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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Epidemiological studies have identified the developing brain as a target of concern for polychlorinated biphenyls (PCBs). In animal models, behavioral deficits caused by developmental exposure to PCBs have been associated with altered patterns of dendritic arborization in functionally relevant brain regions. In vitro studies revealed that PCB 95 promoted dendritic growth in primary rat hippocampal neuron\u2013glia co-cultures via ryanodine receptor 1 (RYR1)-dependent Ca2+ signaling. However, it is not yet known whether RYR1 dysregulation contributes to disruption of dendritic morphogenesis in the intact developing brain or whether PCB 95 affects translationally relevant behavioral endpoints in juvenile animals. To address these data gaps, we assessed Morris water maze (MWM) performance and dendritic arborization of hippocampal CA1 pyramidal neurons in C57BL\/6 mice heterozygous for the human R163C-RYR1 gain-of-function mutation (HET) and congenic wildtype (WT) littermates exposed to vehicle or PCB 95 at 0.1, 1.0, or 6.0 mg\/kg\/d in the dam\u2019s diet from conception through weaning. MWM performance was not altered in HET vehicle controls relative to WT vehicle controls; however, compared to genotype-matched vehicle controls, spatial learning was impaired in WT and HET male and female weanlings in the 1.0 mg\/kg\/d PCB 95 dose group and WT males in the 6.0 mg\/kg\/d PCB 95 dose group. Spatial memory was altered only in WT females exposed to 1.0 or 6.0 mg\/kg\/d PCB 95. Sholl analyses of Golgi-stained hippocampal neurons in male and female WT and HET weanlings from the 1.0 mg\/kg\/d PCB 95 and vehicle groups indicated that relative to WT vehicle controls, basal dendritic arborization was significantly increased in HET vehicle controls and in PCB 95-exposed WT weanlings; however, PCB 95 did not alter basal dendritic growth in HET weanlings relative to genotype-matched vehicle controls. PCB 95 significantly reduced training-induced dendritic arborization in WT but not HET weanlings. Measurement of tritiated ryanodine ([3H]Ry) binding in cortical tissue from these same animals revealed interactions between genotype, PCB 95 exposure, and dose that altered [3H]Ry binding relative to WT vehicle controls. Quantitative analyses confirmed a dose-dependent increase in PCB tissue burden that was not significantly altered by genotype, MWM training, or sex. Serum levels of progesterone, estradiol, cortisol, and thyroid hormone (TH) and brain transcript levels of TH-responsive genes were not significantly altered by genotype or PCB 95 dose. These data demonstrate that PCB 95 caused behavioral deficits coincident with altered patterns of basal and training-induced dendritic arborization. Furthermore, behavioral and dendritic responses to PCB 95 were altered by expression of the human R163C-RYR1 gain-of-function mutation, supporting the involvement of RYR1-dependent mechanisms in PCB 95 DNT in vivo.<\/jats:p>","DOI":"10.3390\/ijms27177801","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:48:36Z","timestamp":1788256116000},"page":"7801","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Expression of the Human R163C-RYR1 Gain-of-Function Mutation Modified 2,2\u2032,3,5\u2032,6-Pentachlorobiphenyl (PCB 95) Developmental Neurotoxicity in Weanling Mice"],"prefix":"10.3390","volume":"27","author":[{"given":"Christopher D.","family":"Barnhart","sequence":"first","affiliation":[{"name":"Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1032-7432","authenticated-orcid":false,"given":"Rebecca J.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunjay","family":"Sethi","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5129-4286","authenticated-orcid":false,"given":"Hao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim M.","family":"Truong","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izabela","family":"Kania-Korwel","sequence":"additional","affiliation":[{"name":"Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9163-927X","authenticated-orcid":false,"given":"Hans-Joachim","family":"Lehmler","sequence":"additional","affiliation":[{"name":"Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac N.","family":"Pessah","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7665-7584","authenticated-orcid":false,"given":"Pamela J.","family":"Lein","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Walz, W. (2005). Neural Circuits and Behavior. Integrative Physiology in the Proteomics and Post-Genomics Age, Humana Press.","DOI":"10.1385\/1592599257"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1111\/febs.16714","article-title":"Environmental experiences shape sexually dimorphic neuronal circuits and behaviour","volume":"291","author":"Setty","year":"2024","journal-title":"FEBS J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"a001727","DOI":"10.1101\/cshperspect.a001727","article-title":"Mechanisms and molecules of neuronal wiring: A primer","volume":"3","author":"Kolodkin","year":"2011","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Tripodi, M., Evers, J.F., Mauss, A., Bate, M., and Landgraf, M. (2008). Structural homeostasis: Compensatory adjustments of dendritic arbor geometry in response to variations of synaptic input. PLoS Biol., 6.","DOI":"10.1371\/journal.pbio.0060260"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1146\/annurev-cellbio-100913-013020","article-title":"Development of dendritic form and function","volume":"31","author":"Lefebvre","year":"2015","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0166-4328(96)02251-6","article-title":"Behavioral consequences of abnormal cortical development: Insights into developmental disabilities","volume":"86","author":"Hohmann","year":"1997","journal-title":"Behav. Brain Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.conb.2009.06.003","article-title":"A synaptic trek to autism","volume":"19","author":"Bourgeron","year":"2009","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.conb.2007.01.009","article-title":"Autism spectrum disorders: Developmental disconnection syndromes","volume":"17","author":"Geschwind","year":"2007","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1034\/j.1601-183X.2003.00037.x","article-title":"Model of autism: Increased ratio of excitation\/inhibition in key neural systems","volume":"2","author":"Rubenstein","year":"2003","journal-title":"Genes Brain Behav."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"a009886","DOI":"10.1101\/cshperspect.a009886","article-title":"Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities","volume":"4","author":"Zoghbi","year":"2012","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Alamdari, S.B., Sadeghi Damavandi, M., Zarei, M., and Khosrowabadi, R. (2022). Cognitive theories of autism based on the interactions between brain functional networks. Front. Hum. Neurosci., 16.","DOI":"10.3389\/fnhum.2022.828985"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Guang, S., Pang, N., Deng, X., Yang, L., He, F., Wu, L., Chen, C., Yin, F., and Peng, J. (2018). Synaptopathology Involved in Autism Spectrum Disorder. Front. Cell. Neurosci., 12.","DOI":"10.3389\/fncel.2018.00470"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9045","DOI":"10.1523\/JNEUROSCI.1229-22.2022","article-title":"Maladaptive laterality in cortical networks related to social communication in autism spectrum disorder","volume":"42","author":"Persichetti","year":"2022","journal-title":"J. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/S0896-6273(03)00631-7","article-title":"The control of dendrite development","volume":"40","author":"Jan","year":"2003","journal-title":"Neuron"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1074-7427(02)00021-7","article-title":"Experience-dependent changes in dendritic arbor and spine density in neocortex vary qualitatively with age and sex","volume":"79","author":"Kolb","year":"2003","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0959-4388(99)80028-2","article-title":"Synaptic plasticity in cortical systems","volume":"9","author":"Klintsova","year":"1999","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/86006","article-title":"How do dendrites take their shape?","volume":"4","author":"Scott","year":"2001","journal-title":"Nat. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.1073\/pnas.1013580108","article-title":"Involvement of ryanodine receptors in neurotrophin-induced hippocampal synaptic plasticity and spatial memory formation","volume":"108","author":"Adasme","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.tips.2005.12.008","article-title":"The role of the endoplasmic reticulum Ca2+ store in the plasticity of central neurons","volume":"27","author":"Bardo","year":"2006","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s10827-015-0579-z","article-title":"Ryanodine-receptor-driven intracellular calcium dynamics underlying spatial association of synaptic plasticity","volume":"39","author":"Futagi","year":"2015","journal-title":"J. Comput. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Molina Calistro, L., Arancibia, Y., Alarcon, J., and Torres, R.F. (2025). The Ca(2+) Bridge: From Neurons to Circuits in Rett Syndrome. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262110490"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1089\/ars.2017.7277","article-title":"Calcium Release Mediated by Redox-Sensitive RyR2 Channels Has a Central Role in Hippocampal Structural Plasticity and Spatial Memory","volume":"29","author":"More","year":"2018","journal-title":"Antioxid. Redox Signal"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Valdes-Undurraga, I., Lobos, P., Sanchez-Robledo, V., Arias-Cavieres, A., SanMartin, C.D., Barrientos, G., More, J., Munoz, P., Paula-Lima, A.C., and Hidalgo, C. (2023). Long-term potentiation and spatial memory training stimulate the hippocampal expression of RyR2 calcium release channels. Front. Cell. Neurosci., 17.","DOI":"10.3389\/fncel.2023.1132121"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Karagas, N.E., and Venkatachalam, K. (2019). Roles for the Endoplasmic Reticulum in Regulation of Neuronal Calcium Homeostasis. Cells, 8.","DOI":"10.3390\/cells8101232"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1085\/jgp.201711878","article-title":"The structural basis of ryanodine receptor ion channel function","volume":"149","author":"Meissner","year":"2017","journal-title":"J. Gen. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/978-981-10-7757-9_11","article-title":"Ryanodine Receptor Structure and Function in Health and Disease","volume":"87","author":"Santulli","year":"2018","journal-title":"Subcell. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1152\/physrev.00033.2020","article-title":"Calcium-release channels: Structure and function of IP(3) receptors and ryanodine receptors","volume":"102","author":"Woll","year":"2022","journal-title":"Physiol. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1523\/JNEUROSCI.2884-13.2014","article-title":"The environmental neurotoxicant PCB 95 promotes synaptogenesis via ryanodine receptor-dependent miR132 upregulation","volume":"34","author":"Lesiak","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1289\/ehp.1104833","article-title":"PCB-95 modulates the calcium-dependent signaling pathway responsible for activity-dependent dendritic growth","volume":"120","author":"Wayman","year":"2012","journal-title":"Environ. Health Perspect."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1289\/ehp.1104832","article-title":"PCB-95 promotes dendritic growth via ryanodine receptor-dependent mechanisms","volume":"120","author":"Wayman","year":"2012","journal-title":"Environ. Health Perspect."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3163","DOI":"10.1007\/s00204-018-2285-x","article-title":"PCB 95 promotes dendritic growth in primary rat hippocampal neurons via mTOR-dependent mechanisms","volume":"92","author":"Keil","year":"2018","journal-title":"Arch. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3109\/10408449409049308","article-title":"Polychlorinated biphenyls (PCBs): Environmental impact, biochemical and toxic responses, and implications for risk assessment","volume":"24","author":"Safe","year":"1994","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"120081","DOI":"10.1016\/j.envres.2024.120081","article-title":"Comprehensive compilation of congener profiles to support health assessment of environmental exposures to polychlorinated biphenyl mixtures","volume":"263","author":"Schulz","year":"2024","journal-title":"Environ. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"118912","DOI":"10.1016\/j.envres.2024.118912","article-title":"Perinatal exposure to polychlorinated biphenyls (PCBs) and child neurodevelopment: A comprehensive systematic review of outcomes and methodological approaches","volume":"252","author":"Balalian","year":"2024","journal-title":"Environ. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s11121-023-01601-6","article-title":"A Systematic Review and Meta-analysis of Chemical Exposures and Attention-Deficit\/Hyperactivity Disorder in Children","volume":"25","author":"Dimitrov","year":"2024","journal-title":"Prev. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"103260","DOI":"10.1016\/j.arcmed.2025.103260","article-title":"Endocrine Disruptors and Attention Deficit Hyperactivity Disorder: A Systematic Review","volume":"56","author":"Latorre","year":"2025","journal-title":"Arch. Med. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Minuti, A., Floramo, A., Argento, V., Anchesi, I., Muscara, C., Calabro, M., and Silvestro, S. (2026). Polychlorinated Biphenyls, Oxidative Stress, and Brain Health: Mechanistic Links to Neurodegenerative and Neurodevelopmental Diseases. Antioxidants, 15.","DOI":"10.3390\/antiox15020242"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"150","DOI":"10.3892\/ijmm.2021.4983","article-title":"Perspective on prenatal polychlorinated biphenyl exposure and the development of the progeny nervous system (Review)","volume":"48","author":"Wang","year":"2021","journal-title":"Int. J. Mol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"122439","DOI":"10.1016\/j.envpol.2023.122439","article-title":"Persistent organic pollutants exposure and risk of autism spectrum disorders: A systematic review and meta-analysis","volume":"336","author":"Xu","year":"2023","journal-title":"Environ. Pollut."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1289\/ehp.11771","article-title":"Developmental exposure to polychlorinated biphenyls interferes with experience-dependent dendritic plasticity and ryanodine receptor expression in weanling rats","volume":"117","author":"Yang","year":"2009","journal-title":"Environ. Health Perspect."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/369556a0","article-title":"Excitation-contraction uncoupling and muscular degeneration in mice lacking functional skeletal muscle ryanodine-receptor gene","volume":"369","author":"Takeshima","year":"1994","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3309","DOI":"10.1093\/emboj\/17.12.3309","article-title":"Embryonic lethality and abnormal cardiac myocytes in mice lacking ryanodine receptor type 2","volume":"17","author":"Takeshima","year":"1998","journal-title":"EMBO J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1097\/00000542-200612000-00016","article-title":"Pharmacologic and functional characterization of malignant hyperthermia in the R163C RyR1 knock-in mouse","volume":"105","author":"Yang","year":"2006","journal-title":"Anesthesiology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1097\/ALN.0b013e3182a8a998","article-title":"Exome sequencing reveals novel rare variants in the ryanodine receptor and calcium channel genes in malignant hyperthermia families","volume":"119","author":"Kim","year":"2013","journal-title":"Anesthesiology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1159\/000548601","article-title":"Redefining Malignant Hyperthermia: Multi-Omics Insights into a Complex Anesthetic Disorder","volume":"19","author":"Thachuk","year":"2026","journal-title":"Lifestyle Genom."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1124\/mol.110.067959","article-title":"Functional and biochemical properties of ryanodine receptor type 1 channels from heterozygous R163C malignant hyperthermia-susceptible mice","volume":"79","author":"Feng","year":"2011","journal-title":"Mol. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.neuro.2006.08.007","article-title":"Ryanodine receptor type 1 (RyR1) possessing malignant hyperthermia mutation R615C exhibits heightened sensitivity to dysregulation by non-coplanar 2,2\u2032,3,5\u2032,6-pentachlorobiphenyl (PCB 95)","volume":"28","author":"Ta","year":"2007","journal-title":"Neurotoxicology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7646","DOI":"10.1073\/pnas.0701944104","article-title":"Perinatal exposure to a noncoplanar polychlorinated biphenyl alters tonotopy, receptive fields, and plasticity in rat primary auditory cortex","volume":"104","author":"Kenet","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","first-page":"457","article-title":"Long-term effects of developmental exposure to 2,2\u2032,3,5\u2032,6-pentachlorobiphenyl (PCB 95) on locomotor activity, spatial learning and memory and brain ryanodine binding","volume":"18","author":"Schantz","year":"1997","journal-title":"Neurotoxicology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1093\/toxsci\/kfx071","article-title":"Congener-Specific Disposition of Chiral Polychlorinated Biphenyls in Lactating Mice and Their Offspring: Implications for PCB Developmental Neurotoxicity","volume":"158","author":"Lukasiewicz","year":"2017","journal-title":"Toxicol. Sci. Off. J. Soc. Toxicol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1021\/acs.chemrestox.5b00241","article-title":"Effect of pregnancy on the disposition of 2,2\u2032,3,5\u2032,6-pentachlorobiphenyl (PCB 95) atropisomers and their hydroxylated metabolites in female mice","volume":"28","author":"Barnhart","year":"2015","journal-title":"Chem. Res. Toxicol."},{"key":"ref_52","unstructured":"Barnhart, C.D. (2015). In Vivo Evidence of Ryanodine Receptor-Dependent Mechanisms in Structural and Cognitive Correlates of Neurodevelopment and Modification of the Developmental Neurotoxicity of 2,2\u2032,3,5\u2032,6-pentachlorobiphenyl. [Ph.D. Thesis, University of California, Davis]."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/S0165-0173(01)00067-4","article-title":"Applications of the Morris water maze in the study of learning and memory","volume":"36","year":"2001","journal-title":"Brain Res. Brain Res. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1016\/S0092-8674(00)81827-9","article-title":"The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory","volume":"87","author":"Tsien","year":"1996","journal-title":"Cell"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"B\u00e1rez-L\u00f3pez, S., and Guada\u00f1o-Ferraz, A. (2017). Thyroid Hormone Availability and Action during Brain Development in Rodents. Front. Cell. Neurosci., 11.","DOI":"10.3389\/fncel.2017.00240"},{"key":"ref_56","first-page":"248","article-title":"Association between polychlorinated biphenyl exposure and thyroid hormones: A systematic review and meta-analysis","volume":"40","author":"Little","year":"2022","journal-title":"J. Environ. Sci. Health C Toxicol. Carcinog."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2909","DOI":"10.1210\/en.2010-1490","article-title":"Individual polychlorinated biphenyl (PCB) congeners produce tissue- and gene-specific effects on thyroid hormone signaling during development","volume":"152","author":"Giera","year":"2011","journal-title":"Endocrinology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1210\/endo.141.1.7273","article-title":"Developmental exposure to polychlorinated biphenyls exerts thyroid hormone-like effects on the expression of RC3\/neurogranin and myelin basic protein messenger ribonucleic acids in the developing rat brain","volume":"141","author":"Zoeller","year":"2000","journal-title":"Endocrinology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1021\/tx050196m","article-title":"Structure-activity relationship for noncoplanar polychlorinated biphenyl congeners toward the ryanodine receptor-Ca2+ channel complex type 1 (RyR1)","volume":"19","author":"Pessah","year":"2006","journal-title":"Chem. Res. Toxicol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Klocke, C., and Lein, P.J. (2020). Evidence Implicating Non-Dioxin-Like Congeners as the Key Mediators of Polychlorinated Biphenyl (PCB) Developmental Neurotoxicity. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21031013"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Sethi, S., Stietz, K.K.P., Valenzuela, A.E., Klocke, C.R., Silverman, J.L., Puschner, B., Pessah, I.N., and Lein, P.J. (2021). Developmental Exposure to a Human-Relevant Polychlorinated Biphenyl Mixture Causes Behavioral Phenotypes That Vary by Sex and Genotype in Juvenile Mice Expressing Human Mutations That Modulate Neuronal Calcium. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.766826"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1007\/s00204-025-04241-7","article-title":"3,3\u2032-Dichlorobiphenyl (PCB 11) alters the hepatic expression of cytochrome P450 enzymes in the liver of mouse dams exposed orally during pregnancy and lactation","volume":"100","author":"Roach","year":"2026","journal-title":"Arch. Toxicol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Wang, H., Goskowicz, A., Spiegelhoff, A., Kennedy, C.L., Ridlon, M.M., Marek, R.F., Lehmler, H.J., and Keil Stietz, K.P. (2026). Developmental exposure to a human-relevant PCB mixture: Impacts on PCB congeners, metabolites, and drug-metabolizing enzymes in the bladder of post-weaning mice. Arch. Toxicol., 1\u201316.","DOI":"10.1007\/s00204-026-04498-6"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"245","DOI":"10.3109\/10408444.2014.999365","article-title":"Metabolism and metabolites of polychlorinated biphenyls","volume":"45","author":"Grimm","year":"2015","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1021\/acs.est.8b05250","article-title":"Human CYP2A6, CYP2B6, AND CYP2E1 Atropselectively Metabolize Polychlorinated Biphenyls to Hydroxylated Metabolites","volume":"53","author":"Uwimana","year":"2019","journal-title":"Environ. Sci. Technol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1177\/23727322231196794","article-title":"Endocrine-Disrupting Chemicals: Science and Policy","volume":"10","author":"Hilz","year":"2023","journal-title":"Policy Insights Behav. Brain Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1476-069X-14-13","article-title":"Non-monotonic dose-response relationships and endocrine disruptors: A qualitative method of assessment","volume":"14","author":"Lagarde","year":"2015","journal-title":"Environ. Health"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1111\/j.1365-2605.2007.00857.x","article-title":"Thyroid disrupting chemicals: Mechanisms and mixtures","volume":"31","author":"Crofton","year":"2008","journal-title":"Int. J. Androl."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/j.neuro.2011.11.005","article-title":"Developmental thyroid hormone disruption: Prevalence, environmental contaminants and neurodevelopmental consequences","volume":"33","author":"Gilbert","year":"2012","journal-title":"Neurotoxicology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1089\/thy.2007.0107","article-title":"Environmental chemicals impacting the thyroid: Targets and consequences","volume":"17","author":"Zoeller","year":"2007","journal-title":"Thyroid. Off. J. Am. Thyroid. Assoc."},{"key":"ref_71","unstructured":"Robertson, L.W., and Hansen, L.G. (2001). Disruption of steroid hormone signaling by PCBs. PCBs: Recent Advances in Environmental Toxicology and Health Effects, The University Press of Kentucky."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.yhbeh.2018.11.006","article-title":"Endocrine-disrupting chemicals: Effects on neuroendocrine systems and the neurobiology of social behavior","volume":"111","author":"Gore","year":"2019","journal-title":"Horm. Behav."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3948","DOI":"10.1021\/acs.est.9b00535","article-title":"Comparative Analyses of the 12 Most Abundant PCB Congeners Detected in Human Maternal Serum for Activity at the Thyroid Hormone Receptor and Ryanodine Receptor","volume":"53","author":"Sethi","year":"2019","journal-title":"Environ. Sci. Technol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e12526","DOI":"10.1111\/gbb.12526","article-title":"Genetic mutations in Ca(2+) signaling alter dendrite morphology and social approach in juvenile mice","volume":"18","author":"Keil","year":"2018","journal-title":"Genes Brain Behav."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Keil Stietz, K.P., Sethi, S., Klocke, C.R., de Ruyter, T.E., Wilson, M.D., Pessah, I.N., and Lein, P.J. (2021). Sex and Genotype Modulate the Dendritic Effects of Developmental Exposure to a Human-Relevant Polychlorinated Biphenyls Mixture in the Juvenile Mouse. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.766802"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"7963","DOI":"10.1073\/pnas.0914613107","article-title":"Spatial learning sculpts the dendritic arbor of adult-born hippocampal neurons","volume":"107","author":"Tronel","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1080\/14734220310017456","article-title":"The effects of cerebellar damage on maze learning in animals","volume":"2","author":"Lalonde","year":"2003","journal-title":"Cerebellum"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S0166-4328(99)00173-4","article-title":"Involvement of the hippocampus and associative parietal cortex in the use of proximal and distal landmarks for navigation","volume":"109","author":"Save","year":"2000","journal-title":"Behav. Brain Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0166-4328(02)00237-1","article-title":"Role of the neocortex in the water maze task in the rat: A detailed behavioral and Golgi-Cox analysis","volume":"138","author":"Hoh","year":"2003","journal-title":"Behav. Brain Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.devbrainres.2004.11.004","article-title":"Hydroxylated metabolites of polychlorinated biphenyls inhibit thyroid-hormone-dependent extension of cerebellar Purkinje cell dendrites","volume":"154","author":"Nagata","year":"2005","journal-title":"Brain Res. Dev. Brain Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0006-8993(72)90362-9","article-title":"The effects of early hypo- and hyperthyroidism on the development of rat cerebellar cortex. I. Cell proliferation and differentiation","volume":"44","author":"Nicholson","year":"1972","journal-title":"Brain Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1002\/(SICI)1098-2396(200005)36:2<85::AID-SYN1>3.0.CO;2-Y","article-title":"Chronic social stress reduces dendritic arbors in CA3 of hippocampus and decreases binding to serotonin transporter sites","volume":"36","author":"McKittrick","year":"2000","journal-title":"Synapse"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1146\/annurev.neuro.22.1.105","article-title":"Stress and hippocampal plasticity","volume":"22","author":"McEwen","year":"1999","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/bs.ant.2023.09.003","article-title":"Ryanodine receptor-dependent mechanisms of PCB developmental neurotoxicity","volume":"Volume 10","author":"Aschner","year":"2023","journal-title":"Advances in Neurotoxicology: Neurotoxicity of Halogenated Organic Compounds"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.ceca.2005.01.008","article-title":"Regulation of dendritic growth and plasticity by local and global calcium dynamics","volume":"37","author":"Lohmann","year":"2005","journal-title":"Cell Calcium"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0166-2236(99)01499-X","article-title":"Dendritic spine formation and pruning: Common cellular mechanisms?","volume":"23","author":"Segal","year":"2000","journal-title":"Trends Neurosci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1002\/em.21722","article-title":"Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder","volume":"53","author":"Mitchell","year":"2012","journal-title":"Environ. Mol. Mutagen."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/mp.2010.127","article-title":"Allowing for sex differences increases power in a GWAS of multiplex Autism families","volume":"17","author":"Lu","year":"2012","journal-title":"Mol. Psychiatry"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.envres.2018.12.061","article-title":"Polychlorinated biphenyls influence on autism spectrum disorder risk in the MARBLES cohort","volume":"171","author":"Granillo","year":"2019","journal-title":"Environ. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1093\/scan\/nsw027","article-title":"Sex differences in Autism: A resting-state fMRI investigation of functional brain connectivity in males and females","volume":"11","author":"Alaerts","year":"2016","journal-title":"Soc. Cogn. Affect. Neurosci."},{"key":"ref_91","first-page":"888","article-title":"Reduced Hippocampal Functional Connectivity During Episodic Memory Retrieval in Autism","volume":"27","author":"Cooper","year":"2017","journal-title":"Cereb. Cortex"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1002\/aur.1276","article-title":"Functional assays of local connectivity in the somatosensory cortex of individuals with autism","volume":"6","author":"Coskun","year":"2013","journal-title":"Autism Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.celrep.2013.10.003","article-title":"Local functional overconnectivity in posterior brain regions is associated with symptom severity in autism spectrum disorders","volume":"5","author":"Keown","year":"2013","journal-title":"Cell Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1093\/brain\/awv043","article-title":"Somatosensory cortex functional connectivity abnormalities in autism show opposite trends, depending on direction and spatial scale","volume":"138","author":"Khan","year":"2015","journal-title":"Brain"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"11393","DOI":"10.1021\/es302810t","article-title":"2,2\u2032,3,5\u2032,6-Pentachlorobiphenyl (PCB 95) and its hydroxylated metabolites are enantiomerically enriched in female mice","volume":"46","author":"Barnhart","year":"2012","journal-title":"Environ. Sci. Technol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7801\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T04:27:39Z","timestamp":1788496059000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7801"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":95,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177801"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177801","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,31]]}}}