Key Laboratory of Pollution Processes and Environmental Criteria of Ministry of Education, Tianjin Key Laboratory of Environmental Remediation and Pollution Control, College of Environmental Science and Engineering of Nankai University, Tianjin 300350, China.
Key Laboratory of Pollution Processes and Environmental Criteria of Ministry of Education, Tianjin Key Laboratory of Environmental Remediation and Pollution Control, College of Environmental Science and Engineering of Nankai University, Tianjin 300350, China.
Environ Int. 2022 Jan;158:106928. doi: 10.1016/j.envint.2021.106928. Epub 2021 Oct 9.
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-regulated gnrhr2, gnrhr3, gnrhr4, gnrh3, gnrh2 and er2β in the brain, while 17β-estradiol (E2) increased in 250 µg/L due to up-regulated cyp19a. For males, the promotion of T was directly related to the up-regulation of fshr, 3βhsd, star, cyp11 and cyp17 in 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 of cyp11b and hsd11b. The plasma VTG decreased in females but increased in males, which was in accordance with the down and up regulation of erα and er2β in 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.
作为各种环境介质中经常检测到的有机磷酸酯，2-乙基己基二苯基磷酸酯（EHDPHP）对不同性别水生生物的毒性作用尚不清楚。在这项研究中，成年斑马鱼暴露于 2.5、50 和 250μg/L 的 EHDPHP 中 21 天，以研究其性别依赖性生殖毒性及其相关机制。EHDPHP 暴露显著抑制了斑马鱼的繁殖，表现为雌性产卵减少，其后代的生长和发育受到抑制。EHDPHP 对雄性激素和卵黄蛋白原（VTG）变化的影响大于雌性。对于雌性，由于脑中 gnrh2、gnrhr3、gnrhr4、gnrh3、gnrh2 和 er2β 的下调，抑制了睾酮（T）的合成，而 250μg/L 时由于 cyp19a 的上调，17β-雌二醇（E2）增加。对于雄性，T 的促进与性腺中 fshr、3βhsd、star、cyp11 和 cyp17 的上调直接相关，最终导致 E2 增加。两性血浆 11-KT 的减少主要归因于 cyp11b 和 hsd11b 的下调。雌性血浆 VTG 减少，而雄性增加，这与雌性和雄性中 erα 和 er2β 的下调和上调分别一致。所有这些表明 EHDPHP 以性别依赖的方式对斑马鱼表现出生殖毒性。分子对接分析表明，EHDPHP 与雌激素受体（ER）和雄激素受体（AR）的拮抗剂以及 CYP19A1 的激动剂相互作用更强，进一步揭示了 EHDPHP 性别依赖性生殖毒性的机制。本研究强调了在评估内分泌干扰化学物质的毒性时区分雄性和雌性的重要性。
