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

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 AhrCyp1a2(-/-) and poor-affinity AhrCyp1a2(-/-) knockout mice were most susceptible to learning and memory deficits following developmental PCB exposure compared with AhrCyp1a2(+/+) 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 mice were most susceptible to disruption of nigrostriatal function with the greatest deficits in AhrCyp1a2(-/-) mice. We conclude that differences in AHR affinity combined with the absence of CYP1A2 protein affect susceptibility to motor deficits following developmental PCB exposure.

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

“…We have now extended those studies to PCB-induced motor dysfunction and found a similar role for the AHR and CYP1A2 (Stegman et al 2014; Colter et al 2017 submitted). The studies reported here were designed to identify the specific brain regions affected and the critical pathways involved in motor dysfunction.…”

“…These were coplanar PCBs 77, 126, and 169 and non-coplanar PCBs 105, 118, 138, 153, and 180 (ULTRA Scientific, North Kingstown RI) dissolved in corn oil (Kroger). The coplanar PCB concentration insured persistent AHR activation through weaning in the high-affinity Ahr b mice, but not in poor-affinity Ahr d mice (Colter et al 2017 submitted). We used a mixture to better model human exposures because single congeners do not produce the same effects seen in human cohorts (Ulbrich and Stahlmann 2004).…”

“…Our previous work demonstrated that allelic differences in the aryl hydrocarbon receptor (AHR) and cytochrome P450 1A2 (CYP1A2) increased sensitivity to developmental PCB neurotoxicity, leading to greater impairments in learning and memory (Curran et al 2011b, 2012) and in motor function in Ahr b Cyp1a2(−/−) knockout mice (Stegman et al 2014; Colter et al 2017 submitted). The AHR is a ligand-activated transcription factor that binds to coplanar PCBs, dioxins, and polycyclic aromatic hydrocarbons and has been linked to numerous developmental and metabolic pathways, including those in the nervous system (reviewed in Nebert 2017).…”

Perspective on prenatal polychlorinated biphenyl exposure and the development of the progeny nervous system (Review)

“…Cytochrome P450s (CYPs) plays a key role in detoxification or activation of numerous xenobiotics ( 55 ). DL-PCBs bind and activate the aryl hydrocarbon receptor (AhR) to regulate three members of the CYP family: CYP1A1, CYP1A2 and CYP1B1 ( 58 ), which play an important role in the detoxification of PCB ( 59 ).…”

Uncovering Evidence for Endocrine-Disrupting Chemicals That Elicit Differential Susceptibility through Gene-Environment Interactions

“…Some of the effects of EDCs already have well-characterized gene-environment interactions that modulate an organism’s susceptibility [ 16 , 17 , 18 , 19 ]. This is only a drop in the bucket of the many endocrine-disrupting chemicals that may participate in GxE.…”