Emergency and Business Management Office, Chengdu Center for Disease Control and Prevention, Chengdu, Sichuan, People's Republic of China; Department of Occupational and Environmental Health, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, People's Republic of China.
Center of Experimental Teaching for Public Health, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing, People's Republic of China; Laboratory of Tissue and Cell Biology, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing, People's Republic of China.
Chemosphere. 2019 Dec;237:124378. doi: 10.1016/j.chemosphere.2019.124378. Epub 2019 Jul 15.
Benzo[a]pyrene (B[a]P) is a ubiquitous neurotoxic pollutant that widely distributes in the natural environment. However, the exact mechanism of B[a]P-induced neurotoxicity has not been well established. As one key synaptic protein, SNAP-25 plays an important role in the regulation of neurotransmitter release, including synaptic dopamine release. In this study, we demonstrated that, after intragastric administration of B[a]P in rats aged postnatal day 5 for 7 weeks, B[a]P significantly increased the level of dopamine and the expression of SNAP-25, dopamine receptor 1 (DRD1) and DRD 3. Moreover, treatment of B[a]P also caused the ultra-structural pathological changes in the cerebral cortex of rats. To further reveal the potential role of SNAP-25 in the regulation of DRDs, we treated the dopaminergic PC-12 cells with 20 μM B[a]P for 24 h. A significant cytotoxicity and apoptosis were observed, and more importantly, we found that SNAP-25, DRD 1 and DRD 3 co-localized in the cells, and down-regulation of SNAP-25 by CRISPR-Cas9 plasmid remarkably reduced the expression of DRD1 and DRD3. Together, our findings suggest that, synaptic dopamine release may be positively regulated by SNAP-25 via its receptors, and thus affecting the neurotoxicity induced by B[a]P.
苯并[a]芘（B[a]P）是一种普遍存在的神经毒性污染物，广泛分布于自然环境中。然而，B[a]P 诱导神经毒性的确切机制尚未得到很好的阐明。作为一种关键的突触蛋白，突触融合蛋白 25（SNAP-25）在神经递质释放的调节中发挥着重要作用，包括突触多巴胺的释放。在本研究中，我们证实，在大鼠出生后第 5 天经胃内给予 B[a]P 连续给药 7 周后，B[a]P 显著增加了多巴胺的水平和 SNAP-25、多巴胺受体 1（DRD1）和 DRD3 的表达。此外，B[a]P 处理还导致了大鼠大脑皮质的超微结构病理变化。为了进一步揭示 SNAP-25 在调节 DRDs 中的潜在作用，我们用 20μM B[a]P 处理多巴胺能 PC-12 细胞 24 小时。观察到明显的细胞毒性和细胞凋亡，更重要的是，我们发现 SNAP-25、DRD1 和 DRD3 在细胞中共定位，并且通过 CRISPR-Cas9 质粒下调 SNAP-25 显著降低了 DRD1 和 DRD3 的表达。综上所述，我们的研究结果表明，突触多巴胺的释放可能通过其受体被 SNAP-25 正向调节，从而影响 B[a]P 诱导的神经毒性。
