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Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect sensitivity to developmental polychlorinated biphenyl exposure in mice: relevance to studies of human neurological disorders

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Abstract

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that remain a human health concern with newly discovered sources of contamination and ongoing bioaccumulation and biomagnification. Children exposed during early brain development are at highest risk of neurological deficits, but highly exposed adults reportedly have an increased risk of Parkinson’s disease. Our previous studies found allelic differences in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) affect sensitivity to developmental PCB exposure, resulting in cognitive deficits and motor dysfunction. High-affinity Ahr b Cyp1a2(−/−) mice were most sensitive compared with poor-affinity Ahr d Cyp1a2(−/−) and wild-type Ahr b Cyp1a2(+/+) mice. Our follow-up studies assessed biochemical, histological, and gene expression changes to identify the brain regions and pathways affected. We also measured PCB and metabolite levels in tissues to determine if genotype altered toxicokinetics. We found evidence of AHR-mediated toxicity with reduced thymus and spleen weights and significantly reduced thyroxine at P14 in PCB-exposed pups. In the brain, the greatest changes were seen in the cerebellum where a foliation defect was over-represented in Cyp1a2(−/−) mice. In contrast, we found no difference in tyrosine hydroxylase immunostaining in the striatum. Gene expression patterns varied across the three genotypes, but there was clear evidence of AHR activation. Distribution of parent PCB congeners also varied by genotype with strikingly high levels of PCB 77 in poor-affinity Ahr d Cyp1a2(−/−) while Ahr b Cyp1a2(+/+) mice effectively sequestered coplanar PCBs in the liver. Together, our data suggest that the AHR pathway plays a role in developmental PCB neurotoxicity, but we found little evidence that developmental exposure is a risk factor for Parkinson’s disease.

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Fig. 1

Modified from González-Franco et al. (2017)

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References

  • Agency for Toxic Substances and Disease Registry (ATSDR) (2015). 2015 CERCLA National priorities list of hazardous substances. U.S. Department of Health and Human Services, Public Health Service. Atlanta. https://www.atsdr.cdc.gov/spl/

  • Bansal R, Zoeller RT (2008) Polychlorinated biphenyls (Aroclor 1254) do not uniformly produce agonist actions on thyroid hormone responses in the developing rat brain. Endocrinology 149(8):4001–4008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bányiová K, Černá M, Mikeš O, Komprdová K, Sharma A, Gyalpo T, Čupr P, Scheringer M (2017) Long-term time trends in human intake of POPs in the Czech Republic indicate a need for continuous monitoring. Environ Int 108:1–10

    Article  PubMed  Google Scholar 

  • Berghuis SA, Soechitram SD, Hitzert MM, Sauer PJJ, Bos AF (2013) Prenatal exposure to polychlorinated biphenyls and their hydroxylated metabolites is associated with motor development of three-month-old infants. NeuroToxicol 38:124–130

    Article  CAS  Google Scholar 

  • Boucher O, Muckle G, Ayotte P, Dewailly E, Jacobson SW, Jacobson JL. (2016). Altered fine motor function at school age in Inuit children exposed to PCBs, methylmercury, and lead. Environ Int 95:144–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bronstein J, Carvey P, Chen H, Cory-Slechta D, DiMonte D, Duda J, English P, Goldman S, Grate S, Hansen J, Hoppin J, Jewell S, Kamel F, Koroshetz W, Langston JW, Logroscino G, Nelson L, Ravina B, Rocca W, Ross GW, Schettler T, Schwarzschild M, Scott B, Seegal R, Singleton A, Steenland K, Tanner CM, Van Den Eeden S, Weisskopf M (2009) Meeting report: consensus statement-Parkinson’s disease and the environment: collaborative on health and the environment and Parkinson’s Action Network (CHE PAN) conference 26–28 June 2007. Environ Health Perspect 117(1):117–121

    Article  PubMed  Google Scholar 

  • Caudle WM, Richardson JR, Delea KC, Guillot TS, Wang M, Pennell KD, Miller GW (2006) Polychlorinated biphenyl-induced reduction of dopamine transporter expression as a precursor to Parkinson’s disease-associated dopamine toxicity. Toxicol Sci 92:490–499

    Article  CAS  PubMed  Google Scholar 

  • Colter BT, Garber HF, Fleming SM, Fowler JP, Harding GD, Hooven MK, Howes AA, Infante SK, Lang AL, MacDougall MC, Stegman M, Taylor K, Curran CP (2017) Ahr and Cyp1a2 genotypes both affect susceptibility to motor deficits following gestational and lactational exposure to polychlorinated biphenyls. NeuroToxicology (submitted)

  • Costabeber I, Dos Santos JS, Xavier AA, Weber J, Leães FL, Junior SB, Emanuelli T (2006) Levels of polychlorinated biphenyls (PCBs) in meat and meat products from the state of Rio Grande do Sul, Brazil. Food Chem Toxicol 44(1):1–7

    Article  CAS  PubMed  Google Scholar 

  • Curran CP, Miller KA, Dalton TP, Vorhees CV, Miller ML, Shertzer HG et al (2006) Genetic differences in lethality of newborn mice treated in utero with coplanar versus non-coplanar hexabromobiphenyl. Toxicol Sci 89:454–464

    Article  CAS  PubMed  Google Scholar 

  • Curran CP, Vorhees CV, Williams MT, Genter MB, Nebert DW (2011a) In utero and lactational exposure to a complex mixture of polychlorinated biphenyls: toxicity in pups dependent on the Cyp1a2. and Ahr genotypes. Toxicol Sci 119:189–208

    Article  CAS  PubMed  Google Scholar 

  • Curran CP, Nebert DW, Genter MB, Patel KV, Schafer TL, Skelton MR, Williams MT, Vorhees CV (2011b) In utero and lactational exposure to PCBs in mice: adult offspring show altered learning and memory depending on Cyp1a2 and Ahr genotypes. Enironv Health Perspect 119(9):1286–1293

    Article  CAS  Google Scholar 

  • Curran CP, Altenhofen E, .Ashworth AA, .Brown A, Curran MA, Evans A, Floyd R, Fowler JP, Garber H, Hays B, Kamau-Cheggeh C, Kraemer S, Lang AL, Mynhier A, Samuels A, Strohamier C (2012) Ahr d Cyp1a2(−/−) mice show increased susceptibility to PCB-induced developmental neurotoxicity. Neurotoxicology 33(6):1436–1442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Darras VM (2008) Endocrine disrupting polyhalogenated organic pollutants interfere with thyroid hormone signalling in the developing brain. Cerebellum 7(1):26–37

    Article  CAS  PubMed  Google Scholar 

  • Denison MS, Faber SC (2017) And now for something completely different: diversity in ligand-dependent activation of Ah receptor responses. Curr Opin Toxicol 2:124–131

  • Diliberto JJ, Burgin D, Birnbaum LS (1997) Role of CYP1A2 in hepatic sequestration of dioxin: studies using CYP1A2 knock-out mice. Biochem Biophys Res Commun 236:431–433

    Article  CAS  PubMed  Google Scholar 

  • Doull J (2003) The “Red Book” and other risk assessment milestones. Hum Ecol Risk Assess 9:1229–1238

    Article  Google Scholar 

  • Dragin N, Dalton TP, Miller ML, Shertzer HG, Nebert DW (2006) For dioxin-induced birth defects, mouse or human CYP1A2 in maternal liver protects whereas mouse CYP1A1 and CYP1B1 are inconsequential. J Biol Chem 281:18591–18600

    Article  CAS  PubMed  Google Scholar 

  • Fauquier T, Chatonnet F, Picou F, Richard S, Fossat N, Aguilera N, Lamonerie T, Flamant F (2014) Purkinje cells and Bergmann glia are primary targets of the TRα1 thyroid hormone receptor during mouse cerebellum postnatal development. Development 141:166–175

    Article  CAS  PubMed  Google Scholar 

  • Gauger KJ, Giera S, Sharlin DS, Bansal R, Iannacone E, Zoeller RT (2007) Polychlorinated biphenyls 105 and 118 form thyroid hormone receptor agonists after cytochrome P4501A1 activation in rat pituitary GH3 cells. Environ Health Perspect 115:1623–1630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giera S, Bansal R, Ortiz-Toro TM, Taub DG, Zoeller RT (2011) Individual polychlorinated biphenyl (PCB) congeners produce tissue- and gene-specific effects on thyroid hormone signaling during development. Endocrinology 152(7):2909–2919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goldey ES, Crofton KM (1998) Thyroxine replacement attenuates hypothyroxinemia, hearing loss, and motor deficits following developmental exposure to Aroclor 1254 in rats. Toxicol Sci 45(1):94–105

    CAS  PubMed  Google Scholar 

  • Goldman SM (2014) Environmental toxins and Parkinson’s disease. Annu Rev Pharmacol Toxicol 54:141–164

    Article  CAS  PubMed  Google Scholar 

  • Gomara B, Bordajandi LR, Fernandez MA, Herrero L, Abad E, Abalos M, Rivera J, González MJ (2005) Levels and trends of polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (PCBs) in Spanish commercial fish and shellfish products, 1995–2003. J Agric Food Chem 53:8406–8413

    Article  CAS  PubMed  Google Scholar 

  • González-Franco DA, Ramírez-Amaya V, Joseph-Bravo P, Prado-Alcalá RA, Quirarte GL (2017) Differential Arc protein expression in dorsal and ventral striatum after moderate and intense inhibitory avoidance training. Neurobiol Learn Mem 40:17–26

    Article  Google Scholar 

  • Haijima A, Lesmana R, Shimokawa N, Amano I, Takatsuru Y, Koibuchi N (2017) Differential neurotoxic effects of in utero and lactational exposure to hydroxylated polychlorinated biphenyl (OH-PCB 106) on spontaneous locomotor activity and motor coordination in young adult male mice. J Toxicol Sci 42(4):407–416

    Article  PubMed  Google Scholar 

  • Hamilton BA, Frankel WN, Kerrebrock AW, Hawkins TL, FitzHugh W, Kusumi K, Russell LB, Mueller KL, van Berkel V, Birren BW, Kruglyak L, Lander ES (1996) Disruption of the nuclear hormone receptor RORα in staggerer mice. Nature 379:736–739

    Article  CAS  PubMed  Google Scholar 

  • Hatcher-Martin JM, Gearing M, Steenland K, Levey AI, Miller GW, Pennell KD (2012) Association between polychlorinated biphenyls and Parkinson’s disease neuropathology. Neurotoxicology 33:1298–1304

  • Herrick RF, Meeker JD, Altshul L (2011) Serum PCB levels and congener profiles among teachers in PCB-containing schools: a pilot study. Environ Health 10:56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hovander L, Linderholm L, Athanasiadou M, Athanassiadis I, Bignert A, Fängström B, Kocan A, Petrik J, Trnovec T, Bergman A (2006) Levels of PCBs and their metabolites in the serum of residents of a highly contaminated area in eastern Slovakia. Environ Sci Technol 40(12):3696–3703

    Article  CAS  PubMed  Google Scholar 

  • Hu D, Hornbuckle KC (2010) Inadvertent polychlorinated biphenyls in commercial paint pigments. Environ Sci Technol 44(8):2822–2827

    Article  CAS  PubMed  Google Scholar 

  • Jacobson JL, Jacobson SW (1997) Evidence for PCBs as neurodevelopmental toxicants in humans. Neurotoxicology 18:415–424

    CAS  PubMed  Google Scholar 

  • Jacobson JL, Jacobson SW (2003) Prenatal exposure to polychlorinated biphenyls and attention at school age. J Pediatr 143:780–788

    Article  CAS  PubMed  Google Scholar 

  • Kania-Korwel I, Parkin S, Robertson LW, Lehmler H-J (2004) Synthesis of polychlorinated biphenyls and their metabolites with a modified Suzuki-coupling. Chemosphere 56:735–744

    Article  CAS  PubMed  Google Scholar 

  • Kania-Korwel I, Hornbuckle KC, Peck A, Ludewig G, Robertson LW, Sulkowski WW, Espandiari P, Gairola CG, Lehmler H-J (2005) Congener specific tissue distribution of Aroclor 1254 and a highly chlorinated environmental PCB mixture in rats. Environ Sci Technol 39:3513–3520

    Article  CAS  PubMed  Google Scholar 

  • Kania-Korwel I, Shaikh N, Hornbuckle KC, Robertson LW, Lehmler H-J (2007) Enantioselective disposition of PCB 136 (2,2′,3,3′,6,6′-hexachlorobiphenyl) in C57BL/6 mice after oral and intraperitoneal administration. Chirality 19:56–66

    Article  CAS  PubMed  Google Scholar 

  • Kania-Korwel I, Zhao H, Norstrom K, Li X, Hornbuckle KC, Lehmler HJ (2008) Simultaneous extraction and clean-up of polychlorinated biphenyls and their metabolites from small tissue samples using pressurized liquid extraction. J Chromatogr A 1214:37–46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koh WX, Hornbuckle KC, Marek RF, Wang K, Thorne PS (2016) Hydroxylated polychlorinated biphenyls in human sera from adolescents and their mothers living in two U.S. Midwestern communities. Chemosphere 147:389–395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koibuchi N, Chin WW (2000) Thyroid hormone action and brain development. Trends Endocrinol Metab 11(4):123–128

    Article  CAS  PubMed  Google Scholar 

  • Koibuchi N, Yamaoka S, Chin WW (2001) Effect of altered thyroid status on neurotrophin gene expression during postnatal development of the mouse cerebellum. Thyroid 11(3):205–210

    Article  CAS  PubMed  Google Scholar 

  • Lambert GH, Needham LL, Turner W, Lai TJ, Patterson DG Jr, Guo YL (2006) Induced CYP1A2 activity as a phenotypic biomarker in humans highly exposed to certain PCBs/PCDFs. Environ Sci Technol 40(19):6176–6180

    Article  CAS  PubMed  Google Scholar 

  • Langer P, Kocan A, Tajtakova M, Petrik J, Chovancova J, Drobna B et al (2007) Fish from industrially polluted freshwater as the main source of organochlorinated pollutants and increased frequency of thyroid disorders and dysglycemia. Chemosphere 67:S379–S385

    Article  CAS  PubMed  Google Scholar 

  • Lee DW, Notter SA, Thiruchelvam M, Dever DP, Fitzpatrick R, Kostyniak PJ, Cory-Slechta DA, Opanashuk LA (2012) Subchronic polychlorinated biphenyl (Aroclor 1254) exposure produces oxidative damage and neuronal death of ventral midbrain dopaminergic systems. Toxicol Sci 125(2):496–508

    Article  CAS  PubMed  Google Scholar 

  • Lehmler H-J, Robertson LW (2001) Synthesis of polychlorinated biphenyls (PCBs) using the Suzuki-coupling. Chemosphere 45:137–143

    Article  CAS  PubMed  Google Scholar 

  • Lein PJ, Yang D, Bachstetter AD, Tilson HA, Harry GJ, Mervis RF, Kodavanti PR (2007) Ontogenetic alterations in molecular and structural correlates of dendritic growth after developmental exposure to polychlorinated biphenyls. Environ Health Perspect 115(4):556–563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin TM, Ko K, Moore RW, Buchanan DL, Cooke PS, Peterson RE (2001) Role of the aryl hydrocarbon receptor in the development of control and 2,3,7,8-tetrachlorodibenzo-p-dioxin-exposed male mice. J Toxicol Environ Health A 64(4):327–342

    Article  CAS  PubMed  Google Scholar 

  • Lin P, Hu SW, Chang TH (2003) Correlation between gene expression of aryl hydrocarbon receptor (AhR), hydrocarbon receptor nuclear translocator (Arnt), cytochromes P4501A1 (CYP1A1) and 1B1 (CYP1B1), and inducibility of CYP1A1 and CYP1B1 in human lymphocytes. Toxicol Sci 71(1):20–26

    Article  CAS  PubMed  Google Scholar 

  • López-Juárez A, Morales-Lázaro S, Sánchez-Sánchez R, Sunkara M, Lomelí H, Velasco I, Morris AJ, Escalante-Alcalde D (2011) Expression of LPP3 in Bergmann glia is required for proper cerebellar sphingosine-1-phosphate metabolism/signaling and development. Glia 59(4):577–589

    Article  PubMed  PubMed Central  Google Scholar 

  • Maervoet J, Covaci A, Schepens P, Sandau CD, Letcher R (2004) A reassessment of the nomenclature of polychlorinated biphenyl (PCB) metabolites. Environ Health Perspect 112:291–294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marek RF, Thorne PS, DeWall J, Hornbuckle KC (2014) Variability in PCB and OH-PCB serum levels in children and their mothers in urban and rural U.S. communities. Environ Sci Technol 48(22):13459–13467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marek RF, Thorne PS, Herkert NJ, Awad AM, Hornbuckle KC (2017) Airborne PCBs and OH-PCBs inside and outside urban and rural U.S. schools. Environ Sci Technol 51(14):7853–7860

    Article  CAS  PubMed  Google Scholar 

  • Nebert DW (2017) Aryl hydrocarbon receptor (AHR): “pioneer member” of the basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family of “sensors” of foreign and endogenous signals. Prog Lipid Res 67:38–57

    Article  CAS  PubMed  Google Scholar 

  • Nebert DW, Dalton TP (2006) The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer 6:947–960

    Article  CAS  PubMed  Google Scholar 

  • Nebert DW, Wikvall K, Miller WL (2013) Human cytochromes P450 in health and disease. Philos Trans R Soc Lond B Biol Sci 368(1612):20120431

    Article  PubMed  PubMed Central  Google Scholar 

  • Pessah IN, Cherednichenko G, Lein PJ (2010) Minding the calcium store: Ryanodine receptor activation as a convergent mechanism of PCB toxicity. Pharmacol Ther 125:260–285

    Article  CAS  PubMed  Google Scholar 

  • Petersen MS, Halling J, Bech S, Wermuth L, Weihe P, Nielsen F et al (2008) Impact of dietary exposure to food contaminants on the risk of Parkinson’s disease. Neurotoxicology 29:584–590

    Article  CAS  PubMed  Google Scholar 

  • Qiu CH, Miyazaki W, Iwasaki T, Londoño M, Ibhazehiebo K, Shimokawa N, Koibuchi N (2009) Retinoic Acid receptor-related orphan receptor alpha-enhanced thyroid hormone receptor-mediated transcription requires its ligand binding domain which is not, by itself, sufficient: possible direct interaction of two receptors. Thyroid 19(8):893–898

    Article  CAS  PubMed  Google Scholar 

  • Quinn CL, Wania F, Czub G, Breivik K (2011) Investigating intergenerational differences in human PCB exposure due to variable emissions and reproductive behaviors. Environ Health Perspect 119:641–646

    Article  CAS  PubMed  Google Scholar 

  • Ross G (2004) The public health implications of polychlorinated biphenyls (PCBs) in the environment. Ecotoxicol Environ Saf 59:275–291

    Article  CAS  PubMed  Google Scholar 

  • Ruder AM, Hein MJ, Hopf NB, Waters MA. (2014). Mortality among 24,865 workers exposed to polychlorinated biphenyls (PCBs) in three electrical capacitor manufacturing plants: a ten-year update. Int J Hyg Environ Health 217(2–3):176–187

    Article  CAS  PubMed  Google Scholar 

  • Sandau CD, Ayotte P, Dewailly E, Duffe J, Norstrom RJ (2000) Analysis of hydroxylated metabolites of PCBs (OH-PCBs) and other chlorinated phenolic compounds in whole blood from Canadian inuit. Environ Health Perspect 108:611–616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schantz SL, Widholm JJ, Rice DC (2003) Effects of PCB exposure on neuropsychological function in children. Environ Health Perspect 111:357–576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schramm H, Robertson LW, Oesch F (1985) Differential regulation of hepatic glutathione transferase and glutathione peroxidase activities in the rat. Biochem Pharmacol 34:3735–3739

    Article  CAS  PubMed  Google Scholar 

  • Seegal RF, Brosch KO, Bush B (1986) Polychlorinated biphenyls produce regional alterations of dopamine metabolism in rat brain. Toxicol Lett 30:197–202

    Article  CAS  PubMed  Google Scholar 

  • Seegal RF, Bush B, Brosch KO (1994) Decreases in dopamine concentrations in adult, non-human primate brain persist following removal from polychlorinated biphenyls. Toxicology 86:71–87

    Article  CAS  PubMed  Google Scholar 

  • Seegal RF, Brosch KO, Okoniewski RJ (1997) Effects of in utero and lactational exposure of the laboratory rat to 2,4,2′,4′- and 3,4,3′,4′-tetrachlorobiphenyl on dopamine function. Toxicol Appl Pharmacol 146:95–103

    Article  CAS  PubMed  Google Scholar 

  • Seegal RF, Brosch KO, Okoniewski RJ (2005) Coplanar PCB congeners increase uterine weight and frontal cortical dopamine in the developing rat: implications for developmental neurotoxicity. Toxicol Sci 86:125–131

    Article  CAS  PubMed  Google Scholar 

  • Seegal RF, Marek KL, Seibyl JP, Jennings DL, Molho ES, Higgins DS, Factor SA, Fitzgerald EF, Hills EA, Korrick SA, Wolff MS, Haase RF, Todd AC, Parsons P, McCaffrey RJ (2010) Occupational exposure to PCBs reduces striatal dopamine transporter densities only in women: a beta-CIT imaging study. Neurobiol Dis 38(2): 219–225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steenland K, Hein MJ, Cassinelli RT, Prince MM, Nilsen NB, Whelan EA et al (2006) Polychlorinated biphenyls and neurodegenerative disease mortality in an occupational cohort. Epidemiology 17:8–13

    Article  PubMed  Google Scholar 

  • Stegman M, Curran CP, Infante SK, Kromme M, Hays B, Taylor K, Garber H, Lang A (2014) Assessing genetic susceptibility to motor function deficits following developmental exposure to polychlorinated biphenyls. Toxicol Sci Supp 138(1):457–458

    Google Scholar 

  • Stewart P, Reihman J, Lonky E, Darvill T, Pagano J (2000) Prenatal PCB exposure and neonatal behavioral assessment scale (NBAS) performance. Neurotoxicol Teratol 22(1):21–29

    Article  CAS  PubMed  Google Scholar 

  • Takahashi M, Negishi T, Tashior T (2008) Identification of genes mediating thyroid hormone action in the developing mouse cerebellum. J Neurochem 104:640–652

    CAS  PubMed  Google Scholar 

  • Takeuchi S, Shiraishi F, Kitamura S, Kuroki H, Jin K, Kojima H (2011) Characterization of steroid hormone receptor activities in 100 hydroxylated polychlorinated biphenyls, including congeners identified in humans. Toxicology 289:112–121

    Article  CAS  PubMed  Google Scholar 

  • Ulbrich B, Stahlmann R (2004) Developmental toxicity of polychlorinated biphenyls (PCBs): a systematic review of experimental data. Arch Toxicol 78:252–268

  • United Nations Environmental Program (UNEP) (2001). Stockholm convention on persistent organic pollutants. http://chm.pops.int/TheConvention/Overview/tabid/3351/Default.aspx

  • van den Berg M, Birnbaum LS, Denison M, De VM, Farland W, Feeley M et al (2006) The 2005 World Health Organization reevaluation of human and Mammalian toxic equivalency factors for dioxins and dioxin-like compounds. Toxicol Sci 93:223–241

  • Van Dine SE, Siu NY, Toia A, Cuoco JA, Betz AJ, Bolivar VJ, Torres G, Ramos RL (2015) Spontaneous malformations of the cerebellar vermis: prevalence, inheritance, and relationship to lobule/fissure organization in the C57BL/6 lineage. Neuroscience 310:242–251

    Article  PubMed  Google Scholar 

  • Van den Berg BM, Birnbaum L, Bosveld AT, Brunstrom B, Cook P, Feeley M et al (1998) Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environ Health Perspect 106:775–792

    Article  PubMed  PubMed Central  Google Scholar 

  • van den Hurk P, Kubiczak GA, Lehmler HJ, James MO (2002) Hydroxylated polychlorinated biphenyls as inhibitors of the sulfation and glucuronidation of 3-hydroxy-benzo[a]pyrene. Environ Health Perspect 110:343–348

    Article  PubMed  PubMed Central  Google Scholar 

  • Vanden Heuvel JP, Clark GC, Thompson CL, McCoy Z, Miller CR, Lucier GW et al (1993) CYP1A1 mRNA levels as a human exposure biomarker: use of quantitative polymerase chain reaction to measure CYP1A1 expression in human peripheral blood lymphocytes. Carcinogenesis 14:2003–2006

    Article  CAS  PubMed  Google Scholar 

  • Vreugdenhil HJ, Lanting CI, Mulder PG, Boersma ER, Weisglas-Kuperus N (2002) Effects of prenatal PCB and dioxin background exposure on cognitive and motor abilities in Dutch children at school age. J Pediatr 140:48–56

    Article  CAS  PubMed  Google Scholar 

  • Wadzinski TL, Geromini K, McKinley Brewer J, Bansal R, Abdelouahab N, Langlois MF, Takser L, Zoeller RT (2014) Endocrine disruption in human placenta: expression of the dioxin-inducible enzyme, CYP1A1, is correlated with that of thyroid hormone-regulated genes. J Clin Endocrinol Metab 99(12):E2735–E2743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weisskopf MG, Knekt P, O’Reilly EJ, Lyytinen J, Reunanen A, Laden F, Altshul L, Ascherio A (2012) Polychlorinated biphenyls in prospectively collected serum and Parkinson’s disease risk. Mov Disord 27(13):1659–1665

    Article  PubMed  PubMed Central  Google Scholar 

  • Wilhelm M, Wittsiepe J, Lemm F, Ranft U, Krämer U, Fürst P, Röseler SC, Greshake M, Imöhl M, Eberwein G, Rauchfuss K, Kraft M, Winneke G (2008) The Duisburg birth cohort study: influence of the prenatal exposure to PCDD/Fs and dioxin-like PCBs on thyroid hormone status in newborns and neurodevelopment of infants until the age of 24 months. Mutat Res 659(1–2):83–92

    Article  CAS  PubMed  Google Scholar 

  • Zoeller RT, Rovett J (2004) Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings. J Neuroendocrinol 16:809–818

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Institutes of Health (R15ES020053, P20 GM103436, ES05605, and ES013661), the National Science Foundation (RSF-034-07, DUE-STEP-096928), and the following grants from Northern Kentucky University: Faculty Development Project Grants, College of Arts & Sciences Collaborative Faculty-Student Award, Center for Integrative Natural Science and Mathematics Research Grants, and Dorothy Westerman Herrmann funds. We thank Joshua Lambert, University of Kentucky Department of Statistics, Jiaying Weng and Ya Qi, University of Kentucky Department of Statistics Applied Statistics Laboratory, for assistance with data analysis, and we acknowledge the generous donation of Cyp1a2(−/−) knockout mice from Dr. Daniel W. Nebert, University of Cincinnati Department of Environmental Health. We thank the reviewers for their valuable suggestions and careful review of the manuscript.

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  1. Kelsey Klinefelter and Molly Kromme Hooven have contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Sciences, Northern Kentucky University, SC344 Nunn Drive, Highland Heights, KY, 41076, USA

    Kelsey Klinefelter, Molly Kromme Hooven, Chloe Bates, Breann T. Colter, Alexandra Dailey, Smitha Krishnan Infante, Clare Pickering Ludwig & Christine Perdan Curran

  2. Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA

    Kelsey Klinefelter & Molly Kromme Hooven

  3. Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA

    Alejandro López-Juárez

  4. Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA, 52242, USA

    Izabela Kania-Korwel & Hans-Joachim Lehmler

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Correspondence to Christine Perdan Curran.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed, and all protocols were approved by the Northern Kentucky University Institutional Animal Care and Use Committee.

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Klinefelter, K., Hooven, M.K., Bates, C. et al. Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect sensitivity to developmental polychlorinated biphenyl exposure in mice: relevance to studies of human neurological disorders. Mamm Genome 29, 112–127 (2018). https://doi.org/10.1007/s00335-017-9728-1

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