Ahr and Cyp1a2 genotypes both affect susceptibility to motor deficits following gestational and lactational exposure to polychlorinated biphenyls
| Autor: | Anna L. Lang, Sheila M. Fleming, Gregory D. Harding, Kelsey Taylor, Molly Kromme Hooven, Helen Frances Garber, Amy Ashworth Howes, Jocelyn Phillips Fowler, Smitha Krishnan Infante, Breann T. Colter, Christine Perdan Curran, Melinda Curran MacDougall, Melinda Stegman |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Cerebellum Genotype 010501 environmental sciences Toxicology 01 natural sciences Article Mice 03 medical and health sciences 0302 clinical medicine Cytochrome P-450 CYP1A2 Pregnancy Internal medicine medicine Animals Learning 0105 earth and related environmental sciences Mice Knockout 2. Zero hunger Behavior Animal biology General Neuroscience CYP1A2 Aryl hydrocarbon receptor Polychlorinated Biphenyls 3. Good health 030104 developmental biology Endocrinology medicine.anatomical_structure Receptors Aryl Hydrocarbon Maternal Exposure 13. Climate action Prenatal Exposure Delayed Effects Rotarod Performance Test Knockout mouse biology.protein Gestation Female Animal studies Motor learning 030217 neurology & neurosurgery Hormone |
| DOI: | 10.1101/184010 |
| Popis: | 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 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 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. |
| Databáze: | OpenAIRE |
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