School of Public Health, Seoul National University, Seoul 08826, Republic of Korea.
School of Public Health, Seoul National University, Seoul 08826, Republic of Korea; Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon 34114, Republic of Korea.
Ecotoxicol Environ Saf. 2019 May 30;173:174-181. doi: 10.1016/j.ecoenv.2019.02.015. Epub 2019 Feb 14.
Gemfibrozil, a lipid-regulating pharmaceutical, has been widely used for treating dyslipidemia in humans and detected frequently in freshwater environments. Since plasma cholesterol is a precursor of steroid hormones, the use of gemfibrozil may influence the sex hormone balances. However, its endocrine toxicity following long-term exposure is not well understood. The purpose of the present study is to investigate the effects of gemfibrozil on sex hormones and reproductive outcomes in a freshwater fish, following a long-term (155 d) exposure. For this purpose, Japanese medaka embryos (F0) were exposed to a series of gemfibrozil concentrations, i.e., 0, 0.04, 0.4, 3.7, and 40 mg/L for 155 d, and reproductive parameters, sex hormones, and associated gene expressions were assessed. For comparison, a short-term exposure (21 d) was performed separately with adult medaka and measured for sex hormones and related gene expressions. Following the 155 d long-term exposure, the fecundity showed a decreasing pattern. In addition, at 3.7 mg/L gemfibrozil, testosterone (T) level in the female fish was significantly decreased, and the hatchability of F1 fish was significantly decreased. The estrogen receptor (er) or vitellogenin (vtg) genes in gonads and liver were up-regulated. However, plasma cholesterol levels did not show significant changes in both sexes. The observations from the short-term (21 d) exposure were different from those of the long-term exposure. Following the short-term exposure, decreased 17β-estradiol (E2), and 11-ketotestosterone (11-KT) levels along with decrease plasma cholesterol were observed in the male fish. The hormone disruption following the short-term exposure appears to be associated with the hypocholesterolemic activity of gemfibrozil. Our results show that the mechanisms of gemfibrozil toxicity may depend on the exposure duration. Consequences of long-term exposure to other fibrates in the water environment warrant further investigations.
吉非贝齐是一种调节血脂的药物，广泛用于治疗人类的血脂异常，并经常在淡水环境中检测到。由于血浆胆固醇是甾体激素的前体，因此使用吉非贝齐可能会影响性激素平衡。然而，其长期暴露后的内分泌毒性尚不清楚。本研究的目的是在一种淡水鱼类中研究吉非贝齐在长期（155 天）暴露后对性激素和生殖结果的影响。为此，将日本青鳉胚胎（F0）暴露于一系列吉非贝齐浓度，即 0、0.04、0.4、3.7 和 40 mg/L 下 155 天，评估生殖参数、性激素和相关基因表达。为了进行比较，还分别对成年青鳉进行了短期（21 天）暴露，并测量了性激素和相关基因表达。在 155 天的长期暴露后，繁殖力呈下降趋势。此外，在 3.7 mg/L 吉非贝齐处理组，雌鱼的睾酮（T）水平显著降低，F1 鱼的孵化率显著降低。性腺和肝脏中的雌激素受体（er）或卵黄蛋白原（vtg）基因上调。然而，雌雄两性的血浆胆固醇水平均无显著变化。短期（21 天）暴露的观察结果与长期暴露的观察结果不同。在短期暴露后，雄鱼的 17β-雌二醇（E2）和 11-酮睾酮（11-KT）水平降低，同时血浆胆固醇降低。短期暴露后的激素紊乱似乎与吉非贝齐的降胆固醇活性有关。我们的研究结果表明，吉非贝齐毒性的机制可能取决于暴露时间。水环境中其他贝特类药物的长期暴露后果需要进一步研究。
