Metal-organic frameworks for the treatment of endocrine-disrupting chemicals

The endocrine system is a network of glands located throughout the body, with each gland producing a specific hormone ( Table 2 ). A hormone is a natural chemical released into the bloodstream that travels to specific tissues or organs, where it binds to receptors to regulate various bodily functions. When these receptors are triggered, various responses occur, such as changes in metabolism, hormone production, or changes in behavior. Some glands produce a single hormone; for example, the parathyroid gland produces parathyroid hormone. Other glands produce multiple hormones, such as the pituitary gland, which produces prolactin and growth hormone. Breast milk production in a new mother is regulated by prolactin, a hormone that is released only during breastfeeding. Both childhood and adult growth and development depend on growth hormone. Besides their endocrine functions, some glands also perform other significant roles. For example, the pancreas produces insulin (a hormone that regulates blood sugar), and digestive enzymes, which are not part of the endocrine system. As a result of the endocrine system, the body can adapt to environmental changes, such as dietary requirements (e.g., hunger, starvation, obesity). Among its functions, it regulates reproductive health and supports the normal growth of the body and brain. Additionally, metabolic adjustments help to maintain the daily physiological processes and overall health of the body. When hormones are not produced or function properly, severe diseases can develop, potentially leading to death. For example, aldosterone is a critical component of life, and adrenal disorders can be fatal. Hormonal imbalances, such as under- or over-secretion of thyroid hormone, can lead to metabolic disturbances, neurobiological changes, and physical dysfunctions. Numerous circumstances are associated with hormone dysfunction, including infertility, growth disorders, sleep problems, and chronic illnesses. Table 2 The role of the Endocrine system in secreting major hormones for body functionality Endocrine gland Images of the glands Hormones EDCs that effects the endocrine glands General effects of an endocrine gland on Human body development and metabolism Reference Pituitary gland growth hormone, TSH, ACTH, LH, FSH, Prolactin, Oxytocin, Vasopressin bisphenol A/BPA and analogues, phthalates, PBDEs/PFAS through thyroid-axis feedback, PCBs it regulates a variety of vital functions such as growth, metabolism, stress and immune responses, reproduction, milk production, milk release during nursing, contractions of the uterus during childbirth, electrolyte balance, and blood pressure regulation in both males and females. Miao.et al. 33 Pineal gland melatonin carbamate insecticides, phthalates, and phenols as sleep/circadian disruptors, possibly other neuroendocrine-active pollutants circadian rhythms of sleep, wakefulness, and activity. Popovska-Gorevski.et al. 34 ; Zheng.et al. 35 Thyroid gland thyroid hormones and calcitonin perchlorate, nitrate, thiocyanate, PBDE flame retardants, PCBs/dioxin-like compounds, PFAS, BPA, phthalates metabolism and calcium homeostasis. Horton.et al. 36 ; Lee.et al. 37 Parathyroid parathyroid hormone PFAS, especially PFOA, PFOS, PFHxS calcium balance Di Nisio.et al. 38 ; Galloway.et al. 39 Hypothalamus GHRH, TRH, CRH, GnRH, dopamine BPA and bisphenol analogs, phthalates, PFAS, PCBs, PBDEs, pesticides it regulates growth, metabolism, stress and immune responses, reproduction, and lactation (where dopamine inhibits prolactin production). Wang.et al. 40 ; Özgen.et al. 41 ; Zhang.et al. 42 Pancreas insulin, glucagon BPA/BPS/BPF, phthalates, especially DEHP metabolites, PFAS; PCBs/dioxins regulation of blood sugar and other nutrients. Liu.et al. 43 ; Sears.et al. 44 ; Hinson.et al. 45 Adrenal glucocorticoids, mineralocorticoids, sex steroids Phthalates, PFAS, organophosphate and organochlorine pesticides, BPA/phenols, PCBs/dioxins stress and immune responses, blood pressure, and water balance. Liu.et al. 43 ; Sears.et al. 44 ; Stüfchen.et al. 46 Ovary (female) sex steroids, specifically estrogens and progesterone BPA and bisphenol analogs, phthalates, PFAS, pesticides, parabens, benzophenones, chlorophenols reproduction in females Park.et al. 47 ; Pollack.et al. 48 Testis (male) sex steroids, particularly androgens (testosterone) phthalates, especially DEHP/DBP/DiNP metabolites, BPA and bisphenols PFAS, PCBs/dioxins, organophosphate pesticides, flame retardants reproduction in males Woodward.et al. 49 ; Change.et al. 50 ; Rodprasert.et al. 51 The role of the Endocrine system in secreting major hormones for body functionality Understanding how xenobiotics disrupt the endocrine system is important. The detailed mechanism of action is shown in Figure 1 . Endocrine disruption is not a receptor-binding process. This process is a change in the conformational output of a liganded receptor and in which co-regulators are suitable for which promoters. 52 , 53 The best example is BPA acting on the estrogen receptor alpha (ERɑ). 54 The ERɑ ligand-binding domain (LBD) folds into a 3-layer helical sandwich, adding an essentially hydrophobic cavity. 52 , 54 When 17β-estradiol (E2) binds, the C-terminal helix H12 closes over the cavity and, together with H3 and H4, completes the activation function-2 (AF-2) surface, which is a hydrophobic groove that docks the LxxLL motifs of p160 coactivators such as SRC-1. 52 , 54 In a crystallographic study, it was reported that BPA does not reproduce this binding mode. One phenol ring anchors to Glu353 and Arg394 in a manner similar to the E2 A-ring; however, the second ring is accommodated differently, resulting in an H12 placement that is only partially agonist-like. The congeners diverge further in the case of bisphenol C, where a 180° rotation about the axis of the anchored ring directs the second ring toward H12 and induces an antagonist orientation. In contrast, bisphenol AF maintains agonist H12 positioning even when bound in the bisphenol C-like mode. Thus, substitution at the single bridging carbon alters the receptor between activating and inhibiting conformations, demonstrating that structural analogy is an unreliable predictor of the activity of BPA substitutes. 52 , 54 Figure 1 Bisphenol-dependent ERα signaling (A) ERα domain organization shows ligand-independent AF-1 and ligand-dependent AF-2. (B) E2 promotes an agonist H12 conformation, BPA induces a partial agonist-like conformation, and BPC shifts H12 toward an antagonist orientation. (C) These conformations produce full, weak, or blocked SRC-1 recruitment, respectively. (D) Despite reduced AF-2 activity, BPA and BPC retain partial transcriptional activity through AF-1, demonstrating that transcriptional output is not directly proportional to coactivator recruitment. Bisphenol-dependent ERα signaling (A) ERα domain organization shows ligand-independent AF-1 and ligand-dependent AF-2. (B) E2 promotes an agonist H12 conformation, BPA induces a partial agonist-like conformation, and BPC shifts H12 toward an antagonist orientation. (C) These conformations produce full, weak, or blocked SRC-1 recruitment, respectively. (D) Despite reduced AF-2 activity, BPA and BPC retain partial transcriptional activity through AF-1, demonstrating that transcriptional output is not directly proportional to coactivator recruitment. For risk assessment, the key factor is the transcriptional outcome, which is not simply a weaker form of estradiol action. Delfosse et al. 52 used fluorescence anisotropy with an SRC-1 NR2 peptide and found that bisphenols do not recruit coactivators well to AF-2, but they still drive transcription. This happens because bisphenols act as partial agonists, mainly activating the N-terminal AF-1 domain, mostly independent of their effect at AF-2 240. As a result, ERα output does not directly match AF-2 engagement. This separation has an important implication: since the balance between AF-1 and AF-2 depends on the promoter and cell type, the same bisphenol can activate transcription in tissues where AF-1 is more important, but act as a partial antagonist of E2 in tissues where AF-2 is more important. 52 Therefore, differences in bisphenol effects across tissues are expected based on structural biology, not due to inconsistent data. However, ERα has some limitations. BPA binds to it much more weakly than E2, about ten thousand times weaker, which does not explain the effects seen at low doses. Takayanagi et al. 55 addressed this by showing that BPA binds to the orphan nuclear receptor ERRγ with an IC 50 of 13.1 nM (241). Later, Okada et al. 56 measured a dissociation constant of 5.50 ± 0.87 nM using saturation binding and Scatchard analysis. ERRγ is always active, so BPA does not need to activate it. Instead, BPA helps ERRγ maintain its normal activity even when inverse agonists are present. 53 The human receptor BPA is not an estrogen receptor; it is incomplete on ERα, and calling BPA a “weak estrogen” underestimates its risk by comparing it to the wrong target. 53 , 54

The endocrine system plays a crucial role in fetal development during pregnancy. Exposure to endocrine-disrupting chemicals (EDCs) can disrupt the mother-to-fetal axis, potentially altering the fetus’s developmental trajectory. 73 Even a minimum level of EDC exposure during pregnancy can affect fetal development. 157 , 158 , 159 Both the placental and blood-brain barriers are very vulnerable to EDCs, posing a direct threat to fetal brain development. Prenatal EDC exposure has been linked to premature birth of infants and disrupted fetal development, both of which can negatively impact brain and cognitive development. 160 During early pregnancy, brain development happens via neurogenesis, neuronal migration, and synaptic pruning, with myelination beginning in the second trimester and continuing throughout life. 161 These processes are highly sensitive to endocrine signaling, and disruption by exogenous chemicals can lead to neurological impairment. 73 The prenatal and early childhood periods are predominantly susceptible to EDCs, as the chemistry between endocrine regulation and brain maturation can affect behavioral development. In another study by Shoaff et al., the consequences of EDC exposure in adolescence on ADHD-related behaviors, 162 were analyzed. It was found that increased exposure to antiandrogenic phthalates was linked with a 34% higher risk of ADHD-related behavior problems. Similarly, dichlorophenol exposure was linked to a 15% increased risk (RR, 1.15; 95% CI, 1.01–1.32). BPA and phthalates, common endocrine-disrupting chemicals found in plastics, have been shown to affect brain structure and function across different developmental stages. Zheng et al. reported reduced brain volumes in the opercular area, higher occipital gyrus, and postcentral gyrus among children exposed to prenatal BPA. 60 Grohs et al. found that elevated BPA exposure was associated with increased mean diffusivity in the splenium and fasciculus. 163 In addition, higher maternal mEP levels were associated with decreased total gray matter volume in children. A meta-analysis investigated the impact of EDC exposure on prenatal neurodevelopment, reviewing 45,373 studies and including 26,005 mother-child pairs. The analysis found that prenatal exposure to EDCs adversely impacts neurobehavioral development, particularly cognition, motor skills, and language acquisition. Exposure to metals was associated with impaired motor development during the first three years. Poly-fluoroalkyl substances (PFAS) were linked to deficits in language development. In a retrospective study conducted in Wuhan, China, involving 285 mother-child pairs, each child’s BMI was measured at age 1 year. Sixteen EDCs were analyzed across the I, II, and III trimesters with the help of liquid chromatography coupled with a triple quadrupole mass spectrometer. The weighted quantile sum (WQS) analysis indicated that urinary concentrations of seven EDCs were strongly correlated with BMIz in the I trimester. Elevated BMIz was associated with 641 differentially methylated DNA positions. EDCs can harm not only the individual who has been exposed, but also future generations. 164 Industrial chemicals have been associated with the global increase in neurodevelopmental disorders such as autism, infant/child depression, and dyslexia. 165 Animal studies have demonstrated that in-utero chemical exposure has causal effects on disease outcomes, potentially passing these effects to subsequent generations via transgenerational epigenetic inheritance. 166 , 167 Maternal exposure to BPA during pregnancy and lactation affects offspring behavior in three ways: anxiety and exploration, learning and memory, and socio-sexual behavior. 166 Perinatal BPA may reduce maternal care behavior in female offspring in mice and rats, demonstrating a transgenerational effect. BPA and other EDCs can disrupt normal steroid programming in the developing rodent brain at very low doses through epigenetic alterations, leading to differential gene expression. 168 Prenatal BPA levels are also linked to embodying behaviors in girls and internalizing behaviors in boys. 169 , 170

Dioxins are persistent organic pollutants that pose significant risks to both human health and the environment. These compounds are primarily generated as byproducts of industrial processes and persist in the environment due to their chemical stability and toxicity. 137 , 138 Research, particularly on 2,3,7,8-TCDD, indicates that concentrations in urban air range from 0.01 to 0.2 pg/m 3 , while soils near contaminated sites may contain up to 200 ng/kg. 138 , 139 The food chain is increasingly exposed to dioxins because they accumulate in adipose tissue. Human exposure occurs primarily through food consumption, including dairy products, meat, fish, and animal fats, according to the World Health Organization. 140 Elevated dioxin levels are associated with carcinogenesis and immunosuppression. 2,3,7,8-TCDD is classified as a Group 1 human carcinogen. 141 , 142 , 143 Dioxins persist in the environment for extended periods and accumulate in soils and sediments, creating prolonged exposure risks for both humans and wildlife. 143 , 144 Recent studies have found that river sediments may contain dioxin concentrations of up to 60 ng/kg, posing a risk to aquatic organisms and to individuals who consume fish from these regions. 143 , 144 Regulatory measures such as the Stockholm Convention have helped to reduce emissions; however, areas with inadequate waste management continue to experience elevated contamination levels. 139 , 145 Advances in detection technologies now make it possible to identify and remediate even trace amounts of dioxins. 146 , 147 Further research is needed to clarify dioxin toxicity, monitor environmental distribution, and inform effective policy development. 148 , 149 , 150 Per- and polyfluoroalkyl substances (PFAS), often called “forever chemicals,” are a large group of synthetic compounds used in many industrial and consumer products because they are highly stable and resist water, oil, and stains. 151 Since their introduction in the 1940s, PFAS have been added to items such as non-stick cookware, waterproof fabrics, firefighting foams, and food packaging, contributing to their widespread presence in the environment. 152 The strong carbon-fluorine bonds in PFAS make them highly persistent in both the environment and living organisms. 151 Studies worldwide have found PFAS contamination in water, soil, air, wildlife, and humans. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), two well-known PFAS, have been measured in groundwater and surface water near industrial sites at levels ranging from a few ng/L to several μg/L. 153 , 154 Tests show that almost 98% of Americans have detectable PFAS in their blood, showing how common exposure. 152 Because PFAS persist and accumulate in living things, they pose serious public health concerns. Studies have linked long-term PFAS exposure to health problems such as immune system effects, liver and thyroid issues, developmental problems, and a higher risk of some cancers. 155 , 156 For instance, a recent study found that children with higher PFAS levels in their blood had more immune-related disorders. 155

N.C.T.: writing – original draft, validation; A.N.: writing – review & editing, visualization, supervision, project administration; C.T.N.: writing – review & editing, supervision.

Human disease and economic damage can result from imprecise or poorly prescribed policies. EDC exposure can be reduced by both individual and government interventions. If these policies are not clearly defined or enforced, EDCs can cause harmful diseases, disability, and economic damage to humans. EDCs can be reduced through policies and interventions implemented at both the individual and governmental level. 204 Health and economic burdens associated with endocrine-disrupting chemicals (EDCs) fall primarily on the public, yet manufacturers are seldom held accountable because of inconsistent or weak regulatory policies. Due to its negative effects on female reproduction, tributyltin (TBT) is banned under the Rotterdam Convention. TBT-based products are still produced in the USA and distributed globally. 205 , 206 Brominated Flame Retardants were required in California until 2015, while they were banned earlier in the EU. This policy divergence contributed to a significant difference in neurocognitive disabilities between the USA and the EU (U.S. $4.5 trillion, 2001–2016) due to their differing policy frameworks. 207 In the U.S., the Food Quality Protection Act (1996) reduced exposure to Organophosphate pesticides, thereby reducing the costs to society. The EU failed to devise analogous policies, emphasizing the need for regulation. 208 It has been established that class-action lawsuits can hold manufacturers responsible for contaminating water with perfluorooctanoic acid (PFOA), as seen in the Baker v. Saint-Gobain case in New York (case no. 1:16-cv-0917). EDC exposures often involve numerous sources and products, and responsibility lies with multiple suppliers rather than a single manufacturer. Thus, the framed regulatory compliance should cover a wide range of industries. 209 Regulations constraining bisphenol-A and phthalates have led to quantifiable reductions in urinary chemical levels. 210 Regulatory approaches are more effective, resulting in faster, more significant reductions in human exposure. About 10 million U.S. dollars have been invested in high-throughput screening programs such as ToxCast and Tox21, creating widespread data on the destructive chemicals investigated by means of various techniques. Despite their limitations (discussed elsewhere), these programs place significant emphasis on the potential for chemical characterization. 211 , 212 Owing to the adverse effects of disrupting chemicals on humans and wildlife, substantial economic losses occur worldwide ( Table 5 ). The economic losses from exposure to disruptive chemicals across diverse life stages and regions, including the U.S, Canada, and the EU, have been widely studied. Human epidemiological studies have linked higher EDC exposure with lower IQ, increased neurodevelopmental problems, and other cognitive or brain-related outcomes. Because most studies are observational, these findings indicate associations rather than confirmed causation. 10 A study conducted in the USA found that prenatal exposure to PBDEs led to IQ loss and intellectual disability, resulting in costs of 266 billion dollars in the US, 11.4 billion dollars in Canada, and 12.6 billion dollars in Europe. The damage to IQ points and intellectual incapacity caused by prenatal exposure to organophosphates cost the United States 44.7 billion, Canada 4.2 billion, and the European Union 194.0 billion EU. 213 , 214 , 215 Table 5 Economic losses due to EDCs effect on humans at different stages of life in the USA, CANADA, and EUROPE 204 , 207 , 213 , 214 , 215 Stage of life Outcome EDCs USA Canada EU Prenatal loss of IQ points and intellectual disability PBDEs 266 billion 11.4 billion 12.6 billion Prenatal cryptorchism PBDEs 35.7 million 7.3 million 172.6 million Prenatal loss of IQ points and intellectual disability organophosphates 44.7 billion 4.2 billion 194.0 billion Prenatal obesity DDE 29.6 million 2.5 million 32.7 million Adulthood (female) fibroids DDE 259.0 million 4.2 million 216.8 million Prenatal type 2 diabetes mellitus DDE 1.8 billion 385.2 million 1.1 billion Adulthood obesity DEHP 1.7 billion 684.8 million 20.8 billion Adulthood type 2 diabetes mellitus DEHP 91.4 million 25.8 million 807.2 million Adulthood (female) endometriosis DEHP 47.0 billion 5.7 billion 1.7 billion Prenatal childhood obesity BPA 2.4 billion 59 million 2.0 billion Adulthood (male) male infertility phthalates 2.5 billion 17.0 million 6.3 billion Economic losses due to EDCs effect on humans at different stages of life in the USA, CANADA, and EUROPE 204 , 207 , 213 , 214 , 215

The most commonly used evaluation methods are static batch adsorption, dynamic adsorption, and reusability. This method uses adsorbents dispersed in non-flowing water samples to determine equilibrium times, initial adsorption rates, and maximum adsorption capacities ( Figure 6 ). Adsorbents based on MOFs that are separable can be evaluated by dynamic adsorption. Water is purified using dynamic adsorption when it passes through fixed adsorbents. This method is more practical than static adsorption for practical water treatment. Figure 6 Dispersion of MOFs in static water for the adsorption of EDCs involving different factors MOFs are dispersed in contaminated static water under controlled mixing conditions to facilitate the adsorption of target pollutants. The experiment enables determination of the equilibrium time, the initial adsorption rate, and the maximum adsorption capacity (Qmax). Static batch adsorption studies are widely used to assess the efficiency and kinetics of MOF-based adsorbents for the removal of endocrine-disrupting chemicals (EDCs). Dispersion of MOFs in static water for the adsorption of EDCs involving different factors MOFs are dispersed in contaminated static water under controlled mixing conditions to facilitate the adsorption of target pollutants. The experiment enables determination of the equilibrium time, the initial adsorption rate, and the maximum adsorption capacity (Qmax). Static batch adsorption studies are widely used to assess the efficiency and kinetics of MOF-based adsorbents for the removal of endocrine-disrupting chemicals (EDCs). The adsorbent flow continuously through the water samples until the saturation level has been reached. Using breakthrough curves, it is possible to determine adsorption capacity and breakthrough volume in a practical evaluation of adsorbents. The dynamic adsorption method has been employed to evaluate a number of MOF composites, including MOF/fiber composites 241 and MOF hydrogel beads 242 ( Figure 7 ). It is important to explore the regeneration performance of these separable MOF-based adsorbents in order to improve their recyclability. In a recent study, the PCN-250(Fe2Mn) MOFs were employed as an active sorbent, later integrated with cobalt ferrite (CoFe 2 O 4 ) magnetic NPs to enhance magnetic properties without requiring complex composites. Under optimized conditions, this method demonstrated good linearity, enrichment factors in the range from 9 to 125, and low limits of detection. Excellent intra- and inter-day accuracy was achieved, with relative standard deviations lower than 15%. In direct urine investigation, matrix effects were originally detected but were insignificant following a 1:5 (v/v) dilution. The approach was magnificently applied to three urine samples, yielding comparative recoveries of 82%–118%. 243 Figure 7 Dynamic adsorption method with fixed bed/flow through system for the treatment of EDCs from water EDC-containing water flows through a fixed-bed adsorption column packed with MOF-based adsorbents, including MOF hydrogel beads, MOF fiber composites, and MOF carbon beads. As water passes through the adsorbent layer, EDC molecules are selectively captured by the MOF materials. The treated effluent exiting the column contains lower levels of EDC contaminants, demonstrating the potential of MOF-based flow-through systems for wastewater purification. Dynamic adsorption method with fixed bed/flow through system for the treatment of EDCs from water EDC-containing water flows through a fixed-bed adsorption column packed with MOF-based adsorbents, including MOF hydrogel beads, MOF fiber composites, and MOF carbon beads. As water passes through the adsorbent layer, EDC molecules are selectively captured by the MOF materials. The treated effluent exiting the column contains lower levels of EDC contaminants, demonstrating the potential of MOF-based flow-through systems for wastewater purification. In another study, magnetic and multi-shelled MOFs were synthesized to remove a small quantity of bisphenols/benzophenones from water. By adopting a solvothermal reaction, a ZIF-67@ZIF-8-based cobalt/zinc-magnetic hierarchical carbon material was prepared using sodium citrate, followed by carbonization, and was used as an adsorbent in high-performance magnetic solid-phase extraction. This material demonstrated an excellent specific surface area and saturation magnetization. Excellent resistance to matrix interference in water samples was achieved, in the range of 74.8%–107% along with target materials. 244 University of Oslo-66-carbon, a carbon-based MOF was developed via a solvothermal process and employed as an adsorbent to enhance the removal of endocrine-disrupting chemicals with low LODs. Accuracy was assessed by means of intra- and inter-day relative standard deviations with values ranging from 1.5% to 10.6% and 6.1%–13.2%, respectively. The application to tap and surface water detection showed spiked recoveries of 77.1%–116.6%, with minimum amounts of nonylphenol noticed in water at low concentrations. 245 A new organic cage compound, Fe 3 O 4 -COOH@CC 3 R-OH, was developed as a highly effective and eco-friendly adsorbent for EDC elimination. With a four-coordinated, shell-like morphology, the material exhibited a high surface area of 94.02 m 2 /g with a pore size of 1.14 nm. The MSPE-HPLC-MS/MS technique demonstrated high sensitivity and accuracy for quantifiable EDC recognition in water trials. 246 Calcium-based MOFS will also have a strong adsorption capacity toward disrupting chemicals. Based on various parameters such as concentration, flow rate, and pollutant removal rate, the adsorption ability of the substances was arranged in the order 17-ethynylestradiol > bisphenol A > perfluorooctanoic acid. Among the proposed models, the Yan model performs best. This study highlights the role of Ca-MOF in water remediation, noting its higher stability and activity. 247 Overall, MOFs show strong potential for removing EDCs from water, and combining technological progress with effective policy regulation could help better protect ecosystems.

At present, the ecosystem is polluted with disruptive chemicals such as dichlorodiphenyltrichloroethane (DDT), bisphenol A (BPA), and phthalates generated from common plastic materials, packaging supplies, and toys ( Figure 2 ). Furniture and flooring treated with flame retardants also contribute significantly to exposure. 57 Numerous EDCs have been identified; many potential EDCs remain unexamined, raising further concerns. Chemicals leach into soil and water, creating hotspots of EDC contamination, especially in highly industrialized areas. 58 The bioaccumulation of EDCs occurs throughout the food chain, starting with absorption by microorganisms, plants, and smaller animals, gradually concentrating in larger predators, including humans. Several endocrine-related disorders are associated with such bioaccumulation, such as cryptorchidism, testicular cancer, early female puberty, leukemia, and neurobehavioral disorders. 59 Since the 1970s, plastic production has increased dramatically, from 50–300 million tons per day, and chemical sales have increased from $171 billion in 1970 to over $4 trillion in 2013, indicating that EDC exposure is also increasing. Different studies conducted in several countries on the effects of EDC exposure on the human brain are presented in Table 3 . Figure 2 EDC sources include food production systems, medical products, industrial activities, and personal/home care products Major contaminants include pesticides, bisphenols, phthalates, PFASs, pharmaceuticals, PAHs, PCBs, dioxins, parabens, triclosan, and flame retardants. These pollutants can enter water, soil, air, and food chains, increasing risks to human health and ecosystems. Table 3 Effect of different EDCs on the human brain Continent/Country Exposure to EDCs Imaging method Outcome of the study Reference North America- Canada BPA MRI BPA exposure was associated with changes in brain volume in several regions. Some areas involved in language, vision, and movement showed reduced volume, while parts of the limbic system, including the hippocampus, amygdala, and entorhinal area, showed increased volume. Zheng.et al. 60 Europe-Netherlands phthalates MRI higher phthalate exposure was associated with lower total gray matter volume. Reduced gray matter volume partly explained the association between phthalate exposure and lower child intelligence scores. Ghassabian.et al. 61 North America-Canada phthalates DTI-MRI phthalate exposure was linked to changes in white matter structure. These changes were observed in brain pathways involved in vision, emotion, behavior, and cognitive processing. Some white matter changes were also related to internalizing and externalizing behavioral problems. England-Mason.et al. 62 Asia-Taiwan phthalates fMRI phthalate exposure was associated with reduced brain volume and reduced white matter integrity in several regions, including the cingulate cortex, cerebellum, corpus callosum, corona radiata, and superior frontal lobes. These brain changes were linked with lower neurodevelopmental scores. Shen.et al. 63 Asia-Taiwan phthalates rs-fMRI/mfALFF/ReHo phthalate exposure was associated with reduced brain activity in the right superior frontal gyrus and right middle frontal gyrus. These regions are important for attention, working memory, and executive function. Weng.et al. 64 Europe-Netherlands OP DTI organophosphate exposure was associated with altered white matter structure. Reduced fractional anisotropy and increased mean diffusivity were found in several brain tracts involved in motor control, attention, emotion, and communication between brain regions. van den Dries.et al. 65 Europe-France DAP, DM, DE fMRI exposure was associated with changes in brain activity during response-inhibition tasks. Children showed lower activity in frontal brain regions during successful inhibition, which may indicate more efficient or altered neural processing. Binter.et al. 66 North America-USA DAP fMRI DAP exposure was associated with increased activity in brain regions involved in cognitive control and flexible thinking, especially the left inferior frontal and inferior parietal lobes. Sagiv.et al. 67 North America-USA PAH MRI PAH exposure was linked to behavioral and brain-function changes. Increased shyness was related to more internalizing problems, and children showed increased activity in the left anterior cingulate cortex during cognitive conflict tasks. Liu.et al. 68 Europe-Netherlands PAH MRI PAH exposure was associated with changes in brain structure. In children carrying the APOE ε4 allele, PAH exposure was linked to increased white matter volume. Other pollutant exposures were associated with reduced subcortical gray matter volume. The subcortical gray matter of Cu, Fe, Si, and Zn decreased in adults with higher versus lower polygenic risk scores (PRS) for Alzheimer’s disease (AD) during prenatal exposure. In childhood, higher PRS for AD resulted in decreased subcortical gray matter for Cu and Si, while Cu exposure also reduced corpus callosum volume. Essers.et al. 69 North America-USA PAH MRI/DTI PAH exposure was associated with altered brain structure and function. Children showed changes in cortical thickness, smaller and less organized white matter in some regions, altered brain metabolites, reduced cortical blood flow, and changes in subcortical gray matter organization. Peterson.et al. 70 North America-Canada PAH MRI prenatal PAH exposure modified the relationship between maternal stress and child hippocampal volume. Smaller right hippocampal subregions were associated with lower performance IQ. Margolis.et al. 71 Europe-Netherlands PAH MRI, DTI, fMRI PAH exposure was associated with reduced hippocampal volume. Guxens.et al. 72 Europe-Netherlands PAH MRI multipollutant analysis showed that PAH exposure was associated with reduced volume in subcortical brain regions, including the hippocampus and amygdala. Cajachagua-Torres.et al. 73 North America-Canada PCB DTI PCB exposure was associated with increased fractional anisotropy in several parts of the corpus callosum, especially the splenium. This suggests altered white matter development. Migneron-Foisy.et al. 74 North America-Canada PCBE fMRI higher cord-blood PCBE exposure was associated with increased activity in the right orbitofrontal cortex during a conditioning task. Lamoureux-Tremblay.et al. 75 North America-USA DDT, DDE fNIRS DDT/DDE exposure was associated with increased cortical activity in brain regions involved in social cognition and working memory, including the right temporal cortex and right superior parietal lobe. Binter.et al. 76 Asia-Taiwan Lead MRI lead exposure was associated with reduced frontal lobe volume and reduced calcarine cortex volume. Shen.et al. 63 North America-Canada Lead DTI no clear association was found between lead exposure and fractional anisotropy or fiber tract density in the studied white matter tracts. Migneron-Foisy.et al. 74 North America-Canada Lead fMRI higher prenatal or postnatal lead exposure was associated with increased activation in the right dorsolateral prefrontal cortex compared with moderate or low exposure. Lamoureux-Tremblay.et al. 75 North America-Canada Hg DTI mercury exposure was associated with increased fractional anisotropy in parts of the corpus callosum, including the posterior midbody, isthmus, and splenium. Migneron-Foisy.et al. 74 Asia-Taiwan Hg fMRI mercury exposure was associated with reduced volume in the frontal lobe, temporal lobe, corpus callosum, and hippocampus. Shen.et al. 63 Europe-Netherlands Cu, Si, Zn MRI, DTI, fMRI copper and silicon exposure were associated with increased global mean diffusivity, suggesting altered brain microstructure. Zinc exposure was associated with increased cortical surface area in regions involved in motor function, visual processing, and spatial cognition. Guxens.et al. 72 EDC sources include food production systems, medical products, industrial activities, and personal/home care products Major contaminants include pesticides, bisphenols, phthalates, PFASs, pharmaceuticals, PAHs, PCBs, dioxins, parabens, triclosan, and flame retardants. These pollutants can enter water, soil, air, and food chains, increasing risks to human health and ecosystems. Effect of different EDCs on the human brain The link between phthalate exposure and changes in gray matter and then to IQ is not complete. In the Generation R study, Ghassabian and colleagues. 61 measured phthalate levels in pregnant mothers, scanned their children’s brains at age 10, and tested their IQ at 14. They found that higher levels of monoethyl phthalate (mEP) in mothers were linked to smaller total gray matter volume in their children ( β = −10.7 per log10 increase in creatinine-adjusted mEP; 95% CI: −18.12, −3.28). Gray matter volume explained part of the connection between mEP and IQ. However, the mediated effect was β = −0.31 (95% CI: −0.62, 0.01; p = 0.05), so gray matter volume explained only 18% of the association. Gray matter volume is a real but partial mediator, and about 80% of the link between exposure and IQ is not explained by changes in brain volume, with the confidence interval almost including zero. Therefore, loss of brain volume should be seen more as a sign of developmental problems rather than the direct cause. 61 Mechanisms that happen at a smaller scale than what structural MRI can detect are probably responsible for most of the unexplained effects, and the thyroid is the strongest candidate. 77 , 78 Phthalate-related thyroid disruption can last long after exposure ends. 79 For example, Sousa-Vidal and colleagues gave pregnant Wistar rats di(2-ethylhexyl) phthalate at two different doses during pregnancy and found changes in the hypothalamic-pituitary-thyroid axis in the offspring even at postnatal day 90 45 . This matters because thyroid hormone is needed for oligodendrocyte development and myelin gene expression, so thyroid problems during pregnancy are more likely to cause issues with myelination than with neuron loss. 80 Since BDNF-TrkB signaling supports both myelination and synaptic function, 81 a thyroid-related block in oligodendrocyte development and a problem with synaptic plasticity are not separate, but two parts of the same problem. This kind of failure would slow nerve conduction and reduce network efficiency but would not greatly affect overall brain volume. This matches what the Generation R mediation analysis found. Imaging suggests this type of mechanism, but cannot prove it. To test it, researchers need to use diffusion and myelin-water imaging along with thyroid-axis biomarkers, instead of only looking at brain volume. 81 Many EDCs have been detected in human serum, adipose tissue, and umbilical cord blood, including polychlorinated biphenyls (PCBs), BPAs, and phthalates. People living near petrochemical industries or those involved in manufacturing, distributing, and disposing of petrochemical products are disproportionately exposed to EDCs. 9 , 82 The improper disposal of petrochemical products leads to further contamination of soil, water, and crops. 3 , 10 , 83 Agronomic practices, packaging, and processing are common routes by which EDCs enter the food supply. 9 , 82 They are commonly present in personal care products and cleaning products, such as perfluoroalkyl substances (PFAS), parabens, and triclosan, sometimes concealed under the term “fragrance”. 10 PFAS is also found in nonstick cookware, water-resistant clothes, and food packages. PFAS are a large group of human-made chemicals comprising around 15,000 compounds. As well as reducing fetal growth and contributing to metabolic disorders, these substances have been associated with increased cancer rates and thyroid dysfunction. 3 , 9 , 11 , 22 Phthalates have a significant impact on reproductive health and metabolism due to their antiandrogenic properties. 9 , 84 BPA, one of the most common bisphenols in plastic containers and thermal receipts, disrupts endocrine function. While BPA has been restricted, 10 , 12 , 85 substances such as bisphenol S and bisphenol F continue to pose similar risks. BPA is a canonical example of regrettable substitution; hundreds of bisphenols are used with similar or even more harmful effects. 86 Humans are exposed to EDCs through inhalation, ingestion, and dermal absorption from indoor dust, air, and water sources. 87 Different concentrations (ng/L to low-μg/L) of EDCs have been commonly reported in surface waters in Serbia, Mexico, China, coastal China, and Canada, with concentrations below 1 μg/L. These locations were contaminated with E2 and EE2 compounds, which pose significant ecological and estrogenic risks. 88 , 89 , 90 , 91 In other parts of the globe, such as Lahore wastewater, median E3 levels reached 1310 ng/L; in Slovenia, endocrine disruptors reached 35 μg/L in wastewater; and western Kenyan WWTP influents contained steroid hormones up to 670 ng/L. Treated effluents did not always eliminate risk, as Slovenian surface waters reached 400 ng/L for some EDs, and Kenyan WWTP effluents contained steroid medians up to 270 ng/L. 92 , 93 The India multi-matrix study reported extremely high DEHP means of 2706.135 μg/L in river water, 3203.33 μg/L in groundwater and 1005.490 ng/g in agricultural soils, while the Ganga/Sundarban study reported Σ7 plasticizers up to 7.63 μg/L in river water. 94 , 95 In the South China Sea reserve study, cumulative EDCs reached 411.89 ng/g dry weight in surface sediment, while the Indian agricultural soil dataset reported DEHP at 1005.490 ng/g. 94 , 96 EDCs not only act as nonspecific environmental stressors; many perturb discrete endocrine and neuroendocrine nodes that map onto disease phenotypes. Bisphenols, including BPA and several BPA substitutes, activate ERα-dependent transcriptional programs in ERα-positive human cell models, with BPAF often showing greater potency than BPA and bisphenol mixtures showing additive ERα activity. 97 , 98 These findings provide a mechanistic basis for estrogen-sensitive developmental and reproductive outcomes, although ERα-rich cancer-cell models should be interpreted as hazard-identification systems rather than direct human disease models. 97 , 98 In adipocyte-relevant and metabolic models, some bisphenols and phthalate/plasticizer substitutes or additives can interact with PPARγ, which is a master regulator of adipogenesis, and promote the accumulation of lipids, secretion of leptin/adipsin, oxidative stress, dysregulation of adipokines, and impaired metabolic homeostasis. 99 , 100 In male reproductive toxicity, some DEHP/MEHP have stronger mechanistic support, such as MEHP, which suppresses Leydig-cell testosterone synthesis via oxidative stress and inhibits the cAMP/PKA/SF-1/StAR pathway by downstream reduction of steroidogenic proteins (StAR, P450scc, and 3β-HSD). 101 Exposure to prenatal DEHP in mice produces persistent reductions in testosterone, semen quality, and steroidogenic gene expression, particularly Hsd3b2 and Hsd17b3, supporting an adverse-outcome pathway from fetal steroidogenic disruption to later reproductive impairment. 102 In cases of ADHD and neurodevelopmental disorders in babies or neonates, the BPA-related mechanisms can alter glucuronidation capacity and trafficking of dopamine transporter, while the epidemiologic evidence is very inconsistent. Therefore, ADHD can be considered biologically plausible and not a definitive causal endpoint. 103 , 104 , 105 The mechanisms by which EDCs act in the body are complex because endogenous hormones are not natural ligands and do not interact with hormone receptors with the same specificity and affinity. Nevertheless, EDCs interfere with those endogenous systems. 10 EDCs disrupt endocrine functioning by multiple interconnected mechanisms, such as when synthetic or environmental chemicals bind to receptors that are regulated by endogenous hormones. This enzyme activation is associated with altered sexual development, infertility, reproductive tract cancers, prostate cancer, and thyroid-related transcriptional changes, which are due to some EDCs such as DDT and certain polychlorinated biphenyls (PCBs). 106 , 107 , 108 Also, EDCs can block the normal function of hormones by acting as receptor antagonists. Androgen receptor signaling is inhibited by dichlorodiphenylethylene, lindane, and dieldrin. These are compounds that interfere with fetal masculinization and cause genital tract abnormalities. 109 Hormone sensitivity is altered by changes in receptor expression, internalization, or degradation in cases of di(2-ethylhexyl) phthalate, bisphenol A (BPA), and DDT in reproductive, neural, and thyroid systems. 110 The binding of hormones to their receptors may disrupt intracellular signaling pathways in hormone-responsive cells. The disruptions affect calcium signaling, insulin signaling, G protein-coupled receptor (GPCR) activity, nuclear receptor signaling, and steroid receptor co-regulators. A number of xenoestrogens are known to cause such effects, including BPA, UV-filter chemicals, tolylfluanid, methoxyacetic acid, diethylstilbestrol (DES), PCBs, octylphenol, and similar compounds. 111 , 112 , 113 , 114 It has been shown that pesticides, phthalates, PCBs, BPA, and DES can alter DNA methylation, histone modifications, microRNAs, and long non-coding RNAs, resulting in altered expression of hormone receptors or hormone-responsive genes, 115 , 116 , 117 for long-term effects on the endocrine system. Perchlorate inhibitors decrease thyroid hormone production, phthalates suppress testosterone synthesis, and atrazine or certain neonicotinoids increase estrogen synthesis via aromatase-related pathways. 109 In addition, chemicals such as BPA, imidazoline, and dichlorodiphenyldichloroethylene may disrupt hormone transport across cell membranes. 109 Circulating hormone levels and tissue bioavailability may be altered by changes in serum binding or distribution, as observed with BPA, malathion, and DES effects on testosterone, estrogen, and sex hormone-binding globulin. 109 Hormone metabolism and clearance may be modified when glucuronidation or sulfation pathways are affected by PCB metabolites, hexachlorobenzene metabolites, and chlorophenolic preservatives. Finally, the fate of hormone-producing or hormone-responsive cells may be redirected, as proliferation, differentiation, migration, apoptosis, and tissue organization can be altered by PCBs, oxybenzone, triclosan, and tebuconazole in neural, mammary, endometrial, placental, and reproductive tissues. 109

Accurate detection and quantification of endocrine-disrupting chemicals (EDCs) are essential for effective environmental and human health monitoring. This task is complicated by the chemical diversity of EDCs, their broad range of physicochemical properties, and their frequent occurrence at trace levels in complex matrices. 171 , 172 No single analytical method can comprehensively detect all EDCs, so both targeted and non-targeted approaches are used. The main techniques for EDC quantification are liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS) ( Table 4 ). High-resolution mass spectrometry (HRMS) is increasingly used for broad screening and for identifying previously unrecognized EDCs. 171 Biomonitoring typically relies on blood, serum, and urine, although other matrices such as breast milk, saliva, dried blood spots, water, and solids are also analyzed to capture a wider range of exposure pathways. 172 , 189 LC-MS/MS is preferred for targeted analysis because of its sensitivity, selectivity, and ability to quantify multiple EDCs at once, including bisphenols, parabens, phthalate metabolites, and per- and polyfluoroalkyl substances (PFAS). 172 , 190 For example, one solid-phase extraction (SPE)-LC-MS/MS method was developed to detect 59 EDCs in amniotic fluid using only 500 μL of sample, with low detection limits that allowed prenatal exposure to be assessed at trace levels. 190 Overall, LC-MS/MS remains a key tool for multiplexed EDC measurement in biological matrices. 171 High-throughput methods such as ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) are increasingly adopted for large-scale studies, especially in urine, water, and environmental samples. 191 , 192 , 193 GC-MS/MS continues to be valuable for the analysis of volatile, hydrophobic, or labile EDCs and is often used in conjunction with LC-MS/MS to cover a broader spectrum of chemical classes. 171 , 172 Table 4 Different types of EDC, sources of EDC, detection and quantification methods, and disease caused by EDCs EDC category Sample source Detection and quantification Disease linkage/Health impact Key Reference(s) Bisphenol A (BPA) water, dairy, human placenta, saliva GC-MS, HPLC-MS/MS, Emerging: Tyrosinase-based electrochemical biosensors. reduced egg viability, metabolic disorders, and breast cancer progression (ER pathway). Kiejza.et al. 173 ; Luis-Sunga.et al. 174 ; De Nys.et al. 175 Phthalates food packaging, PVC, human saliva/urine GC-MS; Electrochemical impedance platforms (LOD: 4.5 \times 10 9 M). interference with androgen production is linked to male reproductive developmental issues. Aydın.et al. 176 ; Aydın.et al. 177 ; Jafari.et al. 178 PFAS (“Forever Chemicals”) drinking water, consumer coatings LC-MS/MS; Advanced Fluorine-NMR. weakened bone density in teens, immune deficiencies, and potential kidney/testicular cancers. Camdzic.et al. 179 ; Gauthier.et al. 180 ; Faber.et al. 181 Atrazine (Herbicide) ground water, surface runoff electrospun SnO 2 nanofiber platforms; Silver nanoparticle (AgNP) sensors. disruption of the hypothalamic-pituitary-gonadal axis; potential link to TGCC. Hernández-Del Castillo.et al. 182 ; Farwa.et al. 183 Polychlorinated Biphenyls (PCBs) household dust, Indoor air, Soil high-Res GC-MS; Microbial sensing approaches. strongest association with neurological disorders and cognitive decline in children. Ren.et al. 184 ; da Costa Filho.et al. 185 ; Lin.et al. 186 Perchlorate aquatic ecosystems, tap water carbon nanotube solid-contact ISEs (LOD: 1.8\times 10 –7 M). thyroid hormone disruption; cognitive impairment during fetal development. Hassan.et al. 187 ; Itterheimová.et al. 188 Different types of EDC, sources of EDC, detection and quantification methods, and disease caused by EDCs High-resolution mass spectrometry (HRMS) is increasingly utilized for suspect screening and non-targeted analysis, thereby expanding the detection of unknown and emerging EDCs. Recent workflows have demonstrated the application of HRMS to urine and follicular fluid samples. 171 , 194 , 195 Electrochemical biosensors are being developed as rapid and cost-effective alternatives for water monitoring; however, chromatography-mass spectrometry remains the primary method for accurate quantification and regulatory compliance. 196 Sample preparation is a crucial step in EDC analysis. Solid-phase extraction (SPE) is widely used to concentrate and clean up both environmental and biological samples before LC-MS/MS analysis. 192 , 197 QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) methods have also made EDC extraction simpler, as shown in recent work on human urine, where they reduced matrix interference and improved sensitivity. 198 , 199 Magnetic solid-phase extraction (MSPE) is another effective approach, using magnetic materials such as C18-coated nanoparticles to extract EDCs from complex matrices such as water and beverages. 200 , 201 Water remains the most commonly analyzed matrix for EDCs, while urine is often used to detect short-lived metabolites and serum to measure more persistent compounds. Human milk and environmental solids are also being studied more often to assess exposure in mothers and infants and to track long-term contamination. 171 , 189 , 202 , 203 Optimal EDC analysis requires selecting appropriate analytical techniques and sample preparation protocols based on the chemical characteristics of the target analytes and the sample matrix. SPE, QuEChERS, and MSPE are essential for achieving reliable measurements. 196 , 198 , 200 Further development of AI-based quantification and analytical techniques will help with faster detection in the future.

Bisphenols (4,4 -isopropylidenediphenol 2,2-bis (4-hydroxy-phenyl)- propane), a benzene-related compound with two -OH groups at the para position allowing them to attach to androgen and estrogen receptors as either an antagonist or agonist. 128 BPA is also termed a xenoestrogen due to its analogy with diethylstilbestrol and increases the ER with lower affinity than 17β-estradiol. 129 , 130 BPA is used in the manufacturing of polycarbonate plastics, aluminum cans, and numerous consumer goods such as receipt paper. Plastics are hardened using BPA. BPA, along with polycarbonate plastics, is used in various consumer products such as baby bottles, and epoxy resins are used to line aluminum food cans. Health experts from Europe are now concerned about BPA’s impact on human health. Nevertheless, BPA is not completely banned in some countries, including the United States. The rules and regulations for banning BPA vary across countries, including Canada, the United States, and the European Union (EU). A European Union expert committee supported a proposal by the European Commission to ban certain bisphenols from food contact materials by 2024. However, on a global scale, BPA and most other plastic-related chemicals remain inadequately regulated or not entirely regulated, posing significant risks to human health. People are most likely exposed to BPA because of their diet. BPA is not only found in food and beverages, but exposure can also occur through contaminated air, dust, and water, further increasing overall exposure. Bisphenol A can also leach from polycarbonate tableware, containers, and bottles, in addition to epoxy resin coatings on canned foods, and can create more consequences from the liquid’s temperature than from its age. In 2003–2004, 93% of 2517 urine samples collected from elderly people were found to have a noticeable amount of BPA. The National Health and Nutrition Examination Survey results clearly represent exposure to these chemicals in countries such as the U.S. In animals, BPA has been found to affect fetuses and newborns, another cause for concern, especially for parents. There is a correlation between BPA levels and obesity in both animals and humans. In addition to disrupting metabolic function, it causes insulin resistance, dyslipidemia, and elevated leptin levels. It has been reported that both children and adults with obesity have elevated urinary BPA levels, and young girls with high BPA levels are at an increased risk of obesity. 131 , 132 BPA causes serious problems in pregnant women, as shown in Figure 3 . Figure 3 Effect of Bisphenols on pregnant women and fetus Bisphenols can disrupt placental structure and function by altering endocrine signaling, hormone secretion, trophoblast activity, and cellular integrity. These disruptions are associated with pregnancy complications, including preeclampsia, gestational diabetes, preterm birth, fetal growth restriction, and low birth weight. Bisphenol exposure may also contribute to broader maternal and fetal health effects, including impaired vascular remodeling, reduced blood supply, and teratogenic outcomes. Effect of Bisphenols on pregnant women and fetus Bisphenols can disrupt placental structure and function by altering endocrine signaling, hormone secretion, trophoblast activity, and cellular integrity. These disruptions are associated with pregnancy complications, including preeclampsia, gestational diabetes, preterm birth, fetal growth restriction, and low birth weight. Bisphenol exposure may also contribute to broader maternal and fetal health effects, including impaired vascular remodeling, reduced blood supply, and teratogenic outcomes. The significant impact of obesity includes its role in triggering early puberty. BPA increases obesity by disrupting metabolism and endocrine balance; care should be taken to minimize BPA exposure in young girls. 133 A comparison of European and Chinese studies found higher levels of BPA than in the U.S. 134 , 135 As an alternative to BPA, BPS has been detected in 85% of “BPA-free” products. 126 Since BPS is used in materials marketed as safer, children in eco-friendly kindergartens were exposed to higher levels of this chemical. Despite its restrictions, BPS and BPF have long-term effects comparable to those of BPA. 136 Since BPA levels exceed the revised EFSA tolerable daily intake, immediate risk mitigation measures are necessary.

Phthalates are chemical compounds derived from phthalic acid. One or more carboxylic groups are directly attached to the benzene ring at varied positions, along with alkyl groups, which results in the formation of substituted phthalates of different reactivity. Phthalates are common EDCs, used for making plastic more durable and pliable; they are also used as fragrance stabilizers in perfumes and cosmetic products. 118 In a study by Iman Al-Saleh and Rola Elkhatib, 47/47 fragrances tested had detectable phthalates at levels above EU regulatory guidelines (demonstrating issues with industry compliance). 119 Parabens and triclosan are used as anti-microbials to increase the shelf-life of products, not for fragrance stability specifically. Generally, phthalates are used as plasticizers in the large-scale production of PVC and allied products. 120 , 121 Because phthalates possess a range of beneficial properties, they are used in a variety of polymer additives to enhance flexibility, compatibility, durability, insolubility, transparency, electrical resistance, and resistance to heat and weather, among others. As plasticizers, they are mainly used for flexible PVC products, cosmetics, children’s products, pharmaceutical devices, adhesives and sealants, building materials, coatings, and food packaging. 120 , 121 In addition to ortho -phthalates, dibutyl phthalates, diisobutyl phthalates, diisononyl phthalates, and di(2-ethylhexyl) phthalates also fall under this category. 122 Chemicals such as phthalates can inhibit testosterone production in the male fetus. They can also cause infertility, reduce the sperm count, and decrease the ovarian reserve in males and females. 118 , 123 Phthalates also increase the risk of metabolic conditions such as diabetes and insulin resistance in humans. 124 , 125 Phthalates were detected in over 70% of urine samples from Korean preschool children, indicating widespread exposure. Children’s eating habits, compared with their body weight, and their contact with plastic products were associated with higher levels of DEHP metabolites (Mapp and mCMHP). 126 The presence of low molecular weight phthalates, such as mEP and mBP, has also been detected in toys, food packaging, and personal care products. 127 In Korean children, LMW phthalates were found at higher levels compared to DEHP metabolites, indicating distinct exposure patterns compared to other countries. Children attending eco-friendly kindergartens exhibited minimal DEHP levels but higher LMW phthalates, suggesting different environmental sources. 126

EDCs such as bisphenols, phthalates, per- and polyfluoroalkyl substances, pesticides, and steroidal hormones are major environmental and public health concerns because they can interfere with estrogenic, androgenic, thyroid, metabolic, reproductive, and neurodevelopmental processes. Their effects also depend on dose, timing of exposure, immune and endocrine status, and whether the chemical persists or accumulates in the body. Another concern is “regrettable substitution,” where restricted compounds such as bisphenol A (BPA) are replaced by similar alternatives such as bisphenol S (BPS) or bisphenol F (BPF) that may pose comparable endocrine risks. For that reason, EDC regulation should move beyond single-compound control and take a broader class-based approach, supported by continuous biomonitoring and early evaluation of substitute chemicals. MOFs are a promising option for EDC remediation because they combine high porosity, adjustable pore size, large surface area, and adsorption sites that can be chemically tailored. Future research should focus on MOFs that are water-stable, affordable, regenerable, and non-toxic, while still being able to remove a wide range of EDCs under realistic wastewater conditions. That includes dealing with changing pH, natural organic matter, competing pollutants, and different ionic strengths. The main challenges are scaling up green synthesis, maintaining long-term structural stability, preventing metal or linker leaching, improving regeneration, proving cost-effectiveness, and testing the materials in pilot-scale continuous-flow systems. From a policy perspective, MOF-based treatment should complement upstream chemical management rather than replace it. Progress will depend on closer collaboration among researchers, industry, wastewater authorities, and regulators to establish standard testing methods, assess life cycle impacts, evaluate the toxicity of spent MOFs, and define clear regulatory criteria. Together, source reduction, safer substitution, better monitoring, and advanced materials such as MOFs offer a more complete strategy for reducing EDC exposure and protecting human and aquatic health.

During the preparation of this manuscript, the authors used generative AI tools to assist with improving the language, readability, and clarity of the text originally written by the authors. All AI-generated suggestions were carefully reviewed and edited by the authors. The authors take full responsibility for the content of this publication.

To properly assess MOFs, it is important to compare them directly with the technologies they are meant to replace. Most current removal methods have specific shortcomings, rather than being generally ineffective. For instance, activated carbon is not always outperformed by MOFs: Azmi et al. 235 found that MOFs have less reactivity than activated carbon for 2-chlorophenol. MOFs are less effective when the contaminant is small or not very aromatic, because π-π stacking and pore-shape selectivity are less important for small or highly polar substances. 248 Membrane filtration can remove EDCs, but it only concentrates them in a separate stream instead of destroying them. 249 Chlorination can actually make things worse for bisphenols, since chlorinated BPA forms quickly and can be even more estrogenic than the original compound. 250 Conventionally activated sludge mainly removes hydrophobic EDCs by adsorbing them onto biosolids, which merely shifts the contamination rather than solving the problem. 251 Therefore, the benefits of MOFs are more limited than often claimed: they provide better capacity and selectivity for bulky aromatic EDCs at low concentrations, but serve a specific purpose rather than replacing current methods entirely. A key measurement issue in MOF research is often overlooked, which makes it difficult to compare studies. Osterrieth et al. 252 gave eighteen pre-measured adsorption isotherms to 61 labs working with porous materials and asked them to calculate Brunauer-Emmett-Teller (BET) surface areas. The same data produced a wide range of reported values. This variation happens even before considering how the materials were made, and is simply due to how each person chooses the fitting range. 252 Since surface area is often used to explain adsorption performance, including values over 3000 m 2 /g, normalizing adsorption capacities to reported BET area is not reliable. 253 There is also real batch-to-batch variation in materials that are supposed to be identical, such as UiO-66, which is important for water treatment. It is best to share raw isotherms along with BET values and use a clear assignment method, such as BETSI 247. In addition, the most impressive results in this field, including those from our own lab, usually come from single research groups and have not been independently repeated, so these results should be treated with caution. The main disagreement here concerns the hazard that MOFs are intended to address, not about the MOFs themselves. Leaving this out of a review gives a misleading picture of what is known. In 2023, the EFSA CEP Panel lowered the tolerable daily intake (TDI) for BPA from 4 μg/kg body weight per day to 0.2 ng/kg per day, which is about a 20,000-fold decrease. 12 The panel identified effects on Th17 cells as the main concern and stated that dietary exposure is a health risk for all age groups. However, the European Medicines Agency and the German Federal Institute for Risk Assessment disagreed and did not support the new value, while the US Food and Drug Administration still considers BPA safe at current dietary exposure levels. 12 More than 40 academic scientists supported the EFSA approach in Environmental Health Perspectives, but another analysis argued that the evidence EFSA used does not justify such a large reduction. 254 This disagreement is not about one side being clearly wrong, but about differences in methods. EFSA did a systematic review that included non-guideline academic studies using sensitive, non-standard endpoints. 12 , 254 In contrast, the EMA wanted proof of causality within each study, not conclusions drawn from several studies together. The BfR argued that limiting the literature search to 2013–2018 and always using worst-case assumptions led to too much caution. These are reasonable differences in how evidence is judged, not arguments about the data itself. 255 The CLARITY-BPA program was set up to solve this, but did not settle the issue: the main guideline-compliant study found that effects below 25,000 μg/kg body weight per day were not dose-responsive and showed no clear pattern within or across organs. 255 Guideline studies are designed to find monotonic dose-response and to allow high-dose extrapolation, so they cannot detect low-dose effects that disappear at higher doses. These effects are usually seen as statistical noise. This is a limitation of the study design, not proof that the effect does not exist. On the other hand, the fact that academic studies show different results across endpoints and labs does not prove the effect is real. The key question is whether low-dose, non-monotonic effects can be reliably reproduced across labs under blinded conditions. Until this is answered, both the EFSA TDI and the FDA position are reasonable ways to interpret uncertain evidence. This uncertainty directly affects targets for remediation technologies such as MOFs: a 20,000-fold change in tolerable intake means the required removal efficiency also changes, so any adsorbent performance metric in this review depends on which reference value is used based on the earlier analysis, not on tradition, and the reasons for them are clearly explained. 256 , 257 , 258 For water-stable frameworks, the main concern is not general stability but the specific risk of hydrolysis at the metal-carboxylate bond. 259 Zr(IV) in the Zr 6 O 4 (OH) 4 node of UiO-66 acts as a hard Lewis acid with high charge density, forming a strong bond with hard carboxylate oxygen donors. 260 In contrast, divalent-node frameworks used in early adsorption studies, such as ZIF-8 and MOF-5, do not form such strong bonds, making them more likely to undergo hydrolysis. 261 Choosing a framework should be based on matching the hard and soft acid-base properties of the node and linker, so stability can be predicted in advance rather than explained after problems occur. 240 This involves using pores smaller than those in larger pores; as a result, microporous frameworks perform better than large-pore frameworks in real samples, as shown in practice. 240 However, this approach creates a trade-off with intraparticle mass transfer, which should be measured directly, not just assumed. For standard reporting, the BET round-robin shows that adsorption capacities cannot be fairly compared until the denominator is standardized, so sharing raw isotherms should come before setting new capacity records. 252 For node leaching and spent-sorbent toxicity, frameworks that rely on labile nodes for Lewis-acid binding are also likely to release metals, which connects leaching to binding chemistry. Leaching must be measured in the actual use matrix. 262 In pilot-scale continuous flow systems, batch equilibrium capacity and column breakthrough differ whenever intraparticle diffusion, not equilibrium, controls the rate. This is especially important for microporous frameworks with bulky adsorbates, making breakthrough behavior difficult to predict from batch isotherms. The lack of this data in the literature is the main barrier to determining if these systems are ready for use.

Hazardous and toxic chemicals, which are a major pollution threat, lead to the development of many incurable diseases and finally to death. About 9 million people are suffering from these toxic chemicals, and 1.8 million deaths occur every year owing to this exposure. 1 Of the 350,000 chemicals listed for universal use, only 5% have been thoroughly investigated for their health effects. 2 Additionally, the regulatory guidance regarding the use of these chemicals and their adverse effects is another striking feature. 3 , 4 Endocrine-disrupting chemicals (EDCs), a combination of natural and synthetic chemicals, are harmful to the ecosystem. 5 EDCs, also known as endocrine-disrupting chemicals, are widely found in cosmetic products, toys, and pesticides. 3 , 6 , 7 Endocrine glands produce hormones that normalize important biological processes in our body, including growth, fertility, and reproduction. The production and regulation of hormones will be affected by long-term exposure to disrupting chemicals, ultimately leading to immeasurable impacts. Generally, EDCs act like hormone mimics and disrupt the normal functioning of natural hormones. Since disrupting chemicals come from various sources, people are exposed to them through air, water, food, and physical contact. 8 It leads to adverse health issues, including cancer, neurodevelopmental damage, and infertility. 9 , 10 , 11 , 12 EDCs comprise a highly diverse class of chemical substances that can be classified by chemical structure (aromatic/aliphatic), origin and use, mechanisms, reactivity, and their impact. 13 The categories of disrupting chemicals comprise agrochemicals such as pesticides, herbicides, and fungicides; industrial organic solvents and byproducts; pharmaceutical compounds; catalysts; and plastic-related contaminants such as bisphenols and phthalates ( Table 1 ). Among these, bisphenols and phthalates were the most studied and, due to their rapid metabolism and excretion, with half-lives of less than 24 h, were classified as non-persistent EDCs. 14 However, despite their short biological half-lives, the widespread use of bisphenols and phthalates in a variety of consumer products results in continuous, chronic exposure. This determined exposure has been recognized as a global problem disturbing populations of all ages throughout their lifetimes. 15 EDCs act mainly by binding to hormone receptors such as estrogen, androgen, thyroid, and other nuclear receptors (agonists, antagonists, or partial modulators) and thereby generating abnormal transcriptional and cell-signaling responses. 16 , 17 EDCs alter hormone synthesis via disruption of major steps involved in steroidogenesis and thyroid hormone production, such as enzymes (aromatase), hydroxysteroid dehydrogenases, thyroid peroxidase, and different pathways controlling iodide handling and glandular output. 18 , 19 , 20 Also, EDCs can alter hormone metabolism, clearance, and transport by targeting cytochrome P450 enzymes, sulfotransferases, glucuronidation pathways, deiodinases, and carrier proteins such as transthyretin, thereby altering the balance between active and inactive pools of hormones. 20 , 21 All these activity of EDCs disrupts endocrine feedback loops and reprogram the target tissues, especially during sensitive developmental windows, producing reproductive, metabolic, thyroidal, and neurodevelopmental effects. Table 1 Common sources of EDCs, types, and routes of exposure Sources containing EDCs EDCs Exposure Pesticides DDT, chlorpyrifos, 2,4-D, glyphosate, pyrethroids contact with skin and inhalation Children’s products lead, phthalates, cadmium oral consumption and skin contact Food contact materials BPA, phthalates, phenol contact with skin and/or inhalation Electronics and Building materials brominated flame retardants, PCBs inhaling Personal care products, medical tubing phthalates, parabens, insect repellants application to the skin, intravenous tubing Antibacterials triclosan application to skin Textiles, clothing perfluorochemicals contact with skin and inhalation Furniture treated with flame. BFRs contact with skin and inhalation. BPA: bisphenol A; 2,4-D: 2,4-dichlorophenoxyacetic acid; DDT: dichlorodiphenyltrichloroethane; PCBs: polychlorinated biphenyls. Common sources of EDCs, types, and routes of exposure BPA: bisphenol A; 2,4-D: 2,4-dichlorophenoxyacetic acid; DDT: dichlorodiphenyltrichloroethane; PCBs: polychlorinated biphenyls. The impact of EDCs on human health and other living beings has increased the need to find new strategies for removal and treatment. 22 , 23 EDCs can be removed by conventional methods such as adsorption, chlorination, coagulation-flocculation, photocatalytic oxidation, ozonation and membrane filtration, and biological treatment methods. 24 Adsorption is the most common and effective treatment technique used to remove 99.9% of EDCs. Adsorption is an efficient, cost-effective, and easy-to-operate method. 25 Based on the choice of adsorbent, the efficiency of adsorption might change. Some studies on adsorbents, including carbon-based materials, mesoporous silica, and zeolites, have exhibited efficient EDC adsorption from water bodies. 26 , 27 , 28 , 29 Among the different materials used so far, metal-organic frameworks (MOFs) are considered the most effective and novel porous materials for EDC treatment and removal. The physicochemical characteristics of MOFs, such as high pore volume and surface area, chemical and thermal stability, and firm structure, make them suitable for the adsorption of hydrogen, carbon dioxide, and methane for storage. 30 MOFs can replace conventional materials and treatment methods to remove EDCs from water bodies. 31 MOFs can also be used as co-ordination polymers that are made of mixed metal ions with ligands to form a strong bond that forms an open structure, crystalline framework. 32 Many MOFs are synthesized by using selective metal clusters and organic linkers for various purposes. 32 Due to the flexibility of MOFs, the porosity, architecture, functionality, shape, and size (microporous to mesoporous) can be easily modified. 30 Additionally, researchers are developing water-stable MOFs to explore their real-world applications in water recycling methods. The objective of this review article is to summarize recent advances in the development of novel MOFs to address evolving environmental issues, with a focus on their ability to adsorb EDCs from water.

The authors declare no competing interests.

Due to their structural diversity and exceptional properties, MOFs have attracted significant attention as microporous crystalline materials. These MOFs have a large surface area, stable porosity, adaptable pores, tunable pore shapes/sizes, and good thermal stability. With their large surface area and adjustable pore sizes/shapes, MOFs can lead to increased extraction efficiencies, while functionalization can promote hydrophilic/ hydrophobic interactions between analytes and MOFs, making them ideal extraction substitutes. Due to increased water pollution from multiple EDCs, the development of effective treatment techniques has become increasingly necessary. EDCs have been removed from water sources using several methods, including membrane filtration, activated carbon adsorption, flocculation and coagulation, chlorination, biological degradation and removal, photocatalytic adsorption, and ozonation. However, only a few studies have reported on the removal of EDCs from contaminated individuals. MOFs are encompassed by microporous crystalline structures fashioned through the linkage between metal ions and heterogeneous ligands. Hybrid inorganic-organic materials have gained significant importance owing to their structural modification and noteworthy properties, including large surface area, stable porosity, functionalized pores, tunable pore sizes/shapes, and good thermal stability. 216 The large surface areas and adjustable pore sizes/shapes will result in maximized extraction efficiencies, while functionalization can promote hydrophilic/hydrophobic relations between analytes and MOFs, thereby making it an ideal candidate for the extraction process 217 , 218 , 219 ( Figure 4 ). Figure 4 EDC contamination in aquatic environments originating from chemical wastewater, pharmaceutical waste, and hormone-related pollutants The use of MOFs for the selective removal of EDCs from water bodies. Key properties of MOFs include tunable pore size, large surface area, high extraction efficiency, functionalizable pore walls, and excellent thermal and chemical stability. EDC contamination in aquatic environments originating from chemical wastewater, pharmaceutical waste, and hormone-related pollutants The use of MOFs for the selective removal of EDCs from water bodies. Key properties of MOFs include tunable pore size, large surface area, high extraction efficiency, functionalizable pore walls, and excellent thermal and chemical stability. Researchers have synthesized MIL-53, 68, 100, and 101 series of MOFs for the adsorption of dyes, pesticides, antibiotics, and metal ions. 220 , 221 , 222 The UiO series of MOFs and PCN series of MOFs were synthesized for the adsorption of pharmaceutical compounds, dyes, and heavy metals in 2008. 223 Many MOFs were designed to be utilized for water treatment, recycling, and adsorption progressions, including UiO-66 175 , ZIF-8, MIL-100 (Al, Cr, Fe) 224 , 225 and MIL-101-Cr. 226 There are several advantages to MOFs when compared to other adsorbents, which include their ability to create infinite network structures and to act as molecular sieves for adsorbing organic pollutants/impurities owing to their unique physical, chemical, and structural characteristics, which can be regulated by selecting a suitable metal framework. It is ideal to prepare highly porous MOFs by clustering metal carboxylate secondary building units (SBUs). The basic mechanisms involved in the adsorption of EDCs are represented in Figure 5 . Figure 5 Schematic illustrates the principal mechanisms underlying the adsorption and removal of EDCs by MOFs Functionalized MOF surfaces facilitate EDC adsorption via hydrogen bonding, π-π interactions, hydrophobic interactions, and electrostatic attraction. The breathing effect demonstrates the pH-responsive structural flexibility of MOFs, which modulates pore size and adsorption characteristics. Integration of MOFs into membranes and utilization of charge-based interactions further enhance selective EDC capture, separation efficiency, and overall water purification performance. Schematic illustrates the principal mechanisms underlying the adsorption and removal of EDCs by MOFs Functionalized MOF surfaces facilitate EDC adsorption via hydrogen bonding, π-π interactions, hydrophobic interactions, and electrostatic attraction. The breathing effect demonstrates the pH-responsive structural flexibility of MOFs, which modulates pore size and adsorption characteristics. Integration of MOFs into membranes and utilization of charge-based interactions further enhance selective EDC capture, separation efficiency, and overall water purification performance. The direct interactions between carboxylic acids and other organic linkers make them suitable for creating supramolecular structures and strong crystal networks with 50% porosity. 227 In general, the organic linkers (or analogous molecules) are utilized to develop multidimensional lattices of di-, tri-, or tetradentate ligands, whereas, in zeolites, similar porous structures are only possible with limited cations such as Al, P, and Si. 228 As a result, MOFs have larger surface areas than fundamental porous substances such as carbons and zeolites, in the order of 1000–10000 m 2 /g. 229 Additionally, the reactivity of MOF surfaces can be varied with sulphonate, amine, hydroxyl, carbonyl groups, or other reactive functional groups without any variation in the structural framework. 230 , 231 , 232 For the comprehensive design of hybrid nano architectures with the detailed knowledge of structural assembly and stabilization of the interlinking with MOF and adsorbable media, the flexibility of fabrication techniques should be adapted. 24 MOFs are more effective than conventional adsorbents, such as activated carbon, for removing EDCs. 233 Mixed-linker framework UiO-66-NH 2 /Py adsorbs 385 mg/g of BPA, which is better than activated carbon (156 mg/g). 234 The better efficacy of MOFs is due to the synergistic interaction of hydrogen bonding, π-π stacking, and electrostatic attraction. The adsorption energy between EDCs and MOFs can be very strong, reaching up to −89.4 kJ/mol for BPA. In contrast, traditional adsorbents such as zeolites and granular activated carbon often show lower selectivity because their interactions with organic compounds are weaker. Although activated carbon may perform better than some MOFs for smaller compounds such as 2-chlorophenol, advanced MOF systems generally offer better regeneration efficiency and long-term stability. These materials can retain more than 92% of their adsorption capacity after five reuse cycles and may reduce water treatment costs from about 3.50 to 1.20 per m 3 . 234 , 235 MOFs such as MIL-100(Fe) are also moving closer to commercial feasibility, with costs of around $30 per Kg. Their exceptional selectivity and ultrahigh surface area, often exceeding 3000 square meters per gram, may justify costs nearly ten times higher than those of activated carbon for advanced aquatic remediation applications. 236 , 237 High-performing MOFs such as MOF-801-P and MOF-841 have demonstrated zero capacity loss after five full adsorption/desorption cycles, with regeneration occurring efficiently at room temperature. 238 Modern MOFs can be “tailored” to be reused several times without structural collapse, which is a mechanical necessity for competitive “cost-per-use” metrics against AC. 239 Most of the adsorption results discussed earlier, including those comparing activated carbons, are based on experiments conducted with spiked ultrapure or synthetic water at much higher concentrations than those typically found in the environment. This is a major limitation in MOF remediation research, including in this study, and it should be clearly acknowledged rather than overlooked. Three matrix effects occur simultaneously, and together they are more complex than single-factor studies suggest. Natural organic matter (NOM) competes with EDCs for adsorption sites, leading to causing a 30–60% drop in adsorption in real wastewater. 240 Bicarbonate, which is common in natural waters, removes hydroxyl radicals at a rate of 8.5 × 10 6 M −1 s −1 . This matters especially for MOFs that use both adsorption and photocatalytic degradation, not just pollutant concentration. Phosphate binds strongly to Lewis-acidic metal nodes, causing a nearly permanent loss of active sites that regeneration tests in clean water cannot detect. 240 The overall impact of these factors is often underestimated. These effects are systematic, and microporous structures resist NOM fouling better. These findings have two main implications for reporting data. First, looking only at pH or ionic strength is not enough, since NOM fouling, anion binding, and radical scavenging all interact in complex ways in real water. Second, measuring capacity retention over five regeneration cycles in clean water does not reflect how materials perform in real use, where node poisoning and biofilm formation are bigger problems. El Sawaf et al. 240 highlight important gaps: there is no operational data beyond 30 days, the ecotoxicology of treated water is not fully understood, and there is little pilot-scale field testing. Until these issues are addressed and resolved, claims about practical readiness and cost should be seen as predictions based on lab data rather than proven results.