Insights into the sex-dependent reproductive toxicity of 2-ethylhexyl diphenyl phosphate on zebrafish (Danio rerio)
Insights into the sex-dependent reproductive toxicity of 2-ethylhexyl diphenyl phosphate on zebrafish (Danio rerio)
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深入了解磷酸 2-乙基己基二苯酯对斑马鱼（斑马鱼）的性别依赖性生殖毒性
DOI：
10.1016/j.envint.2021.106928
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发表时间：
2022
影响因子：
11.8
通讯作者：
Lingyan Zhu
中科院分区：
文献类型：
--
作者：
Rongyan Yang;Xiao Wang;Jingwen Wang;Pengyu Chen;Qing Liu;Wenjue Zhong;Lingyan Zhu
作为一种在各种环境介质中经常检测到的有机磷酸酯，2-乙基己基二苯磷酸（EHDPHP）对不同性别水生生物的毒性作用尚不清楚。本研究以成年斑马鱼为研究对象，分别于2.5、50、250µg/L的EHDPHP中暴露21天，研究其性别依赖性生殖毒性及其机制。暴露于EHDPHP显著抑制了斑马鱼的繁殖，雌性产卵减少，后代的生长发育受到抑制。EHDPHP对雄性小鼠性激素和卵黄蛋白原（VTG）的影响大于雌性小鼠。雌性小鼠脑内gnrhr2、gnrhr3、gnrhr4、gnrh3、gnrh2ander2β下调，睾酮(T)的合成受到抑制，而17β-雌二醇（E2）则因cyp19a上调而升高250µg/L。对于雄性，T的提升与性腺中offshr、3βhsd、star、cyp11和cyp17的上调直接相关，最终导致E2升高。两性血浆11-KT的降低主要与cyp11bandhsd11b的下调有关。血浆VTG在女性中呈下降趋势，而在男性中呈上升趋势，这与αander2β在女性和男性中分别呈下降和上升的规律一致。结果表明，EHDPHP对斑马鱼的生殖毒性呈性别依赖关系。分子对接分析表明，EHDPHP与雌激素受体（ER）和雄激素受体（AR）的拮抗作用以及CYP19A1的拮抗作用有较强的相互作用，进一步揭示了EHDPHP的性别依赖性生殖毒性机制。本研究强调了在内分泌干扰物毒性评价中区分雌雄的重要性。
As a frequently detected organophosphate ester in various environmental media, the toxic effects of 2-ethylhexyl diphenyl phosphate (EHDPHP) on aquatic organisms of different sexes remain unclear. In this study, adult zebrafish were exposed to 2.5, 50, 250 µg/L of EHDPHP for 21 days to investigate its sex-dependent reproductive toxicity and related mechanisms. EHDPHP exposure significantly inhibited the reproduction of zebrafish, evidenced by the reduced spawning of females, depressed growth and development of their offspring. EHDPHP induced greater impacts on the changes of sex hormones and vitellogenin (VTG) in the males than females. For females, the synthesis of testosterone (T) was inhibited because of the down-regulatedgnrhr2,gnrhr3,gnrhr4,gnrh3,gnrh2ander2βin the brain, while 17β-estradiol (E2) increased in 250 µg/L due to up-regulatedcyp19a. For males, the promotion of T was directly related to the up-regulation offshr,3βhsd,star, cyp11andcyp17in the gonad, and eventually led to the increase of E2. The decrease of plasma 11-KT in both sexes could be mainly attributed to the down-regulation ofcyp11bandhsd11b. The plasma VTG decreased in females but increased in males, which was in accordance with the down and up regulation oferαander2βin the females and males, respectively. All these indicated EHDPHP displayed reproductive toxicity on zebrafish in a sex dependent manner. Molecular docking analysis indicated stronger interaction of EHDPHP with the antagonisms of estrogen receptor (ER) and androgen receptor (AR), as well as the agonism of CYP19A1, which further revealed the sex-dependent reproductive toxicity mechanism of EHDPHP. This study highlights the importance of distinguishing males and females in toxicity evaluation of endocrine disruption chemicals.