Ahr and Cyp1a2 genotypes both affect susceptibility to motor deficits following gestational and lactational exposure to polychlorinated biphenyls

Breann T. Colter, Helen Frances Garber, Sheila M. Fleming, Jocelyn Phillips Fowler, Gregory D. Harding, Molly Kromme Hooven, Amy Ashworth Howes, Smitha Krishnan Infante, Anna L. Lang, Melinda Curran MacDougall, Melinda Stegman, Kelsey Rae Taylor, Christine Perdan Curran

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Polychlorinated biphenyls (PCBs) are persistent organic pollutants known to cause adverse health effects and linked to neurological deficits in both human and animal studies. Children born to exposed mothers are at highest risk of learning and memory and motor deficits. We developed a mouse model that mimics human variation in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) to determine if genetic variation increases susceptibility to developmental PCB exposure. In our previous studies, we found that high-affinity Ahr b Cyp1a2(−/−) and poor-affinity Ahr d Cyp1a2(−/−) knockout mice were most susceptible to learning and memory deficits following developmental PCB exposure compared with Ahr b Cyp1a2(+/+) wild type mice (C57BL/6J strain). Our follow-up studies focused on motor deficits, because human studies have identified PCBs as a potential risk factor for Parkinson's disease. Dams were treated with an environmentally relevant PCB mixture at gestational day 10 and postnatal day 5. We used a motor battery that included tests of nigrostriatal function as well as cerebellar function, because PCBs deplete thyroid hormone, which is essential to normal cerebellar development. There was a significant effect of PCB treatment in the rotarod test with impaired performance in all three genotypes, but decreased motor learning as well in the two Cyp1a2(−/−) knockout lines. Interestingly, we found a main effect of genotype with corn oil-treated control Cyp1a2(−/−) mice performing significantly worse than Cyp1a2(+/+) wild type mice. In contrast, we found that PCB-treated high-affinity Ahr b mice were most susceptible to disruption of nigrostriatal function with the greatest deficits in Ahr b Cyp1a2(−/−) mice. We conclude that differences in AHR affinity combined with the absence of CYP1A2 protein affect susceptibility to motor deficits following developmental PCB exposure.

Original languageEnglish (US)
Pages (from-to)125-134
Number of pages10
JournalNeurotoxicology
Volume65
DOIs
StatePublished - Mar 2018
Externally publishedYes

Keywords

  • Aryl hydrocarbon receptor
  • Cerebellum
  • CYP1A2
  • Motor function
  • Nigrostriatal pathways
  • Polychlorinated biphenyls

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

Fingerprint

Dive into the research topics of 'Ahr and Cyp1a2 genotypes both affect susceptibility to motor deficits following gestational and lactational exposure to polychlorinated biphenyls'. Together they form a unique fingerprint.

Cite this