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.

Kelsey Klinefelter, Molly Kromme Hooven, Chloe Bates, Breann T Colter, Alexandra Dailey, Smitha Krishnan Infante, Izabela Kania-Korwel, Hans-Joachim Lehmler, Alejandro López-Juárez, Clare Pickering Ludwig, Christine Perdan Curran
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引用次数: 13

Abstract

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that remain a human health concern with newly discovered sources of contamination and ongoing bioaccumulation and biomagnification. Children exposed during early brain development are at highest risk of neurological deficits, but highly exposed adults reportedly have an increased risk of Parkinson's disease. Our previous studies found allelic differences in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) affect sensitivity to developmental PCB exposure, resulting in cognitive deficits and motor dysfunction. High-affinity Ahr b Cyp1a2(-/-) mice were most sensitive compared with poor-affinity Ahr d Cyp1a2(-/-) and wild-type Ahr b Cyp1a2(+/+) 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 tissues to determine if genotype altered toxicokinetics. We found evidence of AHR-mediated toxicity with reduced thymus and spleen weights and significantly reduced thyroxine at P14 in PCB-exposed pups. 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 immunostaining 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 Ahr d Cyp1a2(-/-) while Ahr b Cyp1a2(+/+) 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.

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芳烃受体和CYP1A2的遗传差异影响小鼠对发育多氯联苯暴露的敏感性:与人类神经系统疾病研究的相关性
多氯联苯是一种持久性有机污染物,随着新发现的污染源和持续的生物积累和生物放大,它仍然是人类健康关注的问题。在大脑发育早期暴露于这种物质的儿童患神经功能缺陷的风险最高,但据报道,高度暴露于这种物质的成年人患帕金森病的风险更高。我们之前的研究发现,芳烃受体和细胞色素P450 1A2 (CYP1A2)的等位基因差异影响对发育中多氯联苯暴露的敏感性,导致认知缺陷和运动功能障碍。与低亲和型Ahr d Cyp1a2(-/-)和野生型Ahr b Cyp1a2(+/+)小鼠相比,高亲和型Ahr b Cyp1a2(-/-)小鼠最敏感。我们的后续研究评估了生化、组织学和基因表达的变化,以确定受影响的大脑区域和途径。我们还测量了组织中的多氯联苯和代谢物水平,以确定基因型是否改变了毒性动力学。我们发现了ahr介导的毒性证据,暴露于多氯联苯的幼犬胸腺和脾脏重量减少,P14时甲状腺素显著降低。在大脑中,在小脑中观察到最大的变化,在Cyp1a2(-/-)小鼠中,叶状缺损过度代表。相反,我们发现纹状体中酪氨酸羟化酶免疫染色无差异。基因表达模式在三种基因型中有所不同,但有明确的证据表明AHR激活。亲本多氯联苯同系物的分布也因基因型而异,在低亲和力的Ahr d Cyp1a2(-/-)中,PCB 77的水平非常高,而Ahr b Cyp1a2(+/+)小鼠有效地隔离了肝脏中的共面多氯联苯。总之,我们的数据表明AHR通路在发育性多氯联苯神经毒性中起作用,但我们发现很少有证据表明发育暴露是帕金森病的危险因素。
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