th e impa ct o f PM on in flamma t o r y or oxi da tive s t r e s s mark ers in humans . The pr e sent study i s no t w ithou t limi ta t i on s . Fir st, th e sample si z e wa s rel a t ively mode st, whic h ma y have limi t e d sta ti s tic al pow er t o det ec t small as soc iation s a nd t o expl or e the s e r e lati on ship s in grea ter de ta il . Al thoug h ma ny e pid emiol ogic al st udie s rely on s ub s tan tial ly larger sa mple s, t h e p re sen t work f oc use d on en vironmen tal toxi colog ica l m echa n is m s, whic h involv e more inte n s iv e in dividua l -leve l exp o s ure a nd bioma r k er as se ssm ent s. Seco n d, th e r a nge o f p articul a te mat t e r c oncen tra tion s wa s ge og r a phica lly r e stric t e d. Includ in g participa n ts from a br oade r r ange o f Sp anish c itie s, a s w e ll a s rural ar ea s, wo uld allo w gre ate r variabi lity in e xpo sure l ev el s a nd en h a nce th e ge nera li z abi li ty o f t he f i nding s . T hird, fu tur e s tu die s s ho uld incor pora te ad dition a l cova r i at es to be tt er ac cou n t fo r p ote nt i a l confound in g facto r s , inc luding li fe s tyle , soci oecono m ic s ta tu s, and p r e -e xi st i ng he alth condi t ion s. Four th, s e rum c lotting tim e w as no t s tanda rdize d, wh ich ma y have intr o duced a dditi ona l v ariabili t y in s ome bioc hemic al m ea su r e s. Finall y, e xperimen ta l or qua s i -ex perim ental de sign s t ha t manipul at e or more pr eci s el y control exposu re pe riod s, s uc h a s ap pr o a che s int egrating prio r exposur e m odeling u sing M PP D, may f urthe r c lari fy t e mpo ral d ynamic s and d ose - r e spon s e r e lati on ship s. Furthe r r e se arc h i s need ed to c onti nue e x ploring the l ong- term con sequ enc e s o f PM expo sur e during early lif e, pa rtic ula rly to de termin e h ow such ex po s u re ma y influe nc e he al th outcome s later in a dulth ood a nd aging . U n d ersta n ding whethe r e arly ex pos u re p r e di s po s e s indiv idual s t o f u t ur e c o g nit iv e , em o t i o na l , or o x i d at ive st r ess– r e l at e d al te r a t io ns r e ma i n a k e y r es ear ch pr i or i t y . Lon gitudin al s tudi e s w ill be e ssen tial to cla rify po t e n tial d el ayed ef fect s and to e s t a bl is h c a us a l pa t h w a y s ac r os s t he li fe s p an . N e ver thel es s, the p r e s ent st u dy provide s nov el ev idenc e in thi s fie ld, a s it uni qu ely a pplies t he MPP D mo d el t o simula t e P M ex po s u r e in y oung hea l t hy indivi dual s and exa mines i ts assoc ia tion wi th c ognitiv e, emoti ona l , and biol og ica l marker s, r ev e ali ng meanin gful r e lati on ship s be t w e en env ironmen tal po l lution varia ble s a nd exe cu tive fun cti oni ng, a s w ell as an intere s ting pa tte rn i nvolv ing N RF 2. I mpor ta n t l y, the se finding s eme rge fro m three citi e s with co mplet ely d i s tinc t g eogr aphi cal c h arac teri stic s, of fe ring a s et o f co ntex ts t hat a re high ly r e pre sent ativ e o f We s t e rn het er o ge neity . A c knowl edgements The pre s ent work i s p art of t h e gran t re f erence : P ID2020 -113 812RA - C33 fu nde d by the Spa nis h G ov ernmen t (Mini stry o f S cie nce a nd In nova t i on; MC IN/AEI /10.1303 9 / 50 1100011 033) ( C.L- G) , P R O Y_ S 1 2_2 4 b y G o ve r nm e n t o f Ar ag o n, R &D &I i n pr i or i t y a n d m u lt i d i s ci p l i n a r y r es e ar ch l i n es (C .L-G ) and by Europ ean U ni on , Next Ge nera tion E U ( I n ves t i go) (D . R -S; C .L - G ) . D i ego Rui z-So b r em aza s (M eth odol ogy, S oftwa re, Va lid atio n, Formal a naly si s, I nv es tig ation , D a ta Cu ratio n , Wri ting, Vi su alizati on) , B lanc a Ca tivie la -Camp o s (Inve s t i gatio n, D ata Cu ra tion, W riting ) ; Marí a Ca d als o (Inv e s t ig atio n, Dat a Cura tion , W riting ) ; Ang el B arr a sa ( Metho dolog y, Inves tigati on, D ata Cura tion, W riti ng), Pilar Ca ta lán -Edo (Me t h o dology, Inve st iga t io n, D at a Cura tion, Re sou r c e s, W riti ng , Vi s u a liz a t i on) ; C r i s tia n P e r e z -F erna n dez (Inv e sti g ation, Da ta Cura tion, Wr i ting ) ; Be at r i z F err er (Inv es tigati on, F or ma l Analy si s, Sup ervi s io n); F er n a ndo .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint Sánc hez - S an ted (Inve s tigation , D ata Cu r ation, Wr i ting ); Te r e sa C olomi na ( I nve sti gation, Da ta Cura tion, W riting) ; C a ridad L ópez -Gra ne r o (Me t h o dology , Sof twa r e , Vali d a tion, F ormal analy s i s, Inv e st ig a tion, Dat a C ura t i on , Wri t in g, Vi suali zati on, F unding Acqui si tion) . Conflict of interest s The a ut h o r s d ec lar e no conflic t of in ter e st. Refere nces: Alexis, N. E., Lay, J. C., Zeman, K., Bennett, W. E., Peden, D. B., Soukup, J. M., Devlin, R. B., & Becker, S. (2006). Biological material on inhaled coarse fraction particulate matter activates airway phagocytes in vivo in healthy volunteers. The Journal of allergy and clinical immunology, 117(6), 1396–1403. https://doi.org/10.1016/j.jaci.2006.02.030 American Psychological Association. (2018). Cognitive functioning. APA Dictionary of Psychology. https://dictionary.apa.org/cognitive-functioning Anjilvel, S., & Asgharian, B. (1995). A multiple-path model of particle deposition in the rat lung. Fundamental and Applied Toxicology, 28(1), 41–50. https://doi.org/10.1006/faat.1995.1144 Anjilvel, S., & Asgharian, B. (1995). A multiple-path model of particle deposition in the rat lung. Fundamental and Applied Toxicology, 28(1), 41–50. https://doi.org/10.1006/faat.1995.1144 Applied Research Associates, Inc. (2025). Multiple-Path Particle Dosimetry Model (MPPD v3.04): A computational model for estimating human and laboratory animal inhalation particle dosimetry. Available at: https://www.ara.com/mppd Berg, E.L., Pedersen, L.R., Pride, M.C. et al. Developmental exposure to near roadway pollution produces behavioral phenotypes relevant to neurodevelopmental disorders in juvenile rats. Transl Psychiatry 10, 289 (2020). https://doi.org/10.1038/s41398-020-00978-0 Brooks, A. W., Sandri, B. J., Nixon, J. P., Nurkiewicz, T. R., Barach, P., Trembley, J. H., & Butterick, T. A. (2024). Neuroinflammation and Brain Health Risks in Veterans Exposed to Burn Pit Toxins. International journal of molecular sciences, 25(18), 9759. https://doi.org/10.3390/ijms25189759 Bui, V. K. H., Moon, J.-Y., Chae, M., Park, D., & Lee, Y.-C. (2020). Prediction of aerosol deposition in the human respiratory tract via computational models: A review with recent updates. Atmosphere, 11(2), 137. https://doi.org/10.3390/atmos11020137 Calderón-Garcidueñas, L., Azzarelli, B., Acuna, H., Garcia, R., Gambling, T. M., Osnaya, N., Monroy, S., DEL Tizapantzi, M. R., Carson, J. L., Villarreal-Calderon, A., & Rewcastle, B. (2002). Air pollution and brain damage. Toxicologic pathology, 30(3), 373–389. https://doi.org/10.1080/01926230252929954 Calderón-Garcidueñas, L., Solt, A. C., Henríquez-Roldán, C., Torres-Jardón, R., Nuse, B., Herritt, L., Villarreal-Calderón, R., Osnaya, N., Stone, I., García, R., Brooks, D. M., González- Maciel, A., Reynoso-Robles, R., Delgado-Chávez, R., & Reed, W. (2008). Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults. Toxicologic pathology, 36(2), 289–310. https://doi.org/10.1177/0192623307313011 .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint Calderón-Garcidueñas, L., Stommel, E. W., Rajkumar, R. P., Mukherjee, P. S., & Ayala, A. (2021). Particulate Air Pollution and Risk of Neuropsychiatric Outcomes. What We Breathe, Swallow, and Put on Our Skin Matters. International journal of environmental research and public health, 18(21), 11568. https://doi.org/10.3390/ijerph182111568 Cativiela-Campos, B., Ruiz-Sobremazas, D., Rodulfo-Cárdenas, R., Barrasa, A., Sánchez- Santed, F., Colomina, M. T., Aschner, M., & López-Granero, C. (2025). What are the consequences of PM air pollution exposure on elderly behavior? A systematic review. Environmental pollution (Barking, Essex : 1987), 375, 126279. https://doi.org/10.1016/j.envpol.2025.126279 Chanda, F., Lin, K. X., Chaurembo, A. I., Huang, J. Y., Zhang, H. J., Deng, W. H., Xu, Y. J., Li, Y., Fu, L. D., Cui, H. D., Shu, C., Chen, Y., Xing, N., & Lin, H. B. (2024). PM 2.5-mediated cardiovascular disease in aging: Cardiometabolic risks, molecular mechanisms and potential interventions. The Science of the total environment, 954, 176255. https://doi.org/10.1016/j.scitotenv.2024.176255 Chang, Y. C., Daza, R., Hevner, R., Costa, L. G., & Cole, T. B. (2019). Prenatal and early life diesel exhaust exposure disrupts cortical lamina organization: Evidence for a reelin-related pathogenic pathway induced by interleukin-6. Brain, behavior, and immunity, 78, 105–115. https://doi.org/10.1016/j.bbi.2019.01.013 Childs, E., Dlugos, A., & De Wit, H. (2010). Cardiovascular, hormonal, and emotional responses to the TSST in relation to sex and menstrual cycle phase. Psychophysiology, 47(3), 550–559. https://doi.org/10.1111/j.1469-8986.2009.00961.x Choi, Y., Choi, I. W., & Kwon, J. H. (2025). Assessing inhalation intake of microplastics using MPPD model. Environmental analysis, health and toxicology, 40(Special Issue), e2025s02– e2025s0. https://doi.org/10.5620/eaht.2025s02 Cliff, R., Curran, J., Hirota, J. A., Brauer, M., Feldman, H., & Carlsten, C. (2016). Effect of diesel exhaust inhalation on blood markers of inflammation and neurotoxicity: a controlled, blinded crossover study. Inhalation toxicology, 28(3), 145–153. https://doi.org/10.3109/08958378.2016.1145770 Cory-Slechta, D. A., Merrill, A., & Sobolewski, M. (2023). Air Pollution-Related Neurotoxicity Across the Life Span. Annual review of pharmacology and toxicology, 63, 143–163. https://doi.org/10.1146/annurev-pharmtox-051921-020812 Cristaldi, A., Fiore, M., Oliveri Conti, G., Pulvirenti, E., Favara, C., Grasso, A., Copat, C., & Ferrante, M. (2022). Possible association between PM2.5 and neurodegenerative diseases: A systematic review. Environmental research, 208, 112581. https://doi.org/10.1016/j.envres.2021.112581 Donzelli, G., Llopis-Gonzalez, A., Llopis-Morales, A., Cioni, L., & Morales-Suárez-Varela, M. (2019). Particulate Matter Exposure and Attention-Deficit/Hyperactivity Disorder in Children: A Systematic Review of Epidemiological Studies. International journal of environmental research and public health, 17(1), 67. https://doi.org/10.3390/ijerph17010067 Du, X., Li, X., Qian, P., & Wu, H. (2022). Indoor air pollution from solid fuels use, inflammation, depression and cognitive function in middle-aged and older Chinese adults. Journal of affective disorders, 319, 370–376. https://doi.org/10.1016/j.jad.2022.09.103 Ehsanifar, M., Jafari, A. J., Nikzad, H., Zavareh, M. S., Atlasi, M. A., Mohammadi, H., & Tameh, A. A. (2019). Prenatal exposure to diesel exhaust particles causes anxiety, spatial memory disorders with alters expression of hippocampal pro-inflammatory cytokines and NMDA receptor .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint subunits in adult male mice offspring. Ecotoxicology and environmental safety, 176, 34–41. https://doi.org/10.1016/j.ecoenv.2019.03.090 Ehsanifar, M., Yavari, Z., & Rafati, M. (2022). Exposure to urban air pollution particulate matter: neurobehavioral alteration and hippocampal inflammation. Environmental science and pollution research international, 29(33), 50856–50866. https://doi.org/10.1007/s11356-022-19367-9 Elder, A., Gelein, R., Silva, V., Feikert, T., Opanashuk, L., Carter, J., Potter, R., Maynard, A., Ito, Y., Finkelstein, J., & Oberdörster, G. (2006). Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environmental health perspectives, 114(8), 1172–1178. https://doi.org/10.1289/ehp.9030 Fan, J., McCandliss, B. D., Sommer, T., Raz, A., & Posner, M. I. (2002). Testing the efficiency and independence of attentional networks. Journal of cognitive neuroscience, 14(3), 340–347. https://doi.org/10.1162/089892902317361886 Fonken, L. K., Xu, X., Weil, Z. M., Chen, G., Sun, Q., Rajagopalan, S., & Nelson, R. J. (2011). Air pollution impairs cognition, provokes depressive-like behaviors and alters hippocampal cytokine expression and morphology. Molecular psychiatry, 16(10), 987–973. https://doi.org/10.1038/mp.2011.76 Forastiere, F., Spadaro, J. V., Ancona, C., Jovanovic Andersen, Z., Cozzi, I., Gumy, S., Loncar, D., Mudu, P., Medina, S., Perez Velasco, R., Walton, H., Zhang, J., & Krzyzanowski, M. (2024). Choices of morbidity outcomes and concentration-response functions for health risk assessment of long-term exposure to air pollution. Environmental epidemiology (Philadelphia, Pa.), 8(4), e314. https://doi.org/10.1097/EE9.0000000000000314 Garcia, A., Santa-Helena, E., De Falco, A., de Paula Ribeiro, J., Gioda, A., & Gioda, C. R. (2023). Toxicological Effects of Fine Particulate Matter (PM 2.5): Health Risks and Associated Systemic Injuries-Systematic Review. Water, air, and soil pollution, 234(6), 346. https://doi.org/10.1007/s11270-023-06278-9 Gignac, F., Barrera-Gómez, J., Persavento, C., Solé, C., Tena, È., López-Vicente, M., Foraster, M., Amato, F., Alastuey, A., Querol, X., Llavador, H., Apesteguia, J., Júlvez, J., Couso, D., Sunyer, J., & Basagaña, X. (2021). Short-term effect of air pollution on attention function in adolescents (ATENC!Ó): A randomized controlled trial in high schools in Barcelona, Spain. Environment international, 156, 106614. https://doi.org/10.1016/j.envint.2021.106614 Graham, U. M., Pinto, J. M., Weuve, J., Dozier, A. K., Rogers, R., Nag, S., Schneider, J., Kaufman, J. D., Bennett, D. A., & Oberdörster, G. (2025). Nose-to-brain translocation of inhaled ultrafine elongated particles: facts and mysteries. Frontiers in toxicology, 7, 1655149. https://doi.org/10.3389/ftox.2025.1655149 Gunasingam, G., He, R., Taladriz-Blanco, P., Balog, S., Petri-Fink, A., & Rothen-Rutishauser, B. (2024). Combining analytical techniques to assess the translocation of diesel particles across an alveolar tissue barrier in vitro. Particle and fibre toxicology, 21(1), 26. https://doi.org/10.1186/s12989-024-00585-7 Hamanaka, R. B., & Mutlu, G. M. (2018). Particulate Matter Air Pollution: Effects on the Cardiovascular System. Frontiers in endocrinology, 9, 680. https://doi.org/10.3389/fendo.2018.00680 Hou, Y., Yan, W., Guo, L., Li, G., & Sang, N. (2023). Prenatal PM 2.5 exposure impairs spatial learning and memory in male mice offspring: from transcriptional regulation to neuronal morphogenesis. Particle and fibre toxicology, 20(1), 13. https://doi.org/10.1186/s12989-023- 00520-2 .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint Houweling, L., Maitland-Van der Zee, A.-H., Holtjer, J. C. S., Bazdar, S., Vermeulen, R. C. H., Downward, G. S., & Bloemsma, L. D. (2024). The effect of the urban exposome on COVID-19 health outcomes: A systematic review and meta-analysis. Environmental Research, 240(Part 2), 117351. https://doi.org/10.1016/j.envres.2023.117351 Impulsiveness Scale". Journal of Clinical Psychology. 51 (6): 768–74. doi:10.1002/1097 Jalaludin, B., Garden, F. L., Chrzanowska, A., Haryanto, B., Cowie, C. T., Lestari, F., Morgan, G., Mazumdar, S., Metcalf, K., & Marks, G. B. (2022). Associations Between Ambient Particulate Air Pollution and Cognitive Function in Indonesian Children Living in Forest Fire- Prone Provinces. Asia-Pacific journal of public health, 34(1), 96–105. https://doi.org/10.1177/10105395211031735 Junaidi, E. S., Jalaludin, J., & Latif, M. T. (2026). Application of multiple-path particle dosimetry (MPPD) model in aged-specify schoolchildren airways exposed to ambient particulate matter in Malaysia. Aerosol Science and Technology, 60(2), 92–109. https://doi.org/10.1080/02786826.2025.2502492 Kelly, M. M., Tyrka, A. R., Anderson, G. M., Price, L. H., & Carpenter, L. L. (2008). Sex differences in emotional and physiological responses to the Trier Social Stress Test. Journal of behavior therapy and experimental psychiatry, 39(1), 87–98. https://doi.org/10.1016/j.jbtep.2007.02.003 Kleiner, G., Marcuzzi, A., Zanin, V., Monasta, L., & Zauli, G. (2013). Cytokine levels in the serum of healthy subjects. Mediators of inflammation, 2013, 434010. https://doi.org/10.1155/2013/434010 Kyung, S. Y., & Jeong, S. H. (2020). Particulate-Matter Related Respiratory Diseases. Tuberculosis and respiratory diseases, 83(2), 116–121. https://doi.org/10.4046/trd.2019.0025 Lett, E., Stingone, J. A., & Claudio, L. (2017). The Combined Influence of Air Pollution and Home Learning Environment on Early Cognitive Skills in Children. International journal of environmental research and public health, 14(11), 1295. https://doi.org/10.3390/ijerph14111295 Li, W., Khor, T. O., Xu, C., Shen, G., Jeong, W. S., Yu, S., & Kong, A. N. (2008). Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis. Biochemical pharmacology, 76(11), 1485–1489. https://doi.org/10.1016/j.bcp.2008.07.017 López-Granero, C., Polyanskaya, L., Ruiz-Sobremazas, D., Barrasa, A., Aschner, M., & Alique, M. (2023). Particulate Matter in Human Elderly: Higher Susceptibility to Cognitive Decline and Age-Related Diseases. Biomolecules, 14(1), 35. https://doi.org/10.3390/biom14010035 Lovibond, S.H. & Lovibond, P.F. (1995). Manual for the Depression Anxiety & Stress Scales. (2nd Ed.)Sydney: Psychology Foundation. Manojkumar, N., Srimuruganandam, B., & Shiva Nagendra, S. M. (2019). Application of multiple-path particle dosimetry model for quantifying age specified deposition of particulate matter in human airway. Ecotoxicology and environmental safety, 168, 241–248. https://doi.org/10.1016/j.ecoenv.2018.10.091 Mei, H., Wu, D., Yong, Z., Cao, Y., Chang, Y., Liang, J., Jiang, X., Xu, H., Yang, J., Shi, X., Xie, R., Zhao, W., Wu, Y., & Liu, Y. (2024). PM 2.5 exposure exacerbates seizure symptoms and cognitive dysfunction by disrupting iron metabolism and the Nrf2-mediated ferroptosis .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint pathway. The Science of the total environment, 910, 168578. https://doi.org/10.1016/j.scitotenv.2023.168578 Miller, F. J., Asgharian, B., Schroeter, J. D., & Price, O. (2016). Improvements and additions to the Multiple Path Particle Dosimetry model. Journal of Aerosol Science, 99, 14–26. https://doi.org/10.1016/j.jaerosci.2016.01.018 Miller, F. J., Asgharian, B., Schroeter, J. D., & Price, O. (2016). Improvements and additions to the Multiple Path Particle Dosimetry model. Journal of Aerosol Science, 99, 14–26. https://doi.org/10.1016/j.jaerosci.2016.01.018 Mori, A., Ito, S., & Sekine, T. (2024). A revision of the multiple-path particle dosimetry model focusing on tobacco product aerosol dynamics. International journal for numerical methods in biomedical engineering, 40(3), e3796. https://doi.org/10.1002/cnm.3796 National Institute of Environmental Health Sciences. (2025). Air pollution and your health. https://www.niehs.nih.gov/health/topics/agents/air-pollution Nephew, B. C., Nemeth, A., Hudda, N., Beamer, G., Mann, P., Petitto, J., Cali, R., Febo, M., Kulkarni, P., Poirier, G., King, J., Durant, J. L., & Brugge, D. (2020). Traffic-related particulate matter affects behavior, inflammation, and neural integrity in a developmental rodent model. Environmental research, 183, 109242. https://doi.org/10.1016/j.envres.2020.109242 Oberdörster, G., Sharp, Z., Atudorei, V., Elder, A., Gelein, R., Kreyling, W., & Cox, C. (2004). Translocation of inhaled ultrafine particles to the brain. Inhalation toxicology, 16(6-7), 437–445. https://doi.org/10.1080/08958370490439597 Onivefu, A. P., & Imarhiagbe, O. (2024). Types of Air Pollutants. En S. C. Izah, M. C. Ogwu, & A. Shahsavani (Eds.), Air Pollutants in the Context of One Health (The Handbook of Environmental Chemistry, Vol. 134). Springer. https://doi.org/10.1007/698_2024_1128 Oquendo, M. A., Baca García, E., Graver, R., Morales, M., Montalvan, V., & Mann, J. (2001). Spanish adaptation of the Barratt Impulsiveness Scale (BIS-11). European Journal of Psychiatry, 15(3), 147–155. Patten, K.T., González, E.A., Valenzuela, A. et al. Effects of early life exposure to traffic-related air pollution on brain development in juvenile Sprague-Dawley rats. Transl Psychiatry 10, 166 (2020). https://doi.org/10.1038/s41398-020-0845-3 Patton, J.H.; Stanford, M.S.; Barratt, E.S. (November 1995). "Factor structure of the Barratt Pons, D., Atienza, F. L., Balaguer, I., & García-Merita, M. L. (2000). Satisfaction with Life Scale: analysis of factorial invariance for adolescents and elderly persons. Perceptual and Motor Skills, 91, 62–68. Pozzer, A., Anenberg, S. C., Dey, S., Haines, A., Lelieveld, J., & Chowdhury, S. (2023). Mortality Attributable to Ambient Air Pollution: A Review of Global Estimates. GeoHealth, 7(1), e2022GH000711. https://doi.org/10.1029/2022GH000711 Pujol, J., Martínez-Vilavella, G., Macià, D., Fenoll, R., Alvarez-Pedrerol, M., Rivas, I., Forns, J., Blanco-Hinojo, L., Capellades, J., Querol, X., Deus, J., & Sunyer, J. (2016). Traffic pollution exposure is associated with altered brain connectivity in school children. NeuroImage, 129, 175–184. https://doi.org/10.1016/j.neuroimage.2016.01.036 Qi, J., Zhao, N., Liu, M., Guo, Y., Fu, J., Zhang, Y., Wang, W., Su, Z., Zeng, Y., Yao, Y., & Hu, K. (2024). Long-term exposure to fine particulate matter constituents and cognitive impairment .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint among older adults: An 18-year Chinese nationwide cohort study. Journal of hazardous materials, 468, 133785. https://doi.org/10.1016/j.jhazmat.2024.133785 Qi, J., Zhao, N., Liu, M., Guo, Y., Fu, J., Zhang, Y., Wang, W., Su, Z., Zeng, Y., Yao, Y., & Hu, K. (2024). Long-term exposure to fine particulate matter constituents and cognitive impairment among older adults: An 18-year Chinese nationwide cohort study. Journal of hazardous materials, 468, 133785. https://doi.org/10.1016/j.jhazmat.2024.133785 Rentschler, K. M., & Kodavanti, U. P. (2024). Mechanistic insights regarding neuropsychiatric and neuropathologic impacts of air pollution. Critical reviews in toxicology, 54(10), 953–980. https://doi.org/10.1080/10408444.2024.2420972 Ruiz-Sobremazas, D., Rodulfo-Cárdenas, R., Ruiz-Coca, M., Morales-Navas, M., Teresa Colomina, M., López-Granero, C., Sánchez-Santed, F., & Perez-Fernandez, C. (2023). Uncovering the link between air pollution and neurodevelopmental alterations during pregnancy and early life exposure: A systematic review. Neuroscience and biobehavioral reviews, 152, 105314. https://doi.org/10.1016/j.neubiorev.2023.105314 Saenen, N. D., Provost, E. B., Viaene, M. K., Vanpoucke, C., Lefebvre, W., Vrijens, K., Roels, H. A., & Nawrot, T. S. (2016). Recent versus chronic exposure to particulate matter air pollution in association with neurobehavioral performance in a panel study of primary schoolchildren. Environment international, 95, 112–119. https://doi.org/10.1016/j.envint.2016.07.014 Schraufnagel, D.E. The health effects of ultrafine particles. Exp Mol Med 52, 311–317 (2020). https://doi.org/10.1038/s12276-020-0403-3 Seaton, A., MacNee, W., Donaldson, K., & Godden, D. (1995). Particulate air pollution and acute health effects. Lancet (London, England), 345(8943), 176–178. https://doi.org/10.1016/s0140-6736(95)90173-6 Serafini, M. M., Maddalon, A., Iulini, M., & Galbiati, V. (2022). Air Pollution: Possible Interaction between the Immune and Nervous System?. International journal of environmental research and public health, 19(23), 16037. https://doi.org/10.3390/ijerph192316037 Siddique, S., Banerjee, M., Ray, M. R., & Lahiri, T. (2011). Attention-deficit hyperactivity disorder in children chronically exposed to high level of vehicular pollution. European journal of pediatrics, 170(7), 923–929. https://doi.org/10.1007/s00431-010-1379-0 Steinle, S., Reis, S., Sabel, C. E., Semple, S., Twigg, M. M., Braban, C. F., Leeson, S. R., Heal, M. R., Harrison, D., Lin, C., & Wu, H. (2015). Personal exposure monitoring of PM2.5 in indoor and outdoor microenvironments. The Science of the total environment, 508, 383–394. https://doi.org/10.1016/j.scitotenv.2014.12.003 Stroop, J. R. (1935). Studies of interference in serial verbal reactions. Journal of Experimental Psychology, 18(6), 643–662. https://doi.org/10.1037/h0054651 Sukumaran, K., Botternhorn, K. L., Schwartz, J., Gauderman, J., Cardenas-Iniguez, C., McConnell, R., Hackman, D. A., Berhane, K., Ahmadi, H., Abad, S., Habre, R., & Herting, M. M. (2024). Associations between Fine Particulate Matter Components, Their Sources, and Cognitive Outcomes in Children Ages 9-10 Years Old from the United States. Environmental health perspectives, 132(10), 107009. https://doi.org/10.1289/EHP14418 Sunyer, J., Esnaola, M., Alvarez-Pedrerol, M., Forns, J., Rivas, I., López-Vicente, M., Suades- González, E., Foraster, M., Garcia-Esteban, R., Basagaña, X., Viana, M., Cirach, M., Moreno, T., Alastuey, A., Sebastian-Galles, N., Nieuwenhuijsen, M., & Querol, X. (2015). Association .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint between traffic-related air pollution in schools and cognitive development in primary school children: a prospective cohort study. PLoS medicine, 12(3), e1001792. https://doi.org/10.1371/journal.pmed.1001792 Sunyer, J., Esnaola, M., Alvarez-Pedrerol, M., Forns, J., Rivas, I., López-Vicente, M., Suades- González, E., Foraster, M., Garcia-Esteban, R., Basagaña, X., Viana, M., Cirach, M., Moreno, T., Alastuey, A., Sebastian-Galles, N., Nieuwenhuijsen, M., & Querol, X. (2015). Association between traffic-related air pollution in schools and cognitive development in primary school children: a prospective cohort study. PLoS medicine, 12(3), e1001792. https://doi.org/10.1371/journal.pmed.1001792 Tsiros, P., Cheimarios, N., Tsoumanis, A., Jensen, A. C. Ø., Melagraki, G., Lynch, I., Sarimveis, H., & Afantitis, A. (2022). Towards an in silico integrated approach for testing and assessment of nanomaterials: From predicted indoor air concentrations to lung dose and biodistribution. Environmental Science: Nano, 9, 1282–1297. https://doi.org/10.1039/D1EN00956G Velarde-Mayol, C., Fragua-Gil, S., & García-de-Cecilia, J. M. (2016). Validación de la escala de soledad de UCLA y perfil social en la población anciana que vive sola. Medicina de Familia. SEMERGEN, 42(3), 177–183. https://doi.org/10.1016/j.semerg.2015.05.017 Verma, R., Balhara, Y. P., & Gupta, C. S. (2011). Gender differences in stress response: Role of developmental and biological determinants. Industrial psychiatry journal, 20(1), 4–10. https://doi.org/10.4103/0972-6748.98407 Weitekamp, C. A., & Hofmann, H. A. (2021). Effects of air pollution exposure on social behavior: a synthesis and call for research. Environmental health: a global access science source, 20(1), 72. https://doi.org/10.1186/s12940-021-00761-8 Welch, B. L. (1951). On the comparison of several mean values: An alternative approach. Biometrika, 38(3/4), 330–336. Woodward, N. C., Haghani, A., Johnson, R. G., Hsu, T. M., Saffari, A., Sioutas, C., Kanoski, S. E., Finch, C. E., & Morgan, T. E. (2018). Prenatal and early life exposure to air pollution induced hippocampal vascular leakage and impaired neurogenesis in association with behavioral deficits. Translational psychiatry, 8(1), 261. https://doi.org/10.1038/s41398-018-0317-1 World Health Organization. (2024). Ambient (outdoor) air pollution and health. https://www.who.int/news-room/fact-sheets/detail/ambient-(outdoor)-air-quality-and-health Wyatt, L.H., Devlin, R.B., Rappold, A.G. et al. Low levels of fine particulate matter increase vascular damage and reduce pulmonary function in young healthy adults. Part Fibre Toxicol 17, 58 (2020). https://doi.org/10.1186/s12989-020-00389-5 Yao, Y., Wang, K., & Xiang, H. (2022). Association between cognitive function and ambient particulate matters in middle-aged and elderly Chinese adults: Evidence from the China Health and Retirement Longitudinal Study (CHARLS). The Science of the total environment, 828, 154297. https://doi.org/10.1016/j.scitotenv.2022.154297 Yu, W., Ye, T., Chen, Z., Xu, R., Song, J., Li, S., & Guo, Y. (2024). Global analysis reveals region-specific air pollution exposure inequalities. One Earth, 7(11), 2063–2071. https://doi.org/10.1016/j.oneear.2024.09.017 Zhang, H., D'Agostino, C., Forman, H. J., Cacciottolo, M., Thorwald, M., Mack, W. J., Liu, Q., Shkirkova, K., Lamorie-Foote, K., Sioutas, C., Pirhadi, M., Mack, W. J., Morgan, T. E., & Finch, .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint C. E. (2021). Urban Air Pollution Nanoparticles from Los Angeles: Recently Decreased Neurotoxicity. Journal of Alzheimer's disease : JAD, 82(1), 307–316. https://doi.org/10.3233/JAD-201577 Zhang, J., Yang, Y., Al-Ahmady, Z. S., Du, W., Duan, J., Liao, Z., Sun, Q., Wei, Z., & Hua, J. (2023). Maternal exposure to PM2.5 induces cognitive impairment in offspring via cerebellar neuroinflammation and oxidative stress. Ecotoxicology and environmental safety, 249, 114425. https://doi.org/10.1016/j.ecoenv.2022.114425 Zimmerman, D. W. (2004). A note on preliminary tests of equality of variances. British Journal of Mathematical and Statistical Psychology, 57(1), 173–181. Zundel, C. G., Ely, S., Brokamp, C., Strawn, J. R., Jovanovic, T., Ryan, P., & Marusak, H. A. (2024). Particulate Matter Exposure and Default Mode Network Equilibrium During Early Adolescence. Brain connectivity, 14(6), 307–318. https://doi.org/10.1089/brain.2023.0072 Nolen-Hoeksema S. (2012). Emotion regulation and psychopathology: the role of gender. Annual review of clinical psychology, 8, 161–187. https://doi.org/10.1146/annurev-clinpsy- 032511-143109 .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprintthis version posted March 25, 2026. ; https://doi.org/10.64898/2026.03.23.713644doi: bioRxiv preprint