Biology subjects

Infante, S. K.

Publications and source records attributed to Infante, S. K..

2 recordsLinked to original sources

bioRxiv2017

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

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that remain a human health concern with the discovery of new sources of contamination and ongoing bioaccumulation and biomagnification. Children exposed during early brain development are at highest risk of neurological deficits, but there is some evidence that high PCB exposure in adults increases the risk of Parkinsons disease. Our previous studies found allelic differences in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) affect susceptibility to developmental PCB exposure, resulting in cognitive deficits and motor dysfunction. High-affinity AhrbCyp1a2(-/-) mice were most susceptible compared with poor-affinity AhrdCyp1a2(-/-) and wild type AhrbCyp1a2(+/+) 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 multiple tissues to determine if genotype altered toxicokinetics. We found evidence of AHR-mediated immune suppression with reduced thymus and spleen weights and significantly reduced thyroxine at P14. 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 immuno-staining 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 AhrdCyp1a2(-/-) while AhrbCyp1a2(+/+) 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 Parkinsons disease.

pharmacology and toxicology↗

bioRxiv2017

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

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 AhrbCyp1a2(-/-) and poor-affinity AhrdCyp1a2(-/-) knockout mice were most susceptible to learning and memory deficits following developmental PCB exposure compared with AhrbCyp1a2(+/+) 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 Parkinsons 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 Ahrb mice were most susceptible to disruption of nigrostriatal function with the greatest deficits in AhrbCyp1a2(-/-) mice. We conclude that differences in both genes affect susceptibility to motor deficits following developmental PCB exposure.

pharmacology and toxicology↗