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
| Autor: | Smitha Krishnan Infante, Alexandra Dailey, Hans-Joachim Lehmler, Izabela Kania-Korwel, Chloe Bates, Molly Kromme Hooven, Kelsey Klinefelter, Breann T. Colter, Alejandro López-Juárez, Christine Perdan Curran, Clare Pickering Ludwig |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0303 health sciences
medicine.medical_specialty Tyrosine hydroxylase CYP1A2 Wild type Neurotoxicity Polychlorinated biphenyl 010501 environmental sciences Biology Aryl hydrocarbon receptor medicine.disease 01 natural sciences 3. Good health 03 medical and health sciences chemistry.chemical_compound Endocrinology chemistry 13. Climate action Internal medicine Genotype biology.protein medicine Toxicokinetics 030304 developmental biology 0105 earth and related environmental sciences |
| DOI: | 10.1101/194472 |
| Popis: | 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 Parkinson’s 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 Parkinson’s disease. |
| Databáze: | OpenAIRE |
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