Li Yi-Zhou, Wu Zi-Yao, Zhu Bi-Qi, Wang Yu-Xiao, Kan Ya-Qi, Zeng Huai-Cai
Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin 541199, China.
Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, Guilin Medical University, Guilin 541199, China.
Toxics. 2022 Jul 23;10(8):413. doi: 10.3390/toxics10080413.
Bisphenol S (BPS), the most common substitute for bisphenol A in manufacturing, is associated with neurotoxicity, but its molecular mechanisms are unclear. Here, we studied the role of the BDNF-TrkB-CREB (brain-derived neurotrophic factor-tropomyosin-related kinase B-CAMP response element-binding protein) signalling pathway in bisphenol S-induced neurotoxicity via methylation regulation in male C57BL/6 mice. The mice were treated with sesame oil or 2, 20 and 200 mg/kg body weight BPS for 28 consecutive days, and the hippocampus was extracted. We recorded the body weight, organ index, and hippocampal pathology and ultrastructure of the mice. The BDNF, TrkB, CREB, phosphorylated (p)-CREB, DNMTs (DNA methyltransferases) levels were determined by qRT-PCR and/or Western blotting. BDNF promoter IV methylation level was detected by bisulfite sequencing PCR. BPS damaged the mouse hippocampus ultrastructure and reduced the number of synapses. Further, it increased the methylation rate of BDNF promoter IV; downregulated BDNF, CREB, p-CREB/CREB and DNMT1 expression; and upregulated DNMT3a and DNMT3b expression. Therefore, we speculate that the BDNF-TrkB-CREB pathway may be involved in BPS-induced neurotoxicity in male mice by regulating methylation.
双酚S（BPS）是制造业中双酚A最常见的替代品，与神经毒性有关，但其分子机制尚不清楚。在此，我们通过甲基化调控研究了BDNF-TrkB-CREB（脑源性神经营养因子-原肌球蛋白相关激酶B-环磷酸腺苷反应元件结合蛋白）信号通路在雄性C57BL/6小鼠双酚S诱导的神经毒性中的作用。将小鼠连续28天用芝麻油或2、20和200mg/kg体重的双酚S处理，然后提取海马体。我们记录了小鼠的体重、器官指数以及海马体病理和超微结构。通过qRT-PCR和/或蛋白质免疫印迹法测定BDNF、TrkB、CREB、磷酸化（p）-CREB、DNA甲基转移酶（DNMTs）水平。通过亚硫酸氢盐测序PCR检测BDNF启动子IV的甲基化水平。双酚S破坏了小鼠海马体的超微结构并减少了突触数量。此外，它增加了BDNF启动子IV的甲基化率；下调了BDNF、CREB、p-CREB/CREB和DNMT1的表达；并上调了DNMT3a和DNMT3b的表达。因此，我们推测BDNF-TrkB-CREB通路可能通过调节甲基化参与雄性小鼠双酚S诱导的神经毒性。
