System Toxicology Research Center, Korea Institute of Toxicology, Daejeon, South Korea.
University of Science & Technology, Daejeon, South Korea.
Environ Monit Assess. 2018 Oct 27;190(11):677. doi: 10.1007/s10661-018-7002-y.
Although medicines are less toxic than other toxicants, increased production and usage of pharmaceuticals have led to many concerns regarding their toxic effects on human and non-target organisms. Additionally, reproductive toxicity after long-term exposure is difficult to anticipate. Tamoxifen (TAM), a selective estrogen receptor modulator, has been widely used as an anticancer drug for mammalian breast and endometrial cancers. With increased TAM usage, it has frequently been reported that TAM is a potential endocrine disruptor capable of interfering with reproduction in non-target organisms. However, the mode of action of TAM in the endocrine system is unknown. In this study, we performed a 21-day chronic toxicity test using the crustacean Daphnia magna and investigated the transcriptional modulation of major genes related to the endocrine system, molting, development, and reproduction (i.e., Dm-vtg2, vmo1, cyp314, usp, and ecrb) after TAM exposure for 3, 6, 12, and 24 h. Our results showed a concentration-dependent decrease in the total number of offspring per individual, except for the concentration 25 μg/L; additionally, the expression of oogenesis-related genes was induced early but was later inhibited by TAM exposure. Additionally, molting-related genes were also downregulated in a time-dependent manner. Our findings suggested that TAM regulates reproduction by interfering with the molecular mechanisms involved in oogenesis and molting. This study supports the hypothesis that D. magna are a useful model to rapidly evaluate the reproductive effects of pharmaceuticals.
尽管药物的毒性比其他毒物低，但随着医药产品生产和使用的增加，人们对其对人类和非靶标生物的毒性作用产生了诸多担忧。此外，长期暴露后的生殖毒性也难以预测。他莫昔芬（TAM）是一种选择性雌激素受体调节剂，已被广泛用于治疗哺乳动物的乳腺癌和子宫内膜癌。随着 TAM 使用量的增加，经常有报道称 TAM 是一种潜在的内分泌干扰物，能够干扰非靶标生物的生殖功能。然而，TAM 在内分泌系统中的作用机制尚不清楚。在这项研究中，我们使用甲壳纲动物大型溞进行了为期 21 天的慢性毒性试验，并研究了 TAM 暴露 3、6、12 和 24 小时后与内分泌系统、蜕皮、发育和生殖相关的主要基因（即 Dm-vtg2、vmo1、cyp314、usp 和 ecrb）的转录调控。我们的结果表明，除了 25μg/L 浓度外，TAM 暴露导致每个个体的总后代数量呈浓度依赖性下降；此外，TAM 暴露早期诱导了与卵子发生相关的基因表达，但随后受到抑制。此外，蜕皮相关基因也呈时间依赖性下调。我们的研究结果表明，TAM 通过干扰卵子发生和蜕皮过程中的分子机制来调节生殖功能。这项研究支持了这样一种假设，即大型溞是一种快速评估药物生殖毒性的有用模型。
