Neutralizing and decoupling the effects of lithium medication

Neutralizing and decoupling the effects of lithium medication | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Neutralizing and decoupling the effects of lithium medication Irfan Ahmed, Muhammad Shehzad Khan, Hina Magsi, Syed Maaz Ahmed Rizvi, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3852850/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Lithium-induced hypothyroidism in the neonate is a growing concern for lactating mothers. Maternal hypothyroidism in the postpartum period could lead to hypothyroidism in the infant via maternal compromised thyroid hormones (likely T4) in breast milk, and lithium in breast milk could have a direct effect on the neonatal thyroid axis. We have investigated lactating dams and pups, lithium-treated, with and without iodine supplement and control dams. We employed Enzym-linked immunosorbent assay and inductively coupled plasma mass spectrometry to assess hormone profiles and intrathyroidal iodine content. The mechanism for supplemented iodine uptake in the presence of lithium is hypothesized by change in membrane potential across the blood vessel and follicular cell(lactocyte) caused by variation in the gradient concentration of negative iodide ion, positive lithium, sodium, and potassium ions. Interestingly, lithium administered directly to pups from control mothers (average dose 900 mg/50kg/24 hours), did not affect their weight, thyroid hormones, blood urea, and intrathyroidal iodine content despite traces of lithium found in their blood and thyroid. The iodine pathway in presence of lithium content in both thyroid follicular cell and lactocyte has been regulated by gradient concentration of negative (iodide) and positive ions (lithium, potassium, and sodium). The results also demonstrate that lithium administration in lactating dams alters thyroid hormones (T4) and blood urea in both dams and pups, which could be reversed by iodine supplement. In future, supplementing iodine may be potentially useful in clinical practices to address the neonate concerns of lactating mothers and their infants either caused by prolonged lithium medication or maternal iodine deficiency. Biological sciences/Biophysics Health sciences/Diseases Health sciences/Molecular medicine Lithium Bipolar disorder Maternal iodine deficiency Thyroid hormones hypothyroidism Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Introduction Lithium-induced hypothyroidism in the neonate is a concern for lactating mothers. Although lithium can be highly effective after giving birth to prevent bipolar relapse, breast-feeding for medicated mothers is controversial because of the potential harms on her child 1 . One of the major concerns is lithium-induced hypothyroidism in the as repeatedly reported in case series 23 – 6 . The direct effects of lithium through breast milk and compromised maternal thyroid dysfunction on neonatal thyroid functioning is still unknown 1 . Maternal thyroid hormones play a key role in the development of their infants’ brains during pregnancy and the postpartum period 7 , 8 Different thyroid dysfunctions, including subclinical hypothyroidism, in mothers increase the risk of preterm birth and low birth weight of the infants 9 . Elevated levels of TSH and decreased free thyroxine (T4) have been also found in the infants of mothers treated for hypothyroidism during pregnancy in a study of 246 treated and 139 control women 10 . The values of TSH and FT4 in newborns of the treated mothers have been observed significantly different from the controls despite adequate supplementation 10 . Further, an increased risk of cardiovascular diseases like hypertension, arrhythmia, and myocardial infarction has been identified in infants due to maternal hypothyroidism 11 . Khatiwada et al. 12 conducted a study to examine the thyroid function and breast milk composition of mothers with hypothyroidism and found lower levels of T4 in their breast milk compared to euthyroid mothers 12 . Agrawal et al. 13 conducted a prospective study in India to examine the hormonal profile in breast milk of hypothyroid mothers and found T4 levels significantly lower in the breast milk of hypothyroid mothers compared to healthy controls 13 . In another study by Mandel et al. 14 thyroid hormone levels were measured in the breast milk of hypothyroid mothers and compared to those of healthy mothers. The results showed that the concentration of T4 in breast milk was significantly lower in hypothyroid mothers compared to healthy mothers. The study concluded that detection and treatment of thyroid insufficiency in pregnancy is feasible, and the treatment may improve thyroid hormone levels in breast milk and benefit infant development 14 . Soldin et al. 15 investigated changes in maternal thyroid hormone levels across pregnancy trimesters and their association with iodine sufficiency. They measured thyroid hormone levels in the breast milk of hypothyroid mothers taking medication and healthy mothers. Results showed that T4 levels were lower in the breast milk of hypothyroid mothers, and T3 and TSH levels were not significantly affected. The study highlights the importance of monitoring maternal thyroid function during pregnancy, especially in mothers with hypothyroidism 15 . In this study, we compared pups of lithium-treated lactating dams with untreated lactating dams. As a further control, a group of pups from untreated dams with normal thyroid hormone levels were treated with a clinically typical dose of lithium carbonate. In addition, benefits of iodine supplementation in the prevention and treatment of neonatal hypothyroidism have been described by our group and others 5 , 16 – 18 and we added, two iodine supplements (0.025% and 0.05) for dams in our experiments. 2. Material and Methods The detailed work flow of the study has been graphically illustrated in Fig. 1 . Institutional Review and Board This study was approved by the animal research ethics committees of the City University of Hong Kong, the University of Hong Kong, and the Department of Health of the Hong Kong Special Administrative Region. Further this study is reported in accordance with ARRIVE guidelines. 2.1 Animal Subjects Pregnant female Sprague Dawley (SD) rats (N = 12, 350–450 g) were selected to enter the study approximately one week prior to giving birth. The University of Hong Kong's Laboratory Animal Unit (AAALAC) provided the animals for the experiments. The rats were housed at Laboratory Animal Research Unit, City University of Hong Kong under a constant temperature of 25 degrees with chow food and drinking water in separate cages. The birth of the baby rats (referred to as pups or subjects) from each dam, was recorded as P1. On the fourth day postpartum P4, all pups from each mother were weighed and the twelve heaviest pups (n = 12) were chosen for breast-feeding, with equal numbers of males and females. This study analyzed three time-points of lactation followed by postpartum: P4, P11, and P18. Total 96 (n = 8×12) pups from 8 dams (N = 2 control, N = 2 lithium, N = 2 lithium + 0.025%iodine and N = 2 lithium + 0.05% iodine in drinking water) were chosen for P18 to demonstrate the effect of iodine supplement on lithium medicated dams and N = 4 control dams with total of 48 pups were chosen to demonstrate the controlled maternal hormones effect on pups (control = 6 x 4 = 24 and lithium = 4 x 6 = 24) for P11. Subjects underwent a range of analyses at the time points, including blood testing and analytical spectroscopy. 2.2 Lithium preparation and administration Lithium carbonate Li 2 CO 3 with the product number (62470-100G-F) was purchased from Sigma Aldrich, United States of America (USA). Lithium with iodine-supplemented groups of dams were administered 900 mg/50kg/12hours of lithium carbonate using gavage till P18. The process of body weight lithium administration has been adopted from the reference 1 . This way, the pups receive lithium through breast milk 1 . To further decouple the lithium effects on lactating pups from controlled hormones of the dam, lithium with a dosage of 900 mg/50kg/24 hours was gavage to half number of pups as four lithium groups (n = 6x4 = 24) from each 4 dam till P11 as per the body weight. The rest of the pups as four controlled group (n = 4x6 = 24) from the same 4 dams were gavaged with water. On P4 each pup was labeled as control and lithium group and was lactated from their respective mothers along with body weight measurement. 2.3 Iodine supplement preparation and administration Molecular iodine (I2, 326143-100G) was purchased from Sigma Aldrich, USA. Two solutions of iodine supplement named 0.025% and 0.05% iodine were prepared by combining 0.25 and 0.5 g of crystal molecular iodine with each 1000 ml of distilled drinking water. A light, sensitive and tightly sealed beaker was magnetically stirred for a total of 48 hours at room temperature to ensure thoroug dissolution of solute in the solvent. The 0.025% and 0.05% iodine supplement solutions were prepared and then placed into 500 milliliter sealed drinking bottles as a fluid intake for lactating dams administered with lithium. 2.4 Blood analysis and Pups Thyroids extraction Eight batches of pups (n = 96) from 8 dams (N = 2 controls, N = 2 lithium, N = 2 lithium + 0.025% iodine and N = 2 lithium + 0.05% iodine) at P18 were sacrificed using surgical procedure for the extraction of blood and thyroid along with their mothers. Xylazine was injected intraperitoneally at a rate of one milliliter per kilogram of body weight to put the subjects to sleep for the experiment after their body weights were measured at time points P18. Similarly, four batches of pups as four lithium (n = 6x4 = 24) and control groups (n = 6x4 = 24) from 4 dams were also sacrificed along with their dams at time point P11. The subjects at time points P11 and P18 were dissected to draw blood from their hearts using 1 ml syringes. To assess the blood's levels of lithium, total thyroxine (T4), and blood urea nitrogen (BUN), the blood was collected in 5ml tubes. ELISA was utilized to analyze total T4 and BUN. Their ELISA sandwich kits were acquired from Cusabio United States. At P11 and P18 postnatal days, all animals’ (pups and dams) total T4 and BUN were measured as per the ELISA protocol defined in reference 1 . Following blood extraction, thyroid glands were extracted from the pups, the protocols of excising thyroid were extracted as per surgery protocols defined in references 1 , 19 , 20 . The thyroids of the pups were removed, and they were sent for the ICP-MS to be analyzed for trace elements such as Li, I, Na, K, and Ca. For thyroid elemental measurements and blood lithium, ICP-MS (Perkin Elmer DRC II) was used in line with the methods supplied by AOAC INTERNATIONAL. Blood lithium at P11 and P18 from dams and pups was collected, and the serum was obtained by centrifuging one milliliter of blood at a rate of 2,500 revolutions per minute for one minute following the protocol defined in [BD]. For the thyroid content of Li, I, Na, K, and Ca, the digestion and measurement protocol was adapted from] 21 for pups at P11 and P18. 2.5 Statistical Analysis At P11 and P18, measures of body weight, blood lithium, total T4, BUN and intra-thyroidal elements were statistically compared across the groups using a one-way analysis of variance (ANOVA). The Tukey test was selected as the statistical method of interest for use in the post-hoc analysis that was carried out. For the results to be regarded as having statistical significance, a p-value threshold of 0.05 was chosen. 3. Results Figure 2 (a) shows T4 hormones and blood urea nitrogen measured from dams using ELISA methods at time point P18. As seen in Fig. 2 (a), the T4 hormones of the dams decrease with the administration of lithium (900 mg/50kg/12 hours) and can be increased to 48.3 nm/L and 55.2 nm/L by supplementing dams with 0.025% and 0.05% iodine, respectively. Similarly, the lithium blood lithium levels changed, the mother to pup blood lithium ratio is 2.57 ± 0.19 (Fig. 2 (b)). Figure 2 (c) displays the pups' T4 hormones and blood urea nitrogen. With lithium administration, the pups’ T4 decreases (p < 0.05) when compared with controls. By supplementing lithium-administered dams, the T4 hormones reverse and approach control hormones along with blood urea nitrogen. Similarly, by increasing the concentration of iodine supplement solution to 0.05%, the T4 hormones further increase and level control hormones, however, the blood urea nitrogen is significantly enhanced (p < 0.05). Further, we measured the lithium and iodine content of pups’ thyroid using ICP-MS, it can be seen in Fig. 2 (d) that by supplementing the lithium administered dams, the iodine content increases significantly (p < 0.05) for 0.025% iodine solution and with 0.05% it levels the control thyroid content, which in turn normalizes the thyroid hormones. Figure 3 (a) shows the control T4 (24 ± 02 nm/L) and blood urea (27.1 ± 02) for a healthy mother. The pups from these mothers (N = 4), were divided into control (n = 24) and lithium-administered groups (n = 24), their corresponding T4 (67.02 ± 17 vs 64.23 ± 19 nm/L) and blood urea (16.95 ± 4.2 vs 16.23 ± 2.02 mg/dL) are also displayed in Fig. 3 (b). It can be statistically compared that there is no significant change across the control and lithium groups even in weight (Fig. 3 (c)) and thyroid iodine content (Fig. 3 (e)) even though lithium was found in the thyroid (Fig. 3 (d)). It should be noted that with the accumulation of lithium, sodium (Na) and potassium (K) are increased. 4. Discussion Figure 4 illustrates the mechanism of reversing lithium, inhibiting thyroid hormone production and maternal iodine-deficient secretion of breast milk by supplementing maternal iodine observed in this study for lactating dams and pups. In control subjects, the iodide ions move from blood vessel to thyroid follicular cell (Fig. (4a)) and in mammary gland lactocytes (Fig. (4b)) through NIS expressed at their respective Bassel membrane 25,29 . The iodine in normal thyroid helps secretion of T3 and T4 hormones and is also incorporated in casein through the mechanism of lactoperoxidase in lactocyte cells to form iodocasein molecules 25 . The iodocasein molecules aggregate inside micelles along with T3 and T4 and then fuse with the apical membrane to release their content by exocytosis to breast milk. When lithium is found in the bloodstream (ie. lithium subjects, both dams and pups), Li + ions enter the follicular (Fig. 4(c)) and lactocytes cells (Fig. 4(d)) causes impaired thyroid hormones (hypothyroidism) 3–5 and less formation of iodocasein molecules, respectively, causing breast milk to be maternal iodine and T4 deficient. The normal amount of maternal iodine and secreted hormones (T3 and T4) are the best possible source for infants 30 to synthesize their hormones 31,32 , however, the presence of lithium in maternal iodine and T4 deficient breast milk, reduces T4 hormones and increases the weight of lactating pups. To reverse this, dams were supplemented with iodine, which resulted in neutralizing the pups’ T4 and weight gain (reversing hypothyroidism). Figs. 4(e) and 4(f) illustrate the hypothesized iodide transport mechanism to follicular cell of thyroid and lactocytes cell of mammary gland in the presence of lithium, respectively. With supplemented iodine to dams, interestingly excess iodine is measured in the pups’ thyroid along with lithium (Fig. 2(d)). The demand for iodine uptake in the newborn is higher than in adult 33 . This supplemented iodide helps in secretion of maternal thyroid hormones even in the presence of lithium (Fig. 2(a)), and also adequate maternal iodine and maternal T4 hormones produced are supplied through breast milk for synthesizes of pups’ hormones (Fig. 2(c)). In thyroid follicular cell and mammary gland lactocytes with administration of lithium medication, the mechanism of excess iodide uptake (in both pups and dams) through NIS can be hypothesized by change in the Bassel membrane potential. The Bassel membrane potential may be caused by excess I - negation ions in the blood vessel (due to iodine supplement) and observed positive ions Li + and possibly observed Na/K (Fig. 3(e)) across the thyroid follicular cell (mammary gland lactocytes 21 ). Interestingly, the adequate maternal iodine and thyroid hormones (T4) of control subjects are also observed here in neutralizing the effects (hypothyroidism) of lithium subjects directly administered to lactating pups. This suggests that maternal iodine, T3 and T4 efficiency are essential for lactating infants and the mother herself as iodine deficiency and lower T4 in maternal breast milk 13,14,15 caused numerous iodine deficient disorders 22 . In future supplementing iodine could be potentially useful in clinical practices to address the neonate concern of lactating mothers and infants caused by long-term lithium medication. Summary Maternal lithium-induced hypothyroidism is associated with infant hypothyroidism. We studied dams and pups during lactation with control, lithium-administered dams, and supplemented them with different iodine concentrations. With ELISA and ICP-MS, the result demonstrated that lithium-administered dams' T4 and blood urea were improved and neutralized along with their pups. These results suggest that lithium-induced hypothyroidism in pups (infants), can be reversed by supplementing the dams (mothers) with iodine. We also hypothesized the mechanism for supplemented iodine uptake in presence of lithium by change in membrane potential caused by change in the gradient concentration of negative iodide ion in blood vessel and positive lithium, sodium, and potassium ions in follicular cell (lactocytes). Further, we extended the study to demonstrate the effects of healthy maternal (mothers) thyroid hormones by directly administering lithium to pups. Interestingly, pups from control dams administered directly with an average dose (900 mg/50kg/24 hours) of lithium, did not affect pups’ weight, thyroid hormones, blood urea and intrathyroidal iodine content despite lithium being detected in their thyroid. This may suggest no induction of lithium-based hypothyroidism in pups (infants) when nursed by healthy dams (mother) during early days of lactation. Declarations Acknowledgement and Funding: This research was supported by funding from the City University of Hong Kong (project number 7005507). Authors’ contribution: IA and CL designed and supervised the whole work. MSK and IA performed the experiments, HM, SMAR, NL, ZA, TA, YZ, MA and VB helped in analyzing the data. MA and VB also contributed in writing the manuscript. All authors have given approval to the final version of the manuscript . Author Disclosure Statement: Condon Lau received funding for the research, and all authors reported no conflict of interest. Availability of Data and Materials: The corresponding author can be contacted through email for availability of data and materials. References Ahmed, I. et al. 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Eur Thyroid J 5 , 145–148 (2016). Raymond, J. & LaFranchi, S. H. Fetal and neonatal thyroid function: Review and summary of significant new findings. Curr Opin Endocrinol Diabetes Obes 17 , 1–7 (2010). Ramezani Tehrani, F., Nazarpour, S. & Behboudi-Gandevani, S. Isolated maternal hypothyroxinemia and adverse pregnancy outcomes: A systematic review. J Gynecol Obstet Hum Reprod 50 , 102057 (2021). Ares, S., Quero, J. & Morreale de Escobar, G. Neonatal iodine deficiency: clinical aspects. J Pediatr Endocrinol Metab 18 Suppl 1 , 1257–1264 (2005). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3852850","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":267563847,"identity":"34f477d5-0f26-4288-8f5e-315310743306","order_by":0,"name":"Irfan Ahmed","email":"","orcid":"","institution":"City University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Irfan","middleName":"","lastName":"Ahmed","suffix":""},{"id":267563848,"identity":"c2d5ecb0-d86d-4be7-baaa-09fdca06d867","order_by":1,"name":"Muhammad Shehzad Khan","email":"","orcid":"","institution":"City University of Hong 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08:44:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3852850/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3852850/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49829503,"identity":"5a07f803-2f81-4653-a243-27bea8e3aae3","added_by":"auto","created_at":"2024-01-18 16:12:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":52911,"visible":true,"origin":"","legend":"\u003cp\u003eWorkflow of the study\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3852850/v1/6e074e281aa0289312ec1b6d.png"},{"id":49828669,"identity":"aa72392a-f151-4361-a168-261da0696bc1","added_by":"auto","created_at":"2024-01-18 16:04:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":44463,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Dams Hormone profile; measured T4 and BUN from [N=2 controls, N= 2 lithium, N= 2 lithium + 0.025% iodine and N= 2 lithium + 0.05% iodine] at P18. (b) Blood lithium in dams and their pups [n=24 controls, n= 24 lithium, n= 24 lithium + 0.025% iodine and n= 24 lithium + 0.05% iodine] at P18. (c) Pups Hormone profile; measured T4 and BUN from pups [n=24 controls, n= 24 lithium, n= 24 lithium + 0.025% iodine and n= 24 lithium + 0.05% iodine] at P18. (d) Measured lithium and iodine content from the thyroid of pups across the groups at P18.\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-3852850/v1/5c731065ae1a8c3aa50b5591.png"},{"id":49828666,"identity":"b4308271-a6f6-47fd-8188-eb7f80408266","added_by":"auto","created_at":"2024-01-18 16:04:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":27946,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Dams [N=4 controls] and (b) pups [Controls n=24 and lithium administered n=24 hormone profile; measured T4 and BUN at P11. (c) Corresponding pups’ weight bar plots. (d) Pups inter thyroid lithium and (e) Ca, Iodine, Sodium, and Potassium concentration across the control and lithium administered pups aT P11.\u003c/p\u003e","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-3852850/v1/3685d0f521fe5f253649f4f2.png"},{"id":49829504,"identity":"1dd81e6a-653d-42fb-8e56-b5d1dae7b50f","added_by":"auto","created_at":"2024-01-18 16:12:43","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":175106,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Iodine pathway in a normal follicular cell through the sodium-iodide symporter (NIS) expressed at its Bessel membrane. The I− enters the colloid where it bonds with tyrosine on thyroglobulin proteins. The iodinated thyroglobulin re-enters the follicular cell and splits into T3 and T4 causing iodine to recycle22. (b) Iodine pathway in a normal lactocyte cell of the mammary gland. The iodide, T3 and T4 transport from blood vessel to a normal lactocytes cell of mammary gland through NIS expressed23,24 at its Bessel Membrane25.The transported iodide inside the lactocyte is incorporated into casein by the action of lactoperoxidase. Iodocasein molecules will be aggregated inside micelles and these micelles fuse with the apical membrane to release their content by exocytosis to breast milk25 with required iodine, T3 and T426. (c) Iodine pathway in a follicular cell in presence of lithium accumulation from blood vessels. Lithium impairs thyroid hormone production (less T4)1 and inhibits recycling of iodine to and from the blood vessel22. (d) Iodine pathway in lactocytes cell of mammary gland with the accumulation of lithium from blood vessel. Less iodide transport to mammary gland possibly due to presence of lithium21 , and less flow of T41 causing milk content to be iodine and T4 deficient. Maternal iodine and T4 deficient breast milk along with lithium21 causes infant hypothyroidim27,28. (e) Supplemented Iodine pathway in follicular cell in presence of lithium possibly caused by changes in potential across the Bessel membrane due to supplemented iodide ion (I-). The supplemented I- in blood vessels and presence of lithium in follicular cells possibly changes the Bessel membrane potential and causes the transport of negative iodide I- \u0026nbsp;into follicular cells already having high positive lithium ion (Li+), potassium and sodium. (f) The supplemented iodide and higher T4 transport to mammary gland in presence of lithium due to hypothesized change in Bessel membrane potential causing milk content to be T3, T4 and iodine efficient. The T3, T4 and iodine-efficient milk even in presence of lithium neutralizes the hormones’ production.\u003c/p\u003e","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-3852850/v1/7bf6e9fbbd8bd4dfe18ff147.png"},{"id":65604818,"identity":"c65e9d48-575f-4964-8161-10d50b3dd813","added_by":"auto","created_at":"2024-09-30 12:24:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":809011,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3852850/v1/1aee10d7-3013-4385-abe6-62e219cb5550.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Neutralizing and decoupling the effects of lithium medication","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eLithium-induced hypothyroidism in the neonate is a concern for lactating mothers. Although lithium can be highly effective after giving birth to prevent bipolar relapse, breast-feeding for medicated mothers is controversial because of the potential harms on her child \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. One of the major concerns is lithium-induced hypothyroidism in the as repeatedly reported in case series\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. The direct effects of lithium through breast milk and compromised maternal thyroid dysfunction on neonatal thyroid functioning is still unknown\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Maternal thyroid hormones play a key role in the development of their infants\u0026rsquo; brains during pregnancy and the postpartum period\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Different thyroid dysfunctions, including subclinical hypothyroidism, in mothers increase the risk of preterm birth and low birth weight of the infants\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Elevated levels of TSH and decreased free thyroxine (T4) have been also found in the infants of mothers treated for hypothyroidism during pregnancy in a study of 246 treated and 139 control women\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. The values of TSH and FT4 in newborns of the treated mothers have been observed significantly different from the controls despite adequate supplementation\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Further, an increased risk of cardiovascular diseases like hypertension, arrhythmia, and myocardial infarction has been identified in infants due to maternal hypothyroidism\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eKhatiwada et al.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e conducted a study to examine the thyroid function and breast milk composition of mothers with hypothyroidism and found lower levels of T4 in their breast milk compared to euthyroid mothers\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Agrawal et al.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e conducted a prospective study in India to examine the hormonal profile in breast milk of hypothyroid mothers and found T4 levels significantly lower in the breast milk of hypothyroid mothers compared to healthy controls\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. In another study by Mandel et al.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e thyroid hormone levels were measured in the breast milk of hypothyroid mothers and compared to those of healthy mothers. The results showed that the concentration of T4 in breast milk was significantly lower in hypothyroid mothers compared to healthy mothers. The study concluded that detection and treatment of thyroid insufficiency in pregnancy is feasible, and the treatment may improve thyroid hormone levels in breast milk and benefit infant development\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Soldin et al.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e investigated changes in maternal thyroid hormone levels across pregnancy trimesters and their association with iodine sufficiency. They measured thyroid hormone levels in the breast milk of hypothyroid mothers taking medication and healthy mothers. Results showed that T4 levels were lower in the breast milk of hypothyroid mothers, and T3 and TSH levels were not significantly affected. The study highlights the importance of monitoring maternal thyroid function during pregnancy, especially in mothers with hypothyroidism\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn this study, we compared pups of lithium-treated lactating dams with untreated lactating dams. As a further control, a group of pups from untreated dams with normal thyroid hormone levels were treated with a clinically typical dose of lithium carbonate. In addition, benefits of iodine supplementation in the prevention and treatment of neonatal hypothyroidism have been described by our group and others\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eand we added, two iodine supplements (0.025% and 0.05) for dams in our experiments.\u003c/p\u003e"},{"header":"2. Material and Methods","content":"\u003cp\u003eThe detailed work flow of the study has been graphically illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eInstitutional Review and Board\u003c/strong\u003e \u003cp\u003e This study was approved by the animal research ethics committees of the City University of Hong Kong, the University of Hong Kong, and the Department of Health of the Hong Kong Special Administrative Region.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eFurther this study is reported in accordance with ARRIVE guidelines.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Animal Subjects\u003c/h2\u003e \u003cp\u003ePregnant female Sprague Dawley (SD) rats (N\u0026thinsp;=\u0026thinsp;12, 350\u0026ndash;450 g) were selected to enter the study approximately one week prior to giving birth. The University of Hong Kong's Laboratory Animal Unit (AAALAC) provided the animals for the experiments. The rats were housed at Laboratory Animal Research Unit, City University of Hong Kong under a constant temperature of 25 degrees with chow food and drinking water in separate cages. The birth of the baby rats (referred to as pups or subjects) from each dam, was recorded as P1.\u003c/p\u003e \u003cp\u003eOn the fourth day postpartum P4, all pups from each mother were weighed and the twelve heaviest pups (n\u0026thinsp;=\u0026thinsp;12) were chosen for breast-feeding, with equal numbers of males and females. This study analyzed three time-points of lactation followed by postpartum: P4, P11, and P18. Total 96 (n\u0026thinsp;=\u0026thinsp;8\u0026times;12) pups from 8 dams (N\u0026thinsp;=\u0026thinsp;2 control, N\u0026thinsp;=\u0026thinsp;2 lithium, N\u0026thinsp;=\u0026thinsp;2 lithium\u0026thinsp;+\u0026thinsp;0.025%iodine and N\u0026thinsp;=\u0026thinsp;2 lithium\u0026thinsp;+\u0026thinsp;0.05% iodine in drinking water) were chosen for P18 to demonstrate the effect of iodine supplement on lithium medicated dams and N\u0026thinsp;=\u0026thinsp;4 control dams with total of 48 pups were chosen to demonstrate the controlled maternal hormones effect on pups (control\u0026thinsp;=\u0026thinsp;6 x 4\u0026thinsp;=\u0026thinsp;24 and lithium\u0026thinsp;=\u0026thinsp;4 x 6\u0026thinsp;=\u0026thinsp;24) for P11. Subjects underwent a range of analyses at the time points, including blood testing and analytical spectroscopy.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Lithium preparation and administration\u003c/h2\u003e \u003cp\u003eLithium carbonate Li\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e with the product number (62470-100G-F) was purchased from Sigma Aldrich, United States of America (USA). Lithium with iodine-supplemented groups of dams were administered 900 mg/50kg/12hours of lithium carbonate using gavage till P18. The process of body weight lithium administration has been adopted from the reference \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. This way, the pups receive lithium through breast milk \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo further decouple the lithium effects on lactating pups from controlled hormones of the dam, lithium with a dosage of 900 mg/50kg/24 hours was gavage to half number of pups as four lithium groups (n\u0026thinsp;=\u0026thinsp;6x4\u0026thinsp;=\u0026thinsp;24) from each 4 dam till P11 as per the body weight. The rest of the pups as four controlled group (n\u0026thinsp;=\u0026thinsp;4x6\u0026thinsp;=\u0026thinsp;24) from the same 4 dams were gavaged with water. On P4 each pup was labeled as control and lithium group and was lactated from their respective mothers along with body weight measurement.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Iodine supplement preparation and administration\u003c/h2\u003e \u003cp\u003eMolecular iodine (I2, 326143-100G) was purchased from Sigma Aldrich, USA. Two solutions of iodine supplement named 0.025% and 0.05% iodine were prepared by combining 0.25 and 0.5 g of crystal molecular iodine with each 1000 ml of distilled drinking water. A light, sensitive and tightly sealed beaker was magnetically stirred for a total of 48 hours at room temperature to ensure thoroug dissolution of solute in the solvent. The 0.025% and 0.05% iodine supplement solutions were prepared and then placed into 500 milliliter sealed drinking bottles as a fluid intake for lactating dams administered with lithium.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Blood analysis and Pups Thyroids extraction\u003c/h2\u003e \u003cp\u003eEight batches of pups (n\u0026thinsp;=\u0026thinsp;96) from 8 dams (N\u0026thinsp;=\u0026thinsp;2 controls, N\u0026thinsp;=\u0026thinsp;2 lithium, N\u0026thinsp;=\u0026thinsp;2 lithium\u0026thinsp;+\u0026thinsp;0.025% iodine and N\u0026thinsp;=\u0026thinsp;2 lithium\u0026thinsp;+\u0026thinsp;0.05% iodine) at P18 were sacrificed using surgical procedure for the extraction of blood and thyroid along with their mothers. Xylazine was injected intraperitoneally at a rate of one milliliter per kilogram of body weight to put the subjects to sleep for the experiment after their body weights were measured at time points P18. Similarly, four batches of pups as four lithium (n\u0026thinsp;=\u0026thinsp;6x4\u0026thinsp;=\u0026thinsp;24) and control groups (n\u0026thinsp;=\u0026thinsp;6x4\u0026thinsp;=\u0026thinsp;24) from 4 dams were also sacrificed along with their dams at time point P11. The subjects at time points P11 and P18 were dissected to draw blood from their hearts using 1 ml syringes. To assess the blood's levels of lithium, total thyroxine (T4), and blood urea nitrogen (BUN), the blood was collected in 5ml tubes. ELISA was utilized to analyze total T4 and BUN. Their ELISA sandwich kits were acquired from Cusabio United States. At P11 and P18 postnatal days, all animals\u0026rsquo; (pups and dams) total T4 and BUN were measured as per the ELISA protocol defined in reference \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFollowing blood extraction, thyroid glands were extracted from the pups, the protocols of excising thyroid were extracted as per surgery protocols defined in references \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. The thyroids of the pups were removed, and they were sent for the ICP-MS to be analyzed for trace elements such as Li, I, Na, K, and Ca.\u003c/p\u003e \u003cp\u003eFor thyroid elemental measurements and blood lithium, ICP-MS (Perkin Elmer DRC II) was used in line with the methods supplied by AOAC INTERNATIONAL. Blood lithium at P11 and P18 from dams and pups was collected, and the serum was obtained by centrifuging one milliliter of blood at a rate of 2,500 revolutions per minute for one minute following the protocol defined in [BD]. For the thyroid content of Li, I, Na, K, and Ca, the digestion and measurement protocol was adapted from]\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003efor pups at P11 and P18.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Statistical Analysis\u003c/h2\u003e \u003cp\u003eAt P11 and P18, measures of body weight, blood lithium, total T4, BUN and intra-thyroidal elements were statistically compared across the groups using a one-way analysis of variance (ANOVA). The Tukey test was selected as the statistical method of interest for use in the post-hoc analysis that was carried out. For the results to be regarded as having statistical significance, a p-value threshold of 0.05 was chosen.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e(a) shows T4 hormones and blood urea nitrogen measured from dams using ELISA methods at time point P18. As seen in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e(a), the T4 hormones of the dams decrease with the administration of lithium (900 mg/50kg/12 hours) and can be increased to 48.3 nm/L and 55.2 nm/L by supplementing dams with 0.025% and 0.05% iodine, respectively. Similarly, the lithium blood lithium levels changed, the mother to pup blood lithium ratio is 2.57\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e(b)). Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e(c) displays the pups' T4 hormones and blood urea nitrogen. With lithium administration, the pups\u0026rsquo; T4 decreases (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) when compared with controls. By supplementing lithium-administered dams, the T4 hormones reverse and approach control hormones along with blood urea nitrogen. Similarly, by increasing the concentration of iodine supplement solution to 0.05%, the T4 hormones further increase and level control hormones, however, the blood urea nitrogen is significantly enhanced (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Further, we measured the lithium and iodine content of pups\u0026rsquo; thyroid using ICP-MS, it can be seen in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e(d) that by supplementing the lithium administered dams, the iodine content increases significantly (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) for 0.025% iodine solution and with 0.05% it levels the control thyroid content, which in turn normalizes the thyroid hormones.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e(a) shows the control T4 (24\u0026thinsp;\u0026plusmn;\u0026thinsp;02 nm/L) and blood urea (27.1\u0026thinsp;\u0026plusmn;\u0026thinsp;02) for a healthy mother. The pups from these mothers (N\u0026thinsp;=\u0026thinsp;4), were divided into control (n\u0026thinsp;=\u0026thinsp;24) and lithium-administered groups (n\u0026thinsp;=\u0026thinsp;24), their corresponding T4 (67.02\u0026thinsp;\u0026plusmn;\u0026thinsp;17 vs 64.23\u0026thinsp;\u0026plusmn;\u0026thinsp;19 nm/L) and blood urea (16.95\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2 vs 16.23\u0026thinsp;\u0026plusmn;\u0026thinsp;2.02 mg/dL) are also displayed in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e(b). It can be statistically compared that there is no significant change across the control and lithium groups even in weight (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e(c)) and thyroid iodine content (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e(e)) even though lithium was found in the thyroid (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e(d)). It should be noted that with the accumulation of lithium, sodium (Na) and potassium (K) are increased.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eFigure \u003cstrong\u003e4\u003c/strong\u003e illustrates the mechanism of reversing lithium, inhibiting thyroid hormone production and maternal iodine-deficient secretion of breast milk by supplementing maternal iodine observed in this study for lactating dams and pups. In control subjects, the iodide ions move from blood vessel to thyroid follicular cell (Fig. (4a)) and in mammary gland lactocytes (Fig. (4b)) through NIS expressed at their respective Bassel membrane\u003csup\u003e25,29\u003c/sup\u003e. The iodine in normal thyroid helps secretion of T3 and T4 hormones and is also incorporated in casein through the mechanism of lactoperoxidase in lactocyte cells to form iodocasein molecules\u003csup\u003e25\u003c/sup\u003e. The iodocasein molecules aggregate inside micelles along with T3 and T4 and then fuse with the apical membrane to release their content by exocytosis to breast milk. When lithium is found in the bloodstream (ie. lithium subjects, both dams and pups), Li\u003csup\u003e+\u003c/sup\u003e ions enter the follicular (Fig. 4(c)) and lactocytes cells (Fig. 4(d)) causes impaired thyroid hormones (hypothyroidism)\u003csup\u003e3\u0026ndash;5\u003c/sup\u003e and less formation of iodocasein molecules, respectively, causing breast milk to be maternal iodine and T4 deficient. The normal amount of maternal iodine and secreted hormones (T3 and T4) are the best possible source for infants\u003csup\u003e30\u003c/sup\u003e to synthesize their hormones\u003csup\u003e31,32\u003c/sup\u003e, however, the presence of lithium in maternal iodine and T4 deficient breast milk, reduces T4 hormones and increases the weight of lactating pups. To reverse this, dams were supplemented with iodine, which resulted in neutralizing the pups\u0026rsquo; T4 and weight gain (reversing hypothyroidism). Figs. 4(e) and 4(f) illustrate the hypothesized iodide transport mechanism to follicular cell of thyroid and lactocytes cell of mammary gland in the presence of lithium, respectively. With supplemented iodine to dams, interestingly excess iodine is measured in the pups\u0026rsquo; thyroid along with lithium (Fig. 2(d)). The demand for iodine uptake in the newborn is higher than in adult \u003csup\u003e33\u003c/sup\u003e. This supplemented iodide helps in secretion of maternal thyroid hormones even in the presence of lithium (Fig. 2(a)), and also adequate maternal iodine and maternal T4 hormones produced are supplied through breast milk for synthesizes of pups\u0026rsquo; hormones (Fig. 2(c)). In thyroid follicular cell and mammary gland lactocytes with administration of lithium medication, the mechanism of excess iodide uptake (in both pups and dams) through NIS can be hypothesized by change in the Bassel membrane potential. The Bassel membrane potential may be caused by excess I\u003csup\u003e- \u003c/sup\u003enegation ions in the blood vessel (due to iodine supplement) and observed positive ions Li\u003csup\u003e+\u003c/sup\u003e and possibly observed Na/K (Fig. 3(e)) across the thyroid follicular cell (mammary gland lactocytes\u003csup\u003e21\u003c/sup\u003e). \u003c/p\u003e\n\u003cp\u003eInterestingly, the adequate maternal iodine and thyroid hormones (T4) of control subjects are also observed here in neutralizing the effects (hypothyroidism) of lithium subjects directly administered to lactating pups. This suggests that maternal iodine, T3 and T4 efficiency are essential for lactating infants and the mother herself as iodine deficiency and lower T4 in maternal breast milk\u003csup\u003e13,14,15\u003c/sup\u003e caused numerous iodine deficient disorders\u003csup\u003e22\u003c/sup\u003e. In future supplementing iodine could be potentially useful in clinical practices to address the neonate concern of lactating mothers and infants caused by long-term lithium medication. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSummary\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMaternal lithium-induced hypothyroidism is associated with infant hypothyroidism. We studied dams and pups during lactation with control, lithium-administered dams, and supplemented them with different iodine concentrations. With ELISA and ICP-MS, the result demonstrated that lithium-administered dams\u0026apos; T4 and blood urea were improved and neutralized along with their pups. These results suggest that lithium-induced hypothyroidism in pups (infants), can be reversed by supplementing the dams (mothers) with iodine. We also hypothesized the mechanism for supplemented iodine uptake in presence of lithium by change in membrane potential caused by change in the gradient concentration of negative iodide ion in blood vessel and positive lithium, sodium, and potassium ions in follicular cell (lactocytes). Further, we extended the study to demonstrate the effects of healthy maternal (mothers) thyroid hormones by directly administering lithium to pups. Interestingly, pups from control dams administered directly with an average dose (900 mg/50kg/24 hours) of lithium, did not affect pups\u0026rsquo; weight, thyroid hormones, blood urea and intrathyroidal iodine content despite lithium being detected in their thyroid. This may suggest no induction of lithium-based hypothyroidism in pups (infants) when nursed by healthy dams (mother) during early days of lactation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement and Funding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by funding from the City University of Hong Kong (project number 7005507).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contribution:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIA and CL designed and supervised the whole work.\u0026nbsp;MSK and IA performed the experiments, HM, SMAR, NL, ZA, TA, YZ, MA and VB\u0026nbsp;helped in analyzing the data. MA and VB also contributed in writing the manuscript.\u0026nbsp;All authors have given approval to the final version of the manuscript\u003cu\u003e.\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Disclosure Statement:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCondon Lau received funding for the research, and all authors reported no conflict of interest. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe corresponding author can be contacted through email for availability of data and materials. \u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eAhmed, I. \u003cem\u003eet al.\u003c/em\u003e Lithium from breast \u0026shy;milk inhibits thyroid iodine uptake and hormone production , which are remedied by maternal iodine supplementation. \u003cem\u003eBipolar Disord\u003c/em\u003e 615\u0026ndash;625 (2021) doi:10.1111/bdi.13047.\u003c/li\u003e\n \u003cli\u003ePoels, E. 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Neonatal iodine deficiency: clinical aspects. \u003cem\u003eJ Pediatr Endocrinol Metab\u003c/em\u003e \u003cstrong\u003e18 Suppl 1\u003c/strong\u003e, 1257\u0026ndash;1264 (2005).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Lithium, Bipolar disorder, Maternal iodine deficiency, Thyroid hormones, hypothyroidism","lastPublishedDoi":"10.21203/rs.3.rs-3852850/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3852850/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eLithium-induced hypothyroidism in the neonate is a growing concern for lactating mothers. Maternal hypothyroidism in the postpartum period could lead to hypothyroidism in the infant via maternal compromised thyroid hormones (likely T4) in breast milk, and lithium in breast milk could have a direct effect on the neonatal thyroid axis. We have investigated lactating dams and pups, lithium-treated, with and without iodine supplement and control dams. We employed Enzym-linked immunosorbent assay and inductively coupled plasma mass spectrometry to assess hormone profiles and intrathyroidal iodine content. The mechanism for supplemented iodine uptake in the presence of lithium is hypothesized by change in membrane potential across the blood vessel and follicular cell(lactocyte) caused by variation in the gradient concentration of negative iodide ion, positive lithium, sodium, and potassium ions. Interestingly, lithium administered directly to pups from control mothers (average dose 900 mg/50kg/24 hours), did not affect their weight, thyroid hormones, blood urea, and intrathyroidal iodine content despite traces of lithium found in their blood and thyroid. The iodine pathway in presence of lithium content in both thyroid follicular cell and lactocyte has been regulated by gradient concentration of negative (iodide) and positive ions (lithium, potassium, and sodium). The results also demonstrate that lithium administration in lactating dams alters thyroid hormones (T4) and blood urea in both dams and pups, which could be reversed by iodine supplement. In future, supplementing iodine may be potentially useful in clinical practices to address the neonate concerns of lactating mothers and their infants either caused by prolonged lithium medication or maternal iodine deficiency.\u003c/p\u003e","manuscriptTitle":"Neutralizing and decoupling the effects of lithium medication","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-18 16:04:38","doi":"10.21203/rs.3.rs-3852850/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3abcce6f-7223-4679-8e89-457b8f234a7e","owner":[],"postedDate":"January 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":28188944,"name":"Biological sciences/Biophysics"},{"id":28188945,"name":"Health sciences/Diseases"},{"id":28188946,"name":"Health sciences/Molecular medicine"}],"tags":[],"updatedAt":"2024-09-30T12:23:50+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-18 16:04:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3852850","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3852850","identity":"rs-3852850","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}