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Environmental Mechanisms of Neurodevelopmental Toxicity

  • Mechanisms of Toxicity (CJ Mattingly and A Planchart, Section Editors)
  • Published:
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Abstract

Purpose of Review

With the incidence of neurodevelopmental disorders on the rise, it is imperative to identify and understand the mechanisms by which environmental contaminants can impact the developing brain and heighten risk. Here, we report on recent findings regarding novel mechanisms of developmental neurotoxicity and highlight chemicals of concern, beyond traditionally defined neurotoxicants.

Recent Findings

The perinatal window represents a critical and extremely vulnerable period of time during which chemical insult can alter the morphological and functional trajectory of the developing brain. Numerous chemical classes have been associated with alterations in neurodevelopment including metals, solvents, pesticides, and, more recently, endocrine-disrupting compounds. Although mechanisms of neurotoxicity have traditionally been identified as pathways leading to neuronal cell death, neuropathology, or severe neural injury, recent research highlights alternative mechanisms that result in more subtle but consequential changes in the brain and behavior. These emerging areas of interest include neuroendocrine and immune disruption, as well as indirect toxicity via actions on other organs such as the gut and placenta.

Summary

Understanding of the myriad ways in which the developing brain is vulnerable to chemical exposures has grown tremendously over the past decade. Further progress and implementation in risk assessment is critical to reducing risk of neurodevelopmental disorders.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Adinolfi M. The development of the human blood-CSF-brain barrier. Dev Med Child Neurol. 1985;27(4):532–7.

    Article  CAS  PubMed  Google Scholar 

  2. Rodier PM. Vulnerable periods and processes during central nervous system development. Environ Health Perspect. 1994;102(Suppl 2):121–4. https://doi.org/10.1289/ehp.94102121.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Bayer SA, Altman J, Russo RJ, Zhang X. Timetables of neurogenesis in the human brain based on experimentally determined patterns in the rat. Neurotoxicology. 1993;14(1):83–144.

    CAS  PubMed  Google Scholar 

  4. Meredith RM. Sensitive and critical periods during neurotypical and aberrant neurodevelopment: a framework for neurodevelopmental disorders. Neurosci Biobehav Rev. 2015;50:180–8. https://doi.org/10.1016/j.neubiorev.2014.12.001.

    Article  CAS  PubMed  Google Scholar 

  5. Kroon T, Sierksma MC, Meredith RM. Investigating mechanisms underlying neurodevelopmental phenotypes of autistic and intellectual disability disorders: a perspective. Front Syst Neurosci. 2013;7:75. https://doi.org/10.3389/fnsys.2013.00075.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Marco EM, Macri S, Laviola G. Critical age windows for neurodevelopmental psychiatric disorders: evidence from animal models. Neurotox Res. 2011;19(2):286–307. https://doi.org/10.1007/s12640-010-9205-z.

    Article  PubMed  Google Scholar 

  7. • Heyer DB, Meredith RM. Environmental toxicology: sensitive periods of development and neurodevelopmental disorders. Neurotoxicology. 2017;58:23–41. https://doi.org/10.1016/j.neuro.2016.10.017. Overview of developmental periods of susceptibility to environmental toxicants and neurodevelopmental disorders and the common pathophysiological mechanisms of neurotoxicants.

    Article  CAS  PubMed  Google Scholar 

  8. Rodier PM. Developing brain as a target of toxicity. Environ Health Perspect. 1995;103(Suppl 6):73–6. https://doi.org/10.1289/ehp.95103s673.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Koger SM, Schettler T, Weiss B. Environmental toxicants and developmental disabilities: a challenge for psychologists. Am Psychol. 2005;60(3):243–55. https://doi.org/10.1037/0003-066X.60.3.243.

    Article  PubMed  Google Scholar 

  10. Rauh VA, Margolis AE. Research review: environmental exposures, neurodevelopment, and child mental health—new paradigms for the study of brain and behavioral effects. J Child Psychol Psychiatry. 2016;57(7):775–93. https://doi.org/10.1111/jcpp.12537.

    Article  PubMed Central  PubMed  Google Scholar 

  11. • Konkel L. Lasting impact of an ephemeral organ: the role of the placenta in fetal programming. Environ Health Perspect. 2016;124(7):A124–9. https://doi.org/10.1289/ehp.124-A124. Critical summary of the role the placenta plays in regulating the fetal environment and how molecular changes in the placenta may contribute to aspects of fetal programming.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Weiss B, Amler S, Amler RW. Pesticides. Pediatrics. 2004;113(4 Suppl):1030–6.

    PubMed  Google Scholar 

  13. Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. Lancet. 2006;368(9553):2167–78. https://doi.org/10.1016/S0140-6736(06)69665-7.

    Article  CAS  PubMed  Google Scholar 

  14. •• Grandjean P, Landrigan PJ. Neurobehavioural effects of developmental toxicity. Lancet neurology. 2014;13(3):330–8. https://doi.org/10.1016/S1474-4422(13)70278-3. A critical follow-up to their landmark 2006 paper and an overview of newly recognised and suspected developmental neurotoxicants with an emphasis on the probability of developmental exposure to unrecognised toxic chemicals.

    Article  CAS  PubMed  Google Scholar 

  15. Risau W, Wolburg H. Development of the blood-brain barrier. Trends Neurosci. 1990;13(5):174–8. https://doi.org/10.1016/0166-2236(90)90043-A.

    Article  CAS  PubMed  Google Scholar 

  16. Cole TB, Jampsa RL, Walter BJ, Arndt TL, Richter RJ, Shih DM, et al. Expression of human paraoxonase (PON1) during development. Pharmacogenetics. 2003;13(6):357–64. https://doi.org/10.1097/01.fpc.0000054092.48725.30.

    Article  CAS  PubMed  Google Scholar 

  17. Mortensen SR, Chanda SM, Hooper MJ, Padilla S. Maturational differences in chlorpyrifos-oxonase activity may contribute to age-related sensitivity to chlorpyrifos. J Biochem Toxicol. 1996;11(6):279–87. https://doi.org/10.1002/(SICI)1522-7146(1996)11:6<279::AID-JBT3>3.0.CO;2-H.

    Article  CAS  PubMed  Google Scholar 

  18. Benke GM, Murphy SD. The influence of age on the toxicity and metabolism of methyl parathion and parathion in male and female rats. Toxicol Appl Pharmacol. 1975;31(2):254–69. https://doi.org/10.1016/0041-008X(75)90161-1.

    Article  CAS  PubMed  Google Scholar 

  19. Tamm C, Ceccatelli S. Mechanistic insight into neurotoxicity induced by developmental insults. Biochem Biophys Res Commun. 2017;482(3):408–18. https://doi.org/10.1016/j.bbrc.2016.10.087.

    Article  CAS  PubMed  Google Scholar 

  20. Bloom B, Cohen RA, Freeman G. Summary health statistics for U.S. children: National Health Interview Survey, 2008. Vital Health Stat. 2009;10(244):1–81.

    Google Scholar 

  21. Rohlman DS, Anger WK, Lein PJ. Correlating neurobehavioral performance with biomarkers of organophosphorous pesticide exposure. Neurotoxicology. 2011;32(2):268–76. https://doi.org/10.1016/j.neuro.2010.12.008.

    Article  CAS  PubMed  Google Scholar 

  22. Costa LG, de Laat R, Tagliaferri S, Pellacani C. A mechanistic view of polybrominated diphenyl ether (PBDE) developmental neurotoxicity. Toxicol Lett. 2014;230(2):282–94. https://doi.org/10.1016/j.toxlet.2013.11.011.

    Article  CAS  PubMed  Google Scholar 

  23. Hackman DA, Farah MJ, Meaney MJ. Socioeconomic status and the brain: mechanistic insights from human and animal research. Nat Rev Neurosci. 2010;11(9):651–9. https://doi.org/10.1038/nrn2897.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Suades-Gonzalez E, Gascon M, Guxens M, Sunyer J. Air pollution and neuropsychological development: a review of the latest evidence. Endocrinology. 2015;156(10):3473–82. https://doi.org/10.1210/en.2015-1403.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. U.S. Environmental Protection Agency. Chemical Hazard Data Availability Study: what do we really know about the safety of high production volume chemicals? 1998.

  26. USGAO. Chemical regulation: options for enhancing the effectiveness of the Toxic Substances Control Act. U.S. Governmental Accounting Office; 2009.

  27. Kalkbrenner AE, Schmidt RJ, Penlesky AC. Environmental chemical exposures and autism spectrum disorders: a review of the epidemiological evidence. Curr Probl Pediatr Adolesc Health Care. 2014;44(10):277–318. https://doi.org/10.1016/j.cppeds.2014.06.001.

    Article  PubMed Central  PubMed  Google Scholar 

  28. •• Lam J, Lanphear BP, Bellinger D, Axelrad DA, McPartland J, Sutton P, et al. Developmental PBDE exposure and IQ/ADHD in childhood: a systematic review and meta-analysis. Environ Health Perspect. 2017; https://doi.org/10.1289/EHP1632. A comprehensive and systematic review of the PBDE literature confirming a strong relationship between early life exposure and adverse cognitive and behavioral outcomes in children.

  29. Tilson HA, MacPhail RC, Crofton KM. Defining neurotoxicity in a decision-making context. Neurotoxicology. 1995;16(2):363–75.

    CAS  PubMed  Google Scholar 

  30. Patisaul HB, Belcher SM. Endocrine disruptors, brain, and behaviors. Oxford series in behavioral neuroendocrinology. New York: Oxford University Press; 2017.

    Book  Google Scholar 

  31. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, et al. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev. 2009;30(4):293–342. https://doi.org/10.1210/er.2009-0002.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. •• Zoeller RT, Brown TR, Doan LL, Gore AC, Skakkebaek NE, Soto AM, et al. Endocrine-disrupting chemicals and public health protection: a statement of principles from The Endocrine Society. Endocrinology. 2012;153(9):4097–110. https://doi.org/10.1210/en.2012-1422. A high-impact, thorough assessment of EDC-related effects on human health including impacts on neurodevolopment and behavior.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Schug TT, Blawas AM, Gray K, Heindel JJ, Lawler CP. Elucidating the links between endocrine disruptors and neurodevelopment. Endocrinology. 2015;156(6):1941–51. https://doi.org/10.1210/en.2014-1734.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Lanphear BP, Hornung R, Khoury J, Yolton K, Baghurst P, Bellinger DC, et al. Low-level environmental lead exposure and children’s intellectual function: an international pooled analysis. Environ Health Perspect. 2005;113(7):894–9. https://doi.org/10.1289/ehp.7688.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Landrigan PJ, Whitworth RH, Baloh RW, Staehling NW, Barthel WF, Rosenblum BF. Neuropsychological dysfunction in children with chronic low-level lead absorption. Lancet. 1975;1(7909):708–12.

    Article  CAS  PubMed  Google Scholar 

  36. Needleman HL, Gunnoe C, Leviton A, Reed R, Peresie H, Maher C, et al. Deficits in psychologic and classroom performance of children with elevated dentine lead levels. N Engl J Med. 1979;300(13):689–95. https://doi.org/10.1056/NEJM197903293001301.

    Article  CAS  PubMed  Google Scholar 

  37. Baranowska-Bosiacka I, Gutowska I, Marchlewicz M, Marchetti C, Kurzawski M, Dziedziejko V, et al. Disrupted pro- and antioxidative balance as a mechanism of neurotoxicity induced by perinatal exposure to lead. Brain Res. 2012;1435:56–71. https://doi.org/10.1016/j.brainres.2011.11.062.

    Article  CAS  PubMed  Google Scholar 

  38. Devi CB, Reddy GH, Prasanthi RP, Chetty CS, Reddy GR. Developmental lead exposure alters mitochondrial monoamine oxidase and synaptosomal catecholamine levels in rat brain. Int J Dev Neurosci. 2005;23(4):375–81. https://doi.org/10.1016/j.ijdevneu.2004.11.003.

    Article  CAS  PubMed  Google Scholar 

  39. McGivern RF, Sokol RZ, Berman NG. Prenatal lead exposure in the rat during the third week of gestation: long-term behavioral, physiological, and anatomical effects associated with reproduction. Toxicol Appl Pharmacol. 1991;110(2):206–15. https://doi.org/10.1016/S0041-008X(05)80003-1.

    Article  CAS  PubMed  Google Scholar 

  40. Sobin C, Montoya MG, Parisi N, Schaub T, Cervantes M, Armijos RX. Microglial disruption in young mice with early chronic lead exposure. Toxicol Lett. 2013;220(1):44–52. https://doi.org/10.1016/j.toxlet.2013.04.003.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Slotkin TA, Oliver CA, Seidler FJ. Critical periods for the role of oxidative stress in the developmental neurotoxicity of chlorpyrifos and terbutaline, alone or in combination. Brain Res Dev Brain Res. 2005;157(2):172–80. https://doi.org/10.1016/j.devbrainres.2005.04.001.

    Article  CAS  PubMed  Google Scholar 

  42. Aldridge JE, Seidler FJ, Meyer A, Thillai I, Slotkin TA. Serotonergic systems targeted by developmental exposure to chlorpyrifos: effects during different critical periods. Environ Health Perspect. 2003;111(14):1736–43. https://doi.org/10.1289/ehp.6489.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Slotkin TA, Cooper EM, Stapleton HM, Seidler FJ. Does thyroid disruption contribute to the developmental neurotoxicity of chlorpyrifos? Environ Toxicol Pharmacol. 2013;36(2):284–7. https://doi.org/10.1016/j.etap.2013.04.003.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Gomez-Gimenez B, Llansola M, Hernandez-Rabaza V, Cabrera-Pastor A, Malaguarnera M, Agusti A, et al. Sex-dependent effects of developmental exposure to different pesticides on spatial learning. The role of induced neuroinflammation in the hippocampus. Food Chem Toxicol. 2017;99:135–48. https://doi.org/10.1016/j.fct.2016.11.028.

    Article  CAS  PubMed  Google Scholar 

  45. Kabuto H, Amakawa M, Shishibori T. Exposure to bisphenol A during embryonic/fetal life and infancy increases oxidative injury and causes underdevelopment of the brain and testis in mice. Life Sci. 2004;74(24):2931–40. https://doi.org/10.1016/j.lfs.2003.07.060.

    Article  CAS  PubMed  Google Scholar 

  46. Franssen D, Gerard A, Hennuy B, Donneau AF, Bourguignon JP, Parent AS. Delayed neuroendocrine sexual maturation in female rats after a very low dose of bisphenol A through altered GABAergic neurotransmission and opposing effects of a high dose. Endocrinology. 2016;157(5):1740–50. https://doi.org/10.1210/en.2015-1937.

    Article  CAS  PubMed  Google Scholar 

  47. Patisaul HB, Sullivan AW, Radford ME, Walker DM, Adewale HB, Winnik B, et al. Anxiogenic effects of developmental bisphenol A exposure are associated with gene expression changes in the juvenile rat amygdala and mitigated by soy. PLoS One. 2012;7(9):e43890. https://doi.org/10.1371/journal.pone.0043890.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. • Rebuli ME, Gibson P, Rhodes CL, Cushing BS, Patisaul HB. Sex differences in microglial colonization and vulnerabilities to endocrine disruption in the social brain. Gen Comp Endocrinol. 2016;238:39–46. https://doi.org/10.1016/j.ygcen.2016.04.018. Important study showing sex-specific alterations in microglia colonization of the hippocampus and amygdala in rats following developmental exposure to BPA.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. He P, He W, Wang A, Xia T, Xu B, Zhang M, et al. PBDE-47-induced oxidative stress, DNA damage and apoptosis in primary cultured rat hippocampal neurons. Neurotoxicology. 2008;29(1):124–9. https://doi.org/10.1016/j.neuro.2007.10.002.

    Article  CAS  PubMed  Google Scholar 

  50. Viberg H, Fredriksson A, Eriksson P. Neonatal exposure to polybrominated diphenyl ether (PBDE 153) disrupts spontaneous behaviour, impairs learning and memory, and decreases hippocampal cholinergic receptors in adult mice. Toxicol Appl Pharmacol. 2003;192(2):95–106. https://doi.org/10.1016/S0041-008X(03)00217-5.

    Article  CAS  PubMed  Google Scholar 

  51. Kodavanti PR, Coburn CG, Moser VC, MacPhail RC, Fenton SE, Stoker TE, et al. Developmental exposure to a commercial PBDE mixture, DE-71: neurobehavioral, hormonal, and reproductive effects. Toxicol Sci. 2010;116(1):297–312. https://doi.org/10.1093/toxsci/kfq105.

    Article  CAS  PubMed  Google Scholar 

  52. Mariani A, Fanelli R, Re Depaolini A, De Paola M. Decabrominated diphenyl ether and methylmercury impair fetal nervous system development in mice at documented human exposure levels. Dev Neurobiol. 2015;75(1):23–38. https://doi.org/10.1002/dneu.22208.

    Article  CAS  PubMed  Google Scholar 

  53. Moller M, Swanepoel T, Harvey BH. Neurodevelopmental animal models reveal the convergent role of neurotransmitter systems, inflammation, and oxidative stress as biomarkers of schizophrenia: implications for novel drug development. ACS Chem Neurosci. 2015;6(7):987–1016. https://doi.org/10.1021/cn5003368.

    Article  CAS  PubMed  Google Scholar 

  54. Wells PG, Bhatia S, Drake DM, Miller-Pinsler L. Fetal oxidative stress mechanisms of neurodevelopmental deficits and exacerbation by ethanol and methamphetamine. Birth Defects Res C Embryo Today. 2016;108(2):108–30. https://doi.org/10.1002/bdrc.21134.

    Article  CAS  PubMed  Google Scholar 

  55. Ikonomidou C, Kaindl AM. Neuronal death and oxidative stress in the developing brain. Antioxid Redox Signal. 2011;14(8):1535–50. https://doi.org/10.1089/ars.2010.3581.

    Article  CAS  PubMed  Google Scholar 

  56. Shoji H, Ikeda N, Hosozawa M, Ohkawa N, Matsunaga N, Suganuma H, et al. Oxidative stress early in infancy and neurodevelopmental outcome in very low-birthweight infants. Pediatr Int. 2014;56(5):709–13. https://doi.org/10.1111/ped.12332.

    Article  CAS  PubMed  Google Scholar 

  57. O’Donovan DJ, Fernandes CJ. Free radicals and diseases in premature infants. Antioxid Redox Signal. 2004;6(1):169–76. https://doi.org/10.1089/152308604771978471.

    Article  CAS  PubMed  Google Scholar 

  58. Shelton JF, Hertz-Picciotto I, Pessah IN. Tipping the balance of autism risk: potential mechanisms linking pesticides and autism. Environ Health Perspect. 2012;120(7):944–51. https://doi.org/10.1289/ehp.1104553.

    Article  PubMed Central  PubMed  Google Scholar 

  59. Kaur P, Radotra B, Minz RW, Gill KD. Impaired mitochondrial energy metabolism and neuronal apoptotic cell death after chronic dichlorvos (OP) exposure in rat brain. Neurotoxicology. 2007;28(6):1208–19. https://doi.org/10.1016/j.neuro.2007.08.001.

    Article  CAS  PubMed  Google Scholar 

  60. Shi X, Gu A, Ji G, Li Y, Di J, Jin J, et al. Developmental toxicity of cypermethrin in embryo-larval stages of zebrafish. Chemosphere. 2011;85(6):1010–6. https://doi.org/10.1016/j.chemosphere.2011.07.024.

    Article  CAS  PubMed  Google Scholar 

  61. Prakash C, Soni M, Kumar V. Biochemical and molecular alterations following arsenic-induced oxidative stress and mitochondrial dysfunction in rat brain. Biol Trace Elem Res. 2015;167(1):121–9. https://doi.org/10.1007/s12011-015-0284-9.

    Article  CAS  PubMed  Google Scholar 

  62. Bjorling-Poulsen M, Andersen HR, Grandjean P. Potential developmental neurotoxicity of pesticides used in Europe. Environ Health. 2008;7(1):50. https://doi.org/10.1186/1476-069X-7-50.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Aldridge JE, Levin ED, Seidler FJ, Slotkin TA. Developmental exposure of rats to chlorpyrifos leads to behavioral alterations in adulthood, involving serotonergic mechanisms and resembling animal models of depression. Environ Health Perspect. 2005;113(5):527–31. https://doi.org/10.1289/ehp.7867.

    Article  PubMed Central  PubMed  Google Scholar 

  64. Aldridge JE, Seidler FJ, Slotkin TA. Developmental exposure to chlorpyrifos elicits sex-selective alterations of serotonergic synaptic function in adulthood: critical periods and regional selectivity for effects on the serotonin transporter, receptor subtypes, and cell signaling. Environ Health Perspect. 2004;112(2):148–55.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Slotkin TA, Seidler FJ. The alterations in CNS serotonergic mechanisms caused by neonatal chlorpyrifos exposure are permanent. Brain Res Dev Brain Res. 2005;158(1–2):115–9. https://doi.org/10.1016/j.devbrainres.2005.06.008.

    Article  CAS  PubMed  Google Scholar 

  66. Slotkin TA, Seidler FJ. Comparative developmental neurotoxicity of organophosphates in vivo: transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems. Brain Res Bull. 2007;72(4–6):232–74. https://doi.org/10.1016/j.brainresbull.2007.01.005.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Johri A, Yadav S, Singh RL, Dhawan A, Ali M, Parmar D. Long lasting effects of prenatal exposure to deltamethrin on cerebral and hepatic cytochrome P450s and behavioral activity in rat offspring. Eur J Pharmacol. 2006;544(1–3):58–68. https://doi.org/10.1016/j.ejphar.2006.06.042.

    Article  CAS  PubMed  Google Scholar 

  68. Shafer TJ, Meyer DA, Crofton KM. Developmental neurotoxicity of pyrethroid insecticides: critical review and future research needs. Environ Health Perspect. 2005;113(2):123–36.

    Article  CAS  PubMed  Google Scholar 

  69. Richardson JR, Taylor MM, Shalat SL, Guillot TS 3rd, Caudle WM, Hossain MM, et al. Developmental pesticide exposure reproduces features of attention deficit hyperactivity disorder. FASEB J. 2015;29(5):1960–72. https://doi.org/10.1096/fj.14-260901.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Mubarak Hossain M, Suzuki T, Sato N, Sato I, Takewaki T, Suzuki K, et al. Differential effects of pyrethroid insecticides on extracellular dopamine in the striatum of freely moving rats. Toxicol Appl Pharmacol. 2006;217(1):25–34. https://doi.org/10.1016/j.taap.2006.07.011.

    Article  CAS  PubMed  Google Scholar 

  71. Elwan MA, Richardson JR, Guillot TS, Caudle WM, Miller GW. Pyrethroid pesticide-induced alterations in dopamine transporter function. Toxicol Appl Pharmacol. 2006;211(3):188–97. https://doi.org/10.1016/j.taap.2005.06.003.

    Article  CAS  PubMed  Google Scholar 

  72. Gillette JS, Bloomquist JR. Differential up-regulation of striatal dopamine transporter and alpha-synuclein by the pyrethroid insecticide permethrin. Toxicol Appl Pharmacol. 2003;192(3):287–93. https://doi.org/10.1016/S0041-008X(03)00326-0.

    Article  CAS  PubMed  Google Scholar 

  73. Kung TS, Richardson JR, Cooper KR, White LA. Developmental deltamethrin exposure causes persistent changes in dopaminergic gene expression, neurochemistry, and locomotor activity in zebrafish. Toxicol Sci. 2015;146(2):235–43. https://doi.org/10.1093/toxsci/kfv087.

    Article  PubMed Central  PubMed  Google Scholar 

  74. Bellou V, Belbasis L, Tzoulaki I, Evangelou E, Ioannidis JP. Environmental risk factors and Parkinson’s disease: an umbrella review of meta-analyses. Parkinsonism Relat Disord. 2016;23:1–9. https://doi.org/10.1016/j.parkreldis.2015.12.008.

    Article  PubMed  Google Scholar 

  75. Landrigan PJ, Benbrook C. GMOs, herbicides, and public health. N Engl J Med. 2015;373(8):693–5. https://doi.org/10.1056/NEJMp1505660.

    Article  PubMed  Google Scholar 

  76. Puzianowska-Kuznicka M, Pietrzak M, Turowska O, Nauman A. Thyroid hormones and their receptors in the regulation of cell proliferation. Acta Biochim Pol. 2006;53(4):641–50.

    CAS  PubMed  Google Scholar 

  77. Ahmed OM, El-Gareib AW, El-Bakry AM, Abd El-Tawab SM, Ahmed RG. Thyroid hormones states and brain development interactions. Int J Dev Neurosci. 2008;26(2):147–209. https://doi.org/10.1016/j.ijdevneu.2007.09.011.

    Article  CAS  PubMed  Google Scholar 

  78. Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev. 2010;31(2):139–70. https://doi.org/10.1210/er.2009-0007.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Pinson A, Bourguignon JP, Parent AS. Exposure to endocrine disrupting chemicals and neurodevelopmental alterations. Andrology. 2016;4(4):706–22. https://doi.org/10.1111/andr.12211.

    Article  CAS  PubMed  Google Scholar 

  80. Zoeller RT, Crofton KM. Thyroid hormone action in fetal brain development and potential for disruption by environmental chemicals. Neurotoxicology. 2000;21(6):935–45.

    CAS  PubMed  Google Scholar 

  81. Frye CA, Bo E, Calamandrei G, Calza L, Dessi-Fulgheri F, Fernandez M, et al. Endocrine disrupters: a review of some sources, effects, and mechanisms of actions on behaviour and neuroendocrine systems. J Neuroendocrinol. 2012;24(1):144–59. https://doi.org/10.1111/j.1365-2826.2011.02229.x.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. • Rebuli ME, Patisaul HB. Assessment of sex specific endocrine disrupting effects in the prenatal and pre-pubertal rodent brain. J Steroid Biochem Mol Biol. 2015; https://doi.org/10.1016/j.jsbmb.2015.08.021. Important summary of the molecular and neuroanatomical changes in the pre-adult rodent brain following developmental exposure to EDCs, with a focus on sex differences.

  83. Wolstenholme JT, Rissman EF, Connelly JJ. The role of bisphenol A in shaping the brain, epigenome and behavior. Horm Behav. 2011;59(3):296–305. https://doi.org/10.1016/j.yhbeh.2010.10.001.

    Article  CAS  PubMed  Google Scholar 

  84. Dickerson SM, Gore AC. Estrogenic environmental endocrine-disrupting chemical effects on reproductive neuroendocrine function and dysfunction across the life cycle. Rev Endocr Metab Disord. 2007;8(2):143–59. https://doi.org/10.1007/s11154-007-9048-y.

    Article  CAS  PubMed  Google Scholar 

  85. Patisaul HB, Adewale HB. Long-term effects of environmental endocrine disruptors on reproductive physiology and behavior. Front Behav Neurosci. 2009;3:10. https://doi.org/10.3389/neuro.08.010.2009.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Cao J, Joyner L, Mickens JA, Leyrer SM, Patisaul HB. Sex-specific Esr2 mRNA expression in the rat hypothalamus and amygdala is altered by neonatal bisphenol A exposure. Reproduction. 2014;147(4):537–54. https://doi.org/10.1530/REP-13-0501.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Rubin BS, Lenkowski JR, Schaeberle CM, Vandenberg LN, Ronsheim PM, Soto AM. Evidence of altered brain sexual differentiation in mice exposed perinatally to low, environmentally relevant levels of bisphenol A. Endocrinology. 2006;147(8):3681–91. https://doi.org/10.1210/en.2006-0189.

    Article  CAS  PubMed  Google Scholar 

  88. Foradori CD, Hinds LR, Hanneman WH, Handa RJ. Effects of atrazine and its withdrawal on gonadotropin-releasing hormone neuroendocrine function in the adult female Wistar rat. Biol Reprod. 2009;81(6):1099–105. https://doi.org/10.1095/biolreprod.109.077453.

    Article  CAS  PubMed  Google Scholar 

  89. Foradori CD, Hinds LR, Hanneman WH, Legare ME, Clay CM, Handa RJ. Atrazine inhibits pulsatile luteinizing hormone release without altering pituitary sensitivity to a gonadotropin-releasing hormone receptor agonist in female Wistar rats. Biol Reprod. 2009;81(1):40–5. https://doi.org/10.1095/biolreprod.108.075713.

    Article  CAS  PubMed  Google Scholar 

  90. Foradori CD, Zimmerman AD, Hinds LR, Zuloaga KL, Breckenridge CB, Handa RJ. Atrazine inhibits pulsatile gonadotropin-releasing hormone (GnRH) release without altering GnRH messenger RNA or protein levels in the female rat. Biol Reprod. 2013;88(1):9. https://doi.org/10.1095/biolreprod.112.102277.

    Article  CAS  PubMed  Google Scholar 

  91. Sullivan AW, Beach EC, Stetzik LA, Perry A, D’Addezio AS, Cushing BS, et al. A novel model for neuroendocrine toxicology: neurobehavioral effects of BPA exposure in a prosocial species, the prairie vole (Microtus ochrogaster). Endocrinology. 2014;155(10):3867–81. https://doi.org/10.1210/en.2014-1379.

    Article  CAS  PubMed  Google Scholar 

  92. Engell MD, Godwin J, Young LJ, Vandenbergh JG. Perinatal exposure to endocrine disrupting compounds alters behavior and brain in the female pine vole. Neurotoxicol Teratol. 2006;28(1):103–10. https://doi.org/10.1016/j.ntt.2005.10.002.

    Article  CAS  PubMed  Google Scholar 

  93. Tabb MM, Blumberg B. New modes of action for endocrine-disrupting chemicals. Mol Endocrinol. 2006;20(3):475–82. https://doi.org/10.1210/me.2004-0513.

    Article  CAS  PubMed  Google Scholar 

  94. Morse DC, Wehler EK, Wesseling W, Koeman JH, Brouwer A. Alterations in rat brain thyroid hormone status following pre- and postnatal exposure to polychlorinated biphenyls (Aroclor 1254). Toxicol Appl Pharmacol. 1996;136(2):269–79. https://doi.org/10.1006/taap.1996.0034.

    Article  CAS  PubMed  Google Scholar 

  95. Goldey ES, Kehn LS, Lau C, Rehnberg GL, Crofton KM. Developmental exposure to polychlorinated biphenyls (Aroclor 1254) reduces circulating thyroid hormone concentrations and causes hearing deficits in rats. Toxicol Appl Pharmacol. 1995;135(1):77–88. https://doi.org/10.1006/taap.1995.1210.

    Article  CAS  PubMed  Google Scholar 

  96. Gauger KJ, Kato Y, Haraguchi K, Lehmler HJ, Robertson LW, Bansal R, et al. Polychlorinated biphenyls (PCBs) exert thyroid hormone-like effects in the fetal rat brain but do not bind to thyroid hormone receptors. Environ Health Perspect. 2004;112(5):516–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  97. Navarro VM, Sanchez-Garrido MA, Castellano JM, Roa J, Garcia-Galiano D, Pineda R, et al. Persistent impairment of hypothalamic KiSS-1 system after exposures to estrogenic compounds at critical periods of brain sex differentiation. Endocrinology. 2009;150(5):2359–67. https://doi.org/10.1210/en.2008-0580.

    Article  CAS  PubMed  Google Scholar 

  98. Zoeller RT. Environmental chemicals impacting the thyroid: targets and consequences. Thyroid. 2007;17(9):811–7. https://doi.org/10.1089/thy.2007.0107.

    Article  CAS  PubMed  Google Scholar 

  99. Giera S, Bansal R, Ortiz-Toro TM, Taub DG, Zoeller RT. Individual polychlorinated biphenyl (PCB) congeners produce tissue- and gene-specific effects on thyroid hormone signaling during development. Endocrinology. 2011;152(7):2909–19. https://doi.org/10.1210/en.2010-1490.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  100. Naveau E, Pinson A, Gerard A, Nguyen L, Charlier C, Thome JP, et al. Alteration of rat fetal cerebral cortex development after prenatal exposure to polychlorinated biphenyls. PLoS One. 2014;9(3):e91903. https://doi.org/10.1371/journal.pone.0091903.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Cao J, Mickens JA, McCaffrey KA, Leyrer SM, Patisaul HB. Neonatal bisphenol A exposure alters sexually dimorphic gene expression in the postnatal rat hypothalamus. Neurotoxicology. 2012;33(1):23–36. https://doi.org/10.1016/j.neuro.2011.11.002.

    Article  CAS  PubMed  Google Scholar 

  102. Cao J, Rebuli ME, Rogers J, Todd KL, Leyrer SM, Ferguson SA, et al. Prenatal bisphenol A exposure alters sex-specific estrogen receptor expression in the neonatal rat hypothalamus and amygdala. Toxicol Sci. 2013;133(1):157–73. https://doi.org/10.1093/toxsci/kft035.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  103. Ceccarelli I, Della Seta D, Fiorenzani P, Farabollini F, Aloisi AM. Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats. Neurotoxicol Teratol. 2007;29(1):108–15. https://doi.org/10.1016/j.ntt.2006.10.011.

    Article  CAS  PubMed  Google Scholar 

  104. Colciago A, Casati L, Mornati O, Vergoni AV, Santagostino A, Celotti F, et al. Chronic treatment with polychlorinated biphenyls (PCB) during pregnancy and lactation in the rat part 2: effects on reproductive parameters, on sex behavior, on memory retention and on hypothalamic expression of aromatase and 5alpha-reductases in the offspring. Toxicol Appl Pharmacol. 2009;239(1):46–54. https://doi.org/10.1016/j.taap.2009.04.023.

    Article  CAS  PubMed  Google Scholar 

  105. Lichtensteiger W, Bassetti-Gaille C, Faass O, Axelstad M, Boberg J, Christiansen S, et al. Differential gene expression patterns in developing sexually dimorphic rat brain regions exposed to antiandrogenic, estrogenic, or complex endocrine disruptor mixtures: glutamatergic synapses as target. Endocrinology. 2015;156(4):1477–93. https://doi.org/10.1210/en.2014-1504.

    Article  CAS  PubMed  Google Scholar 

  106. He Z, Paule MG, Ferguson SA. Low oral doses of bisphenol A increase volume of the sexually dimorphic nucleus of the preoptic area in male, but not female, rats at postnatal day 21. Neurotoxicol Teratol. 2012;34(3):331–7. https://doi.org/10.1016/j.ntt.2012.03.004.

    Article  CAS  PubMed  Google Scholar 

  107. Patisaul HB, Fortino AE, Polston EK. Differential disruption of nuclear volume and neuronal phenotype in the preoptic area by neonatal exposure to genistein and bisphenol-A. Neurotoxicology. 2007;28(1):1–12. https://doi.org/10.1016/j.neuro.2006.10.001.

    Article  CAS  PubMed  Google Scholar 

  108. Bourguignon JP, Franssen D, Gerard A, Janssen S, Pinson A, Naveau E, et al. Early neuroendocrine disruption in hypothalamus and hippocampus: developmental effects including female sexual maturation and implications for endocrine disrupting chemical screening. J Neuroendocrinol. 2013;25(11):1079–87. https://doi.org/10.1111/jne.12107.

    Article  CAS  PubMed  Google Scholar 

  109. Xu X, Xie L, Hong X, Ruan Q, Lu H, Zhang Q, et al. Perinatal exposure to bisphenol-A inhibits synaptogenesis and affects the synaptic morphological development in offspring male mice. Chemosphere. 2013;91(8):1073–81. https://doi.org/10.1016/j.chemosphere.2012.12.065.

    Article  CAS  PubMed  Google Scholar 

  110. Eiland L, Ramroop J, Hill MN, Manley J, McEwen BS. Chronic juvenile stress produces corticolimbic dendritic architectural remodeling and modulates emotional behavior in male and female rats. Psychoneuroendocrinology. 2012;37(1):39–47. https://doi.org/10.1016/j.psyneuen.2011.04.015.

    Article  CAS  PubMed  Google Scholar 

  111. Carrion VG, Wong SS. Can traumatic stress alter the brain? Understanding the implications of early trauma on brain development and learning. J Adolesc Health. 2012;51(2 Suppl):S23–8. https://doi.org/10.1016/j.jadohealth.2012.04.010.

    Article  PubMed  Google Scholar 

  112. McCormick CM, Mathews IZ. Adolescent development, hypothalamic-pituitary-adrenal function, and programming of adult learning and memory. Prog Neuropsychopharmacol Bol Psychiatry. 2010;34(5):756–65. https://doi.org/10.1016/j.pnpbp.2009.09.019.

    Article  CAS  Google Scholar 

  113. Glover V, O’Connor TG, O’Donnell K. Prenatal stress and the programming of the HPA axis. Neurosci Biobehav Rev. 2010;35(1):17–22. https://doi.org/10.1016/j.neubiorev.2009.11.008.

    Article  CAS  PubMed  Google Scholar 

  114. O’Donnell K, O’Connor TG, Glover V. Prenatal stress and neurodevelopment of the child: focus on the HPA axis and role of the placenta. Dev Neurosci. 2009;31(4):285–92. https://doi.org/10.1159/000216539.

    Article  CAS  PubMed  Google Scholar 

  115. Romeo RD. The impact of stress on the structure of the adolescent brain: implications for adolescent mental health. Brain Res. 2017;1654(Pt B):185–91. https://doi.org/10.1016/j.brainres.2016.03.021.

    Article  CAS  PubMed  Google Scholar 

  116. • Bale TL. Sex differences in prenatal epigenetic programming of stress pathways. Stress. 2011;14(4):348–56. https://doi.org/10.3109/10253890.2011.586447. Excellent review of the role epigenetics plays in shaping the developing brain including sexual dimorphisms.

    Article  PubMed  Google Scholar 

  117. Gillette R, Reilly MP, Topper VY, Thompson LM, Crews D, Gore AC. Anxiety-like behaviors in adulthood are altered in male but not female rats exposed to low dosages of polychlorinated biphenyls in utero. Horm Behav. 2017;87:8–15. https://doi.org/10.1016/j.yhbeh.2016.10.011.

    Article  CAS  PubMed  Google Scholar 

  118. Reilly MP, Weeks CD, Topper VY, Thompson LM, Crews D, Gore AC. The effects of prenatal PCBs on adult social behavior in rats. Horm Behav. 2015;73:47–55. https://doi.org/10.1016/j.yhbeh.2015.06.002.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  119. Meserve LA, Murray BA, Landis JA. Influence of maternal ingestion of Aroclor 1254 (PCB) or FireMaster BP-6 (PBB) on unstimulated and stimulated corticosterone levels in young rats. Bul Environ Contam Toxicology. 1992;48(5):715–20.

    CAS  Google Scholar 

  120. Chen F, Zhou L, Bai Y, Zhou R, Chen L. Sex differences in the adult HPA axis and affective behaviors are altered by perinatal exposure to a low dose of bisphenol A. Brain Res. 2014;1571:12–24. https://doi.org/10.1016/j.brainres.2014.05.010.

    Article  CAS  PubMed  Google Scholar 

  121. Ransohoff RM, Brown MA. Innate immunity in the central nervous system. J Clin Invest. 2012;122(4):1164–71. https://doi.org/10.1172/JCI58644.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  122. Madhusudan A, Vogel P, Knuesel I. Impact of prenatal immune system disturbances on brain development. J NeuroImmune Pharmacol. 2013;8(1):79–86. https://doi.org/10.1007/s11481-012-9374-z.

    Article  PubMed  Google Scholar 

  123. Muller N, Myint AM, Schwarz MJ. The impact of neuroimmune dysregulation on neuroprotection and neurotoxicity in psychiatric disorders—relation to drug treatment. Dialogues Clin Neurosci. 2009;11(3):319–32.

    PubMed Central  PubMed  Google Scholar 

  124. Bilbo SD, Schwarz JM. Early-life programming of later-life brain and behavior: a critical role for the immune system. Front Behav Neurosci. 2009;3:14. https://doi.org/10.3389/neuro.08.014.2009.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  125. Bilbo SD, Schwarz JM. The immune system and developmental programming of brain and behavior. Front Neuroendocrinol. 2012;33(3):267–86. https://doi.org/10.1016/j.yfrne.2012.08.006.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  126. Ullian EM, Christopherson KS, Barres BA. Role for glia in synaptogenesis. Glia. 2004;47(3):209–16. https://doi.org/10.1002/glia.20082.

    Article  PubMed  Google Scholar 

  127. Rakic S, Zecevic N. Programmed cell death in the developing human telencephalon. Eur J Neurosci. 2000;12(8):2721–34. https://doi.org/10.1046/j.1460-9568.2000.00153.x.

    Article  CAS  PubMed  Google Scholar 

  128. Streit WJ. Microglia and macrophages in the developing CNS. Neurotoxicology. 2001;22(5):619–24. https://doi.org/10.1016/S0161-813X(01)00033-X.

    Article  CAS  PubMed  Google Scholar 

  129. Nawa H, Takei N. Recent progress in animal modeling of immune inflammatory processes in schizophrenia: implication of specific cytokines. Neurosci Res. 2006;56(1):2–13. https://doi.org/10.1016/j.neures.2006.06.002.

    Article  CAS  PubMed  Google Scholar 

  130. Ransohoff RM, Schafer D, Vincent A, Blachere NE, Bar-Or A. Neuroinflammation: ways in which the immune system affects the brain. Neurotherapeutics. 2015;12(4):896–909. https://doi.org/10.1007/s13311-015-0385-3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  131. Shi L, Fatemi SH, Sidwell RW, Patterson PH. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci. 2003;23(1):297–302.

    PubMed  Google Scholar 

  132. Cai Z, Pan ZL, Pang Y, Evans OB, Rhodes PG. Cytokine induction in fetal rat brains and brain injury in neonatal rats after maternal lipopolysaccharide administration. Pediatr Res. 2000;47(1):64–72. https://doi.org/10.1203/00006450-200001000-00013.

    Article  CAS  PubMed  Google Scholar 

  133. Meyer U, Feldon J, Schedlowski M, Yee BK. Immunological stress at the maternal-foetal interface: a link between neurodevelopment and adult psychopathology. Brain Behav Immun. 2006;20(4):378–88. https://doi.org/10.1016/j.bbi.2005.11.003.

    Article  CAS  PubMed  Google Scholar 

  134. Pang Y, Cai Z, Rhodes PG. Disturbance of oligodendrocyte development, hypomyelination and white matter injury in the neonatal rat brain after intracerebral injection of lipopolysaccharide. Brain Res Dev Brain Res. 2003;140(2):205–14. https://doi.org/10.1016/S0165-3806(02)00606-5.

    Article  CAS  PubMed  Google Scholar 

  135. Deverman BE, Patterson PH. Cytokines and CNS development. Neuron. 2009;64(1):61–78. https://doi.org/10.1016/j.neuron.2009.09.002.

    Article  CAS  PubMed  Google Scholar 

  136. Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A. The role of microglia in the healthy brain. J Neurosci. 2011;31(45):16064–9. https://doi.org/10.1523/JNEUROSCI.4158-11.2011.

    Article  CAS  PubMed  Google Scholar 

  137. Bruce-Keller AJ, Keeling JL, Keller JN, Huang FF, Camondola S, Mattson MP. Antiinflammatory effects of estrogen on microglial activation. Endocrinology. 2000;141(10):3646–56. https://doi.org/10.1210/endo.141.10.7693.

    Article  CAS  PubMed  Google Scholar 

  138. Vegeto E, Bonincontro C, Pollio G, Sala A, Viappiani S, Nardi F, et al. Estrogen prevents the lipopolysaccharide-induced inflammatory response in microglia. J Neurosci. 2001;21(6):1809–18.

    CAS  PubMed  Google Scholar 

  139. Ishihara Y, Itoh K, Ishida A, Yamazaki T. Selective estrogen-receptor modulators suppress microglial activation and neuronal cell death via an estrogen receptor-dependent pathway. J Steroid Biochem Mol Biol. 2015;145:85–93. https://doi.org/10.1016/j.jsbmb.2014.10.002.

    Article  CAS  PubMed  Google Scholar 

  140. • Wise LM, Sadowski RN, Kim T, Willing J, Juraska JM. Long-term effects of adolescent exposure to bisphenol A on neuron and glia number in the rat prefrontal cortex: differences between the sexes and cell type. Neurotoxicology. 2016;53:186–92. https://doi.org/10.1016/j.neuro.2016.01.011. Critical study showing long-term changes in the number of glial cells in the prefrontal cortex of rats following adolescent exposure to BPA.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  141. Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR 3rd, Lafaille JJ, et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell. 2013;155(7):1596–609. https://doi.org/10.1016/j.cell.2013.11.030.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  142. Faleiros BE, Miranda AS, Campos AC, Gomides LF, Kangussu LM, Guatimosim C, et al. Up-regulation of brain cytokines and chemokines mediates neurotoxicity in early acute liver failure by a mechanism independent of microglial activation. Brain Res. 2014;1578:49–59. https://doi.org/10.1016/j.brainres.2014.07.001.

    Article  CAS  PubMed  Google Scholar 

  143. Garay PA, Hsiao EY, Patterson PH, McAllister AK. Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development. Brain Behav Immun. 2013;31:54–68. https://doi.org/10.1016/j.bbi.2012.07.008.

    Article  CAS  PubMed  Google Scholar 

  144. Azcoitia I, Sierra A, Garcia-Segura LM. Localization of estrogen receptor beta-immunoreactivity in astrocytes of the adult rat brain. Glia. 1999;26(3):260–7. https://doi.org/10.1002/(SICI)1098-1136(199905)26:3<260::AID-GLIA7>3.0.CO;2-R.

    Article  CAS  PubMed  Google Scholar 

  145. Arvanitis DN, Wang H, Bagshaw RD, Callahan JW, Boggs JM. Membrane-associated estrogen receptor and caveolin-1 are present in central nervous system myelin and oligodendrocyte plasma membranes. J Neurosci Res. 2004;75(5):603–13. https://doi.org/10.1002/jnr.20017.

    Article  CAS  PubMed  Google Scholar 

  146. Jones KA, Thomsen C. The role of the innate immune system in psychiatric disorders. Mol Cell Neurosci. 2013;53:52–62. https://doi.org/10.1016/j.mcn.2012.10.002.

    Article  CAS  PubMed  Google Scholar 

  147. Fatemi SH, Reutiman TJ, Folsom TD, Huang H, Oishi K, Mori S, et al. Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: implications for genesis of neurodevelopmental disorders. Schizophr Res. 2008;99(1–3):56–70. https://doi.org/10.1016/j.schres.2007.11.018.

    Article  PubMed Central  PubMed  Google Scholar 

  148. Mokarizadeh A, Faryabi MR, Rezvanfar MA, Abdollahi M. A comprehensive review of pesticides and the immune dysregulation: mechanisms, evidence and consequences. Toxicol Mech Methods. 2015;25(4):258–78. https://doi.org/10.3109/15376516.2015.1020182.

    Article  CAS  PubMed  Google Scholar 

  149. Rogers JA, Metz L, Yong VW. Review: endocrine disrupting chemicals and immune responses: a focus on bisphenol-A and its potential mechanisms. Mol Immunol. 2013;53(4):421–30. https://doi.org/10.1016/j.molimm.2012.09.013.

    Article  CAS  PubMed  Google Scholar 

  150. Xu H, Yang M, Qiu W, Pan C, Wu M. The impact of endocrine-disrupting chemicals on oxidative stress and innate immune response in zebrafish embryos. Environ Toxicol Chem. 2013;32(8):1793–9. https://doi.org/10.1002/etc.2245.

    Article  CAS  PubMed  Google Scholar 

  151. Liao SL, Tsai MH, Lai SH, Yao TC, Hua MC, Yeh KW, et al. Prenatal exposure to bisphenol-A is associated with Toll-like receptor-induced cytokine suppression in neonates. Pediatr Res. 2016;79(3):438–44. https://doi.org/10.1038/pr.2015.234.

    Article  CAS  PubMed  Google Scholar 

  152. Diamond B, Huerta PT, Tracey K, Volpe BT. It takes guts to grow a brain: increasing evidence of the important role of the intestinal microflora in neuro- and immune-modulatory functions during development and adulthood. BioEssays. 2011;33(8):588–91. https://doi.org/10.1002/bies.201100042.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  153. Diaz Heijtz R, Wang S, Anuar F, Qian Y, Bjorkholm B, Samuelsson A, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A. 2011;108(7):3047–52. https://doi.org/10.1073/pnas.1010529108.

    Article  PubMed  Google Scholar 

  154. Myatt L. Placental adaptive responses and fetal programming. J Physiol. 2006;572(Pt 1):25–30. https://doi.org/10.1113/jphysiol.2006.104968.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  155. Bronson SL, Bale TL. The placenta as a mediator of stress effects on neurodevelopmental reprogramming. Neuropsychopharmacology. 2016;41(1):207–18. https://doi.org/10.1038/npp.2015.231.

    Article  PubMed  Google Scholar 

  156. Bronson SL, Bale TL. Prenatal stress-induced increases in placental inflammation and offspring hyperactivity are male-specific and ameliorated by maternal antiinflammatory treatment. Endocrinology. 2014;155(7):2635–46. https://doi.org/10.1210/en.2014-1040.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  157. Leazer TM, Klaassen CD. The presence of xenobiotic transporters in rat placenta. Drug Metab Dispos. 2003;31(2):153–67. https://doi.org/10.1124/dmd.31.2.153.

    Article  CAS  PubMed  Google Scholar 

  158. D’Aloisio AA, DeRoo LA, Baird DD, Weinberg CR, Sandler DP. Prenatal and infant exposures and age at menarche. Epidemiology. 2013;24(2):277–84. https://doi.org/10.1097/EDE.0b013e31828062b7.

    Article  PubMed Central  PubMed  Google Scholar 

  159. Esteban-Vasallo MD, Aragones N, Pollan M, Lopez-Abente G, Perez-Gomez B. Mercury, cadmium, and lead levels in human placenta: a systematic review. Environ Health Perspect. 2012;120(10):1369–77. https://doi.org/10.1289/ehp.1204952.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  160. Vizcaino E, Grimalt JO, Fernandez-Somoano A, Tardon A. Transport of persistent organic pollutants across the human placenta. Environ Int. 2014;65:107–15. https://doi.org/10.1016/j.envint.2014.01.004.

    Article  CAS  PubMed  Google Scholar 

  161. Leonetti C, Butt CM, Hoffman K, Hammel SC, Miranda ML, Stapleton HM. Brominated flame retardants in placental tissues: associations with infant sex and thyroid hormone endpoints. Environ Health. 2016;15(1):113. https://doi.org/10.1186/s12940-016-0199-8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  162. Leonetti C, Butt CM, Hoffman K, Miranda ML, Stapleton HM. Concentrations of polybrominated diphenyl ethers (PBDEs) and 2,4,6-tribromophenol in human placental tissues. Environ Int. 2016;88:23–9. https://doi.org/10.1016/j.envint.2015.12.002.

    Article  CAS  PubMed  Google Scholar 

  163. Baldwin KR, Phillips AL, Horman B, Arambula SE, Rebuli ME, Stapleton HM, et al. Sex specific placental accumulation and behavioral effects of developmental Firemaster® 550 exposure in Wistar rats. Sci Rep. 2017;7(1):7118. https://doi.org/10.1038/s41598-017-07216-6.

    Article  PubMed Central  PubMed  Google Scholar 

  164. Irwin MR, Cole SW. Reciprocal regulation of the neural and innate immune systems. Nat Rev Immunol. 2011;11(9):625–32. https://doi.org/10.1038/nri3042.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Funding

This work was supported by R56 NIEHS R56ES022957 to H.B.P., NIEHS P30ES025128 to NCSU, and NIEHS T32ES021432 to NCSU.

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  1. Department of Biological Sciences, North Carolina State University, Raleigh, NC, 27695, USA

    Kylie D. Rock & Heather B. Patisaul

  2. Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA

    Heather B. Patisaul

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Rock, K.D., Patisaul, H.B. Environmental Mechanisms of Neurodevelopmental Toxicity. Curr Envir Health Rpt 5, 145–157 (2018). https://doi.org/10.1007/s40572-018-0185-0

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