Xu Shisan, Zhang Huan, Pao Ping-Chieh, Lee Audrey, Wang Jun, Suen Chan Yu, Manno Iii Francis A M, Wan Chan Shun, Han Cheng Shuk, Chen Xueping
Vitargent (International) Biotechnology Limited, Unit 516, 5/F. Biotech Centre 2, No. 11 Science Park West Avenue, Hong Kong Science Park, Shatin, Hong Kong SAR, People's Republic of China; Department of Biomedical Sciences, College of Veterinary Medicine and Life Science, City University of Hong Kong, Hong Kong SAR, People's Republic of China.
Vitargent (International) Biotechnology Limited, Unit 516, 5/F. Biotech Centre 2, No. 11 Science Park West Avenue, Hong Kong Science Park, Shatin, Hong Kong SAR, People's Republic of China; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, People's Republic of China.
Aquat Toxicol. 2020 May;222:105469. doi: 10.1016/j.aquatox.2020.105469. Epub 2020 Mar 10.
Phthalates are commonly used in plastic products in daily life. The endocrine-disrupting effects of phthalates have been widely reported. Accumulating evidence from human cohorts and lab animals indicate exposure to phthalates might impair neurodevelopment. However, the direct causal relationship and mechanism between phthalates with neurodevelopment and neurotoxicity have not been firmly established. We found that phthalates (i.e. DBP, DINP, BBP) disrupted the expression of estrogen receptors (esr1, esr2a, esr2b), and impaired neurogenesis in the brain of zebrafish during embryonic development. Moreover, the abnormal expression of estrogen receptors, especially esr2a, was partly rescued in zebrafish which exposed to phthalates, with the estrogen receptor antagonist tamoxifen. Hence, impaired neurogenesis of zebrafish exposed to phthalates was partly reversed by tamoxifen treatment. Moreover, our results show that induced pluripotent stem cells (iPSC)-derived human neurons exposed to phthalates triggered double-strand DNA breaks in vitro. Overall, this study demonstrates that exposure to phthalates affects neurodevelopment in zebrafish embryos and induces neurotoxicity in human neurons partly through disrupting the expression of estrogen receptors.
邻苯二甲酸盐常用于日常生活中的塑料制品。邻苯二甲酸盐的内分泌干扰作用已被广泛报道。来自人类队列和实验动物的越来越多的证据表明，接触邻苯二甲酸盐可能会损害神经发育。然而，邻苯二甲酸盐与神经发育和神经毒性之间的直接因果关系及机制尚未完全确立。我们发现，邻苯二甲酸盐（即邻苯二甲酸二丁酯、邻苯二甲酸二异壬酯、邻苯二甲酸丁苄酯）在斑马鱼胚胎发育过程中会破坏雌激素受体（esr1、esr2a、esr2b）的表达，并损害其大脑中的神经发生。此外，在暴露于邻苯二甲酸盐的斑马鱼中，使用雌激素受体拮抗剂他莫昔芬可部分挽救雌激素受体的异常表达。因此，他莫昔芬治疗可部分逆转暴露于邻苯二甲酸盐的斑马鱼受损的神经发生。此外，我们的结果表明，暴露于邻苯二甲酸盐的诱导多能干细胞（iPSC）衍生的人类神经元在体外引发双链DNA断裂。总体而言，本研究表明，接触邻苯二甲酸盐会影响斑马鱼胚胎的神经发育，并部分通过破坏雌激素受体的表达在人类神经元中诱导神经毒性。
