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

Kelsey Klinefelter; Molly Kromme Hooven; Chloe Bates; Breann T Colter; Alexandra Dailey; Smitha Krishnan Infante; Izabela Kania-Korwel; Hans-Joachim Lehmler; Alejandro López-Juárez; Clare Pickering Ludwig; Christine Perdan Curran

doi:10.1007/s00335-017-9728-1

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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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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

Kelsey Klinefelter, Molly Kromme Hooven, Chloe Bates, Breann T Colter, Alexandra Dailey, Smitha Krishnan Infante, Izabela Kania-Korwel, Hans-Joachim Lehmler, Alejandro López-Juárez, Clare Pickering Ludwig, …

Mammalian genome, Vol.29(1-2), pp.112-127

02/2018

DOI: 10.1007/s00335-017-9728-1

PMCID: PMC6425730

PMID: 29197979

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https://www.ncbi.nlm.nih.gov/pmc/articles/6425730View

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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 Cyp1a2(-/-) mice were most sensitive compared with poor-affinity Ahr Cyp1a2(-/-) and wild-type Ahr 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 Cyp1a2(-/-) while Ahr 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.

Liver - pathology

Humans

Risk Factors

Receptors, Aryl Hydrocarbon - genetics

Genotype

Polychlorinated Biphenyls - metabolism

Cytochrome P-450 CYP1A2 - metabolism

Parkinson Disease, Secondary - pathology

Animals

Parkinson Disease, Secondary - genetics

Liver - drug effects

Polychlorinated Biphenyls - toxicity

Cytochrome P-450 CYP1A2 - genetics

Receptors, Aryl Hydrocarbon - metabolism

Mice

Parkinson Disease, Secondary - chemically induced

ISRP Project 1 2015-2020

Synthesis Core

Details

Title: Subtitle: 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
Creators: Kelsey Klinefelter - Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
Molly Kromme Hooven - Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
Chloe Bates - Department of Biological Sciences, Northern Kentucky University, SC344 Nunn Drive, Highland Heights, KY, 41076, USA
Breann T Colter - Department of Biological Sciences, Northern Kentucky University, SC344 Nunn Drive, Highland Heights, KY, 41076, USA
Alexandra Dailey - Department of Biological Sciences, Northern Kentucky University, SC344 Nunn Drive, Highland Heights, KY, 41076, USA
Smitha Krishnan Infante - Department of Biological Sciences, Northern Kentucky University, SC344 Nunn Drive, Highland Heights, KY, 41076, USA
Izabela Kania-Korwel - Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA, 52242, USA
Hans-Joachim Lehmler - Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA, 52242, USA
Alejandro López-Juárez - Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
Clare Pickering Ludwig - Department of Biological Sciences, Northern Kentucky University, SC344 Nunn Drive, Highland Heights, KY, 41076, USA
Christine Perdan Curran - Department of Biological Sciences, Northern Kentucky University, SC344 Nunn Drive, Highland Heights, KY, 41076, USA. Curranc1@nku.edu
Resource Type: Journal article
Publication Details: Mammalian genome, Vol.29(1-2), pp.112-127
DOI: 10.1007/s00335-017-9728-1
PMID: 29197979
PMCID: PMC6425730
NLM abbreviation: Mamm Genome
ISSN: 0938-8990
eISSN: 1432-1777
Publisher: United States
Grant note: R15ES020053 / NIEHS NIH HHS P30 ES005605 / NIEHS NIH HHS RSF-034-07 / National Science Foundation DUE-STEP-096928 / National Science Foundation ES05605 / NIEHS NIH HHS College of Arts & Sciences / Northern Kentucky University P20GM103436 / NIGMS NIH HHS ES013661 / NIEHS NIH HHS
Language: English
Date published: 02/2018
Academic Unit: Occupational and Environmental Health; Iowa Neuroscience Institute; Iowa Superfund Research Program
Record Identifier: 9984001086202771

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