PHARMASPIRE - Volume 15, Issue 03, 2023 , July- September

Pages: 157-169

Date of Publication: 11-Dec-2023

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Neurotoxic environmental pollutants: A comprehensive review on lead, mercury, pesticides, and polychlorinated biphenyls

Author: Kaunava Roy Chowdhury, Arti Singh, Charan Singh

Category: Pharmacology

Abstract:

Environmental toxins are any chemicals or substances that are expelled into the environment by human activity. Negative impacts on human health, such as nervous system impairment, might result from contact with these chemicals. In this article, we will discuss some of the most prevalent environmental toxins that affect the nervous system, as well as their modes of action and the pathological pathways linked to their presence. Lead, mercury, pesticides, and polychlorinated biphenyls are just a few examples of the poisons that fall under this category. Reviewers draw attention to the dangers of environmental contaminants and urge people to take measures to lessen their exposure.

Keywords: Environmental toxins, Lead, Mercury, Nervous system, PCBs, Pesticides

DOI: 10.56933/Pharmaspire.2023.15126

DOI URL: https://doi.org/10.56933/Pharmaspire.2023.15126

References:

1. Chowdhary P, Bharagava RN, Mishra S, Khan N. Role of industries in water scarcity and its adverse effects on environment and human health. In: Environmental Concerns and Sustainable Development. Air, Water and Energy Resources. Vol. 1. Berlin: Springer; 2020. p. 235-56.

2. Rao KN, Brown MA. Mast cells: Multifaceted immune cells with diverse roles in health and disease. Ann N Y Acad Sci 2008;1143:83-104.

3. Wang Y, Xiong L, Tang M. Toxicity of inhaled particulate matter on the central nervous system: Neuroinflammation, neuropsychological effects and neurodegenerative disease. J Appl Toxicol 2017;37:644-67.

4. Spencer PS, Lein PJ. Neurotoxicity. In: Encyclopedia of Toxicology. 3rd ed. Cambridge, MA: Academic Press; 2014. p. 489-500.

5. Winneke G. Developmental aspects of environmental neurotoxicology: Lessons from lead and polychlorinated biphenyls. J Neurol Sci 2011;308:9-15.

6. Pandey G, Madhuri S. Heavy metals causing toxicity in animals and fishes. Res J Anim Vet Fish Sci 2014;2:17-23.

7. Sankhla MS, Kumari M, Nandan M, Kumar R, Agrawal P. Heavy metals contamination in water and their hazardous effect on human health-a review. Int J Curr Microbiol Appl Sci 2016;5:759-66.

8. Collin MS, Venkataraman S, Vijayakumar N, Kanimozhi V, Arbaaz SM, Stacey RS, et al. Bioaccumulation of lead (Pb) and its effects on human: A review. J Hazard Mater Adv 2022;3:100094.

9. Goodlett CR, Horn KH. Mechanisms of alcohol-induced damage to the developing nervous system. Alcohol Res Health 2001;25:175-84.

10. Carpenter DO, editor. Environmental Contaminants and Learning and Memory. In: International Congress Series. Netherlands: Elsevier; 2006.

11. Slotkin TA. Cholinergic systems in brain development and disruption by neurotoxicants: Nicotine, environmental tobacco smoke, organophosphates. Toxicol Appl Pharmacol 2004;198:132-51.

12. Bernhoft RA. Mercury toxicity and treatment: A review of the literature. J Environ Public Health 2012;2012:460508.

13. Bakir F, Rustam H, Tikriti S, Al-Damluji SF, Shihristani H. Clinical and epidemiological aspects of methylmercury poisoning. Postgrad Med J 1980;56:1-10.

14. Bose-O’Reilly S, McCarty KM, Steckling N, Lettmeier B. Mercury exposure and children’s health. Curr Probl Pediatr Adolesc Health Care 2010;40:186-215.

15. Abbasi G, Buser AM, Soehl A, Murray MW, Diamond ML. Stocks and flows of PBDEs in products from use to waste in the U.S. and Canada from 1970 to 2020. Environ Sci Technol 2015;49:1521-8.

16. Dallaire F, Dewailly E, Muckle G, Ayotte P. Time trends of persistent organic pollutants and heavy metals in umbilical cord blood of Inuit infants born in Nunavik (Québec, Canada) between 1994 and 2001. Environ Health Perspect 2003;111:1660-4.

17. Seralini GE, Jungers G. Endocrine disruptors also function as nervous disruptors and can be renamed endocrine and nervous disruptors (ENDs). Toxicol Rep 2021;8:1538-57.

18. Mendola P, Selevan SG, Gutter S, Rice D. Environmental factors associated with a spectrum of neurodevelopmental deficits. Ment Retard Dev Disabil Res Rev 2002;8:188-97.

19. Arbabi M, Hemati S, Amiri M. Removal of lead ions from industrial wastewater: A review of Removal methods. Environment 2015;4:10.

20. Grandjean P, Landrigan PJ. Neurobehavioural effects of developmental toxicity. Lancet Neurol 2014;13:330-8.

21. Demuro A, Parker I, Stutzmann GE. Calcium signaling and amyloid toxicity in Alzheimer disease. J Biol Chem 2010;285:12463-8.

22. Gilgun-Sherki Y, Melamed E, Offen D. The role of oxidative stress in the pathogenesis of multiple sclerosis: The need for effective antioxidant therapy. J Neurol 2004;251:261-8.

23. Brann JH. Sensory Transduction in the Vomeronasal Organ: The Role of Protein Interactions. Florida: The Florida State University; 2005.

24. Simons TJ, Pocock G. Lead enters bovine adrenal medullary cells through calcium channels. J Neurochem 1987;48:383-9.

25. Bressler JP, Goldstein GW. Mechanisms of lead neurotoxicity. Biochem Pharmacol 1991;41:479-84.

26. Hinkle PM, Kinsella PA, Osterhoudt KC. Cadmium uptake and toxicity via voltage-sensitive calcium channels. J Biol Chem 1987;262:16333-7.

27. Marchetti C. Role of calcium channels in heavy metal toxicity. ISRN Toxicol 2013;2013:184360.

28. Russell JM. Sodium-potassium-chloride cotransport. Physiol Rev 2000;80:211-76.

29. Yilmaz M, Christofori G, Lehembre F. Distinct mechanisms of tumor invasion and metastasis. Trends Mol Med 2007;13:535-41.

30. Agarwal H, Menon S, Venkat Kumar S, Rajeshkumar S. Mechanistic study on antibacterial action of zinc oxide nanoparticles synthesized using green route. Chem Biol Interact 2018;286:60-70.

31. Tapiero H, Tew KD. Trace elements in human physiology and pathology: Zinc and metallothioneins. Biomed Pharmacother 2003;57:399-411.

32. Valko M, Jomova K, Rhodes CJ, Ku?a K, Musílek K. Redox- and non-redox-metal-induced formation of free radicals and their role in human disease. Arch Toxicol 2016;90:1-37.

33. Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: Dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 2003;4:517-29.

34. O’Grady S, Morgan MP. Calcium transport and signalling in breast cancer: Functional and prognostic significance. Semin Cancer Biol 2021;72:19-26.

35. Sanders T, Liu Y, Buchner V, Tchounwou PB. Neurotoxic effects and biomarkers of lead exposure: A review. Rev Environ Health 2009;24:15-45.

36. Russell VA. Dopamine hypofunction possibly results from a defect in glutamate-stimulated release of dopamine in the nucleus accumbens shell of a rat model for attention deficit hyperactivity disorder--the spontaneously hypertensive rat. Neurosci Biobehav Rev 2003;27:671-82.

37. Bouabid S, Tinakoua A, Lakhdar-Ghazal N, Benazzouz A. Manganese neurotoxicity: Behavioral disorders associated with dysfunctions in the basal ganglia and neurochemical transmission. J Neurochem 2016;136:677-91.

38. Green KN, Smith IF, Laferla FM. Role of calcium in the pathogenesis of Alzheimer’s disease and transgenic models. Subcell Biochem 2007;45:507-21.

39. Son SM, Byun J, Roh SE, Kim SJ, Mook-Jung I. Reduced IRE1α mediates apoptotic cell death by disrupting calcium homeostasis via the InsP3 receptor. Cell Death Dis 2014;5:e1188.

40. Ercal N, Gurer-Orhan H, Aykin-Burns N. Toxic metals and oxidative stress part I: Mechanisms involved in metal-induced oxidative damage. Curr Top Med Chem 2001;1:529-39.

41. Al-Gubory KH, Fowler PA, Garrel C. The roles of cellular reactive oxygen species, oxidative stress and antioxidants in pregnancy outcomes. Int J Biochem Cell Biol 2010;42:1634-50.

42. Fagiolini M, Jensen CL, Champagne FA. Epigenetic influences on brain development and plasticity. Curr Opin Neurobiol 2009;19:207-12.

43. Feng J, Fouse S, Fan G. Epigenetic regulation of neural gene expression and neuronal function. Pediatr Res 2007;61:58R-63.

44. Sharma V, Yadav S. Lead induced encephalopathy: An overview. Inter J Pharma Bio Sci 2011;2:70-86.

45. Lidsky TI, Schneider JS. Lead neurotoxicity in children: Basic mechanisms and clinical correlates. Brain 2003;126:5-19.

46. Han FX, Banin A, Su Y, Monts DL, Plodinec MJ, Kingery WL, et al. Industrial age anthropogenic inputs of heavy metals into the pedosphere. Naturwissenschaften 2002;89:497-504.

47. Grandjean P, Weihe P, White RF, Debes F, Araki S, Yokoyama K, et al. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol 1997;19:417-28.

48. Ajsuvakova OP, Tinkov AA, Aschner M, Rocha JB, Michalke B, Skalnaya MG, et al. Sulfhydryl groups as targets of mercury toxicity. Coord Chem Rev 2020;417:213343.

49. Balali-Mood M, Naseri K, Tahergorabi Z, Khazdair MR, Sadeghi M. Toxic mechanisms of five heavy metals: Mercury, lead, chromium, cadmium, and arsenic. Front Pharmacol 2021;12:643972.

50. Mason RP, Reinfelder JR, Morel FM. Uptake, toxicity, and trophic transfer of mercury in a coastal diatom. Environ Sci Technol 1996;30:1835-45.

51. Ledwidge R, Patel B, Dong A, Fiedler D, Falkowski M, Zelikova J, et al. NmerA, the metal binding domain of mercuric ion reductase, removes Hg2+ from proteins, delivers it to the catalytic core, and protects cells under glutathione-depleted conditions. Biochemistry 2005;44:11402-16.

52. Kozlowski H, Kolkowska P, Watly J, Krzywoszynska K, Potocki S. General aspects of metal toxicity. Curr Med Chem 2014;21:3721-40.

53. Schaefer JK, Rocks SS, Zheng W, Liang L, Gu B, Morel FM. Active transport, substrate specificity, and methylation of Hg(II) in anaerobic bacteria. Proc Natl Acad Sci U S A 2011;108:8714-9.

54. Balthasar C, Stangl H, Widhalm R, Granitzer S, Hengstschläger M, Gundacker C. Methylmercury uptake into BeWo cells depends on LAT2-4F2hc, a system L Amino acid transporter. Int J Mol Sci 2017;18:1730.

55. Heggland I, Kaur P, Syversen T. Uptake and efflux of methylmercury in vitro: Comparison of transport mechanisms in C6, B35 and RBE4 cells. Toxicol In Vitro 2009;23:1020-7.

56. Díaz-Amaya S, Zhao M, Allebach JP, Chiu GT, Stanciu LA. Ionic strength influences on biofunctional Au-Decorated microparticles for enhanced performance in multiplexed colorimetric sensors. ACS Appl Mater Interfaces 2020;12:32397-409.

57. Shenker BJ, Berthold P, Rooney C, Vitale L, DeBolt K, Shapiro IM. Immunotoxic effects of mercuric compounds on human lymphocytes and monocytes. III. Alterations in B-cell function and viability. Immunopharmacol Immunotoxicol 1993;15:87-112.

58. Ung CY, Lam SH, Hlaing MM, Winata CL, Korzh S, Mathavan S, et al. Mercury-induced hepatotoxicity in zebrafish: In vivo mechanistic insights from transcriptome analysis, phenotype anchoring and targeted gene expression validation. BMC Genomics 2010;11:212.

59. Syversen T, Kaur P. The toxicology of mercury and its compounds. J Trace Elem Med Biol 2012;26:215-26.

60. Andrade VM, Aschner M, Marreilha Dos Santos AP. Neurotoxicity of metal mixtures. Adv Neurobiol 2017;18:227-65.

61. Langford N, Ferner R. Toxicity of mercury. J Hum Hypertens 1999;13:651-6.

62. Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. Lancet 2006;368:2167-78.

63. Baatrup E. Structural and functional effects of heavy metals on the nervous system, including sense organs, of fish. Comp Biochem Physiol C Comp Pharmacol Toxicol 1991;100:253-7.

64. Romero A, Ramos E, de Los Ríos C, Egea J, Del Pino J, Reiter RJ. A review of metal-catalyzed molecular damage: Protection by melatonin. J Pineal Res 2014;56:343-70.

65. Frasco MF, Colletier JP, Weik M, Carvalho F, Guilhermino L, Stojan J, et al. Mechanisms of cholinesterase inhibition by inorganic mercury. FEBS J 2007;274:1849-61.

66. Roy S, Coffee P, Smith G, Liem RK, Brady ST, Black MM. Neurofilaments are transported rapidly but intermittently in axons: Implications for slow axonal transport. J Neurosci 2000;20:6849-61.

67. Luo CL, Chen XP, Yang R, Sun YX, Li QQ, Bao HJ, et al. Cathepsin B contributes to traumatic brain injury-induced cell death through a mitochondria-mediated apoptotic pathway. J Neurosci Res 2010;88:2847-58.

68. Elbaz A, Wei YY, Meng Q, Zheng Q, Yang ZM. Mercuryinduced oxidative stress and impact on antioxidant enzymes in Chlamydomonas reinhardtii. Ecotoxicology 2010;19:1285-93.

69. Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 2009;7:65-74.

70. Tabner BJ, Turnbull S, El-Aganf O, Allsop D. Production of reactive oxygen species from aggregating proteins implicated in Alzheimer’s disease, Parkinson’s disease and other neurodegenerative diseases. Curr Top Med Chem 2001;1:507-17.

71. Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 2004;5:863-73.

72. Hegazy HG, Ali EH, Elgoly AH. Interplay between pro-inflammatory cytokines and brain oxidative stress biomarkers: Evidence of parallels between butyl paraben intoxication and the valproic acid brain physiopathology in autism rat model. Cytokine 2015;71:173-80.

73. Amor S, Peferoen LA, Vogel DY, Breur M, van der Valk P, Baker D, et al. Inflammation in neurodegenerative diseases-an update. Immunology 2014;142:151-66.

74. Agnihotri A, Aruoma OI. Alzheimer’s disease and Parkinson’s disease: A nutritional toxicology perspective of the impact of oxidative stress, mitochondrial dysfunction, nutrigenomics and environmental chemicals. J Am Coll Nutr 2020;39:16-27.

75. D’Ambrosi N, Rossi L. Copper at synapse: Release, binding and modulation of neurotransmission. Neurochem Int 2015;90:36-45.

76. Pizzarelli R, Cherubini E. Alterations of GABAergic signaling in autism spectrum disorders. Neural Plast 2011;2011:297153.

77. Rice D, Barone S Jr. Critical periods of vulnerability for the developing nervous system: Evidence from humans and animal models. Environ Health Perspect 2000;108 Suppl 3:511-33.

78. Crump KL, Trudeau VL. Mercury?induced reproductive impairment in fish. Environ Toxicol Chem 2009;28:895-907.

79. Davidson PW, Myers GJ, Weiss B. Mercury exposure and child development outcomes. Pediatrics 2004;113 Suppl 3:1023-9.

80. Tudi M, Daniel Ruan H, Wang L, Lyu J, Sadler R, Connell D, et al. Agriculture development, pesticide application and its impact on the environment. Int J Environ Res Public Health 2021;18:1112.

81. Kamel F, Hoppin JA. Association of pesticide exposure with neurologic dysfunction and disease. Environ Health Perspect 2004;112:950-8.

82. San Tang K. The potential role of nanoyttria in alleviating oxidative stress biomarkers: Implications for Alzheimer’s disease therapy. Life Sci 2020;259:118287.

83. Wohlfart S, Gelperina S, Kreuter J. Transport of drugs across the blood-brain barrier by nanoparticles. J Control Release 2012;161:264-73.

84. Pacifici RE, Davies KJ. Protein, lipid and DNA repair systems in oxidative stress: The free-radical theory of aging revisited. Gerontology 1991;37:166-80.

85. Katayama A, Bhula R, Burns GR, Carazo E, Felsot A, Hamilton D, et al. Bioavailability of xenobiotics in the soil environment. Rev Environ Contam Toxicol 2010;203:1-86.

86. Colovic MB, Krstic DZ, Lazarevic-Pasti TD, Bondzic AM, Vasic VM. Acetylcholinesterase inhibitors: Pharmacology and toxicology. Curr Neuropharmacol 2013;11:315-35.

87. Wang X, Li H, Wang S, Martínez MA, Ares I, Martínez M, et al. Tefluthrin: Metabolism, food residues, toxicity, and mechanisms of action. Crit Rev Toxicol 2022;52:664-80.

88. Xie Z, Sundström JF, Jin Y, Liu C, Jansson C, Sun C. A selection strategy in plant transformation based on antisense oligodeoxynucleotide inhibition. Plant J 2014;77:954-61.

89. Shaner DL. Role of translocation as a mechanism of resistance to glyphosate. Weed Sci 2009;57:118-23.

90. Alavanja MC, Hoppin JA, Kamel F. Health effects of chronic pesticide exposure: Cancer and neurotoxicity. Annu Rev Public Health 2004;25:155-97.

91. Bjørling-Poulsen M, Andersen HR, Grandjean P. Potential developmental neurotoxicity of pesticides used in Europe. Environ Health 2008;7:50.

92. 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: 258-78.

93. Sweeney MD, Sagare AP, Zlokovic BV. Bloodbrain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 2018;14:133-50.

94. Wu D, Cederbaum AI. Alcohol, oxidative stress, and free radical damage. Alcohol Res Health 2003;27:277-84.

95. Singh A, Kukreti R, Saso L, Kukreti S. Oxidative stress: A key modulator in neurodegenerative diseases. Molecules 2019;24:1583.

96. Farag MR, Khalil SR, Zaglool AW, Hendam BM, Moustafa AA, Cocco R, et al. Thiacloprid induced developmental neurotoxicity via ROS-oxidative injury and inflammation in chicken embryo: The possible attenuating role of chicoric and rosmarinic acids. Biology (Basel) 2021;10:1100.

97. Jones DC, Miller GW. The effects of environmental neurotoxicants on the dopaminergic system: A possible role in drug addiction. Biochem Pharmacol 2008;76:569-81.

98. Kaushal J, Khatri M, Arya SK. A treatise on Organophosphate pesticide pollution: Current strategies and advancements in their environmental degradation and elimination. Ecotoxicol Environ Saf 2021;207:111483.

99. Mercey G, Verdelet T, Renou J, Kliachyna M, Baati R, Nachon F, et al. Reactivators of acetylcholinesterase inhibited by organophosphorus nerve agents. Acc Chem Res 2012;45:756-66.

100.Costa LG, Giordano G, Guizzetti M, Vitalone A. Neurotoxicity of pesticides: A brief review. Front Biosci 2008;13:1240-9.

101. De Felice A, Greco A, Calamandrei G, Minghetti L. Prenatal exposure to the organophosphate insecticide chlorpyrifos enhances brain oxidative stress and prostaglandin E2 synthesis in a mouse model of idiopathic autism. J Neuroinflammation 2016;13:149.

102. Glickman LT, Schofer FS, McKee LJ, Reif JS, Goldschmidt MH. Epidemiologic study of insecticide exposures, obesity, and risk of bladder cancer in household dogs. J Toxicol Environ Health 1989;28:407-14.

103.Emara AM, Draz EI. Immunotoxicological study of one of the most common over-the-counter pyrethroid insecticide products in Egypt. Inhal Toxicol 2007;19:997-1009.

104.Robinson GK, Lenn MJ. The bioremediation of polychlorinated biphenyls (PCBs): Problems and perspectives. Biotechnol Genet Eng Rev 1994;12:139-88.

105. Grimm FA, Hu D, Kania-Korwel I, Lehmler HJ, Ludewig G, Hornbuckle KC, et al. Metabolism and metabolites of polychlorinated biphenyls. Crit Rev Toxicol 2015;45:245-72.

106. Klocke C, Lein PJ. Evidence implicating non-dioxinlike congeners as the key mediators of polychlorinated biphenyl (PCB) developmental neurotoxicity. Int J Mol Sci 2020;21:1013.

107. Panesar HK, Wilson RJ, Lein PJ. Cellular and molecular mechanisms of PCB developmental neurotoxicity. In: Handbook of Neurotoxicity. Berlin: Springer; 2022. p. 1-30.

108.Rodriguez EA. Hydroxylated and Sulfated Metabolites of Lower Chlorinated pcbs Bind with High Affinity to Human Serum Albumin and Exhibit Selective Toxicity to Neuronal Cells. Iowa: The University of Iowa; 2016.

109. Pathak GP, Vrana JD, Tucker CL. Optogenetic control of cell function using engineered photoreceptors. Biol Cell 2013;105:59-72.

110. Handy RD, Henry TB, Scown TM, Johnston BD, Tyler CR. Manufactured nanoparticles: Their uptake and effects on fish-a mechanistic analysis. Ecotoxicology 2008;17:396-409.

111. Nwoko CO. Trends in phytoremediation of toxic elemental and organic pollutants. Afr J Biotechnol 2010;9:6010-6.

112. Huang P, Liu J, Wang W, Zhang Y, Zhao F, Kong D, et al. Zwitterionic nanoparticles constructed from bioreducible RAFT-ROP double head agent for shell shedding triggered intracellular drug delivery. Acta Biomater 2016;40:263-72.

113. Yameen B, Choi WI, Vilos C, Swami A, Shi J, Farokhzad OC. Insight into nanoparticle cellular uptake and intracellular targeting. J Control Release 2014;190:485-99.

114. Andreassen T. The role of plasma-binding proteins in the cellular uptake of lipophilic vitamins and steroids. Horm Metab Res 2006;38:279-90.

115. Kim YA, Park JB, Woo MS, Lee SY, Kim HY, Yoo YH. Persistent organic pollutant-mediated insulin resistance. Int J Environ Res Public Health 2019;16:448.

116. Stemm DN. Interactions between Selenium and Polychlorinated Biphenyls (PCBs). University of Kentucky Doctoral Dissertations. 472; 2005.

117. Petersen MS, Halling J, Bech S, Wermuth L, Weihe P, Nielsen F, et al. Impact of dietary exposure to food contaminants on the risk of Parkinson’s disease. Neurotoxicology 2008;29:584-90.

118. Gupta P, Thompson BL, Wahlang B, Jordan CT, Zach Hilt J, Hennig B, et al. The environmental pollutant, polychlorinated biphenyls, and cardiovascular disease: A potential target for antioxidant nanotherapeutics. Drug Deliv Transl Res 2018;8:740-59.

119. Martyniuk CJ, Sanchez BC, Szabo NJ, Denslow ND, Sepúlveda MS. Aquatic contaminants alter genes involved in neurotransmitter synthesis and gonadotropin release in largemouth bass. Aquat Toxicol 2009;95:1-9.

120. Oleksiak MF, Karchner SI, Jenny MJ, Franks DG, Mark Welch DB, Hahn ME. Transcriptomic assessment of resistance to effects of an aryl hydrocarbon receptor (AHR) agonist in embryos of Atlantic killifish (Fundulus heteroclitus) from a marine Superfund site. BMC Genomics 2011;12:263.

121. Grova N, Schroeder H, Olivier JL, Turner JD. Epigenetic and neurological impairments associated with early life exposure to persistent organic pollutants. Int J Genomics 2019;2019:2085496.

122. Fonnum F, Mariussen E. Mechanisms involved in the neurotoxic effects of environmental toxicants such as polychlorinated biphenyls and brominated flame retardants. J Neurochem 2009;111:1327-47.

123.Mallozzi M, Bordi G, Garo C, Caserta D. The effect of maternal exposure to endocrine disrupting chemicals on fetal and neonatal development: A review on the major concerns. Birth Defects Res C Embryo Today 2016;108:224-42.

124.Carpenter DO, Arcaro K, Spink DC. Understanding the human health effects of chemical mixtures. Environ Health Perspect 2002;110 Suppl 1:25-42.

125.Bal-Price A, Meek MB. Adverse outcome pathways: Application to enhance mechanistic understanding of neurotoxicity. Pharmacol Ther 2017;179:84-95.

126. Gaum PM, Kuczynski I, Schettgen T, Putschögl FM, Kraus T, Fimm B, et al. Adverse health effects of PCBs on fine motor performance--analysis of a neurophysiological pathway in the HELPcB surveillance program. Neurotoxicology 2021;84:146-54.