Faculty of Science, University of Ontario Institute of Technology, 2000 Simcoe St.N., Oshawa, Ontario, L1H 7K4, Canada.
Advanced Environmental Research Institute & Department of Biological Sciences, University of North Texas, 1155 Union Circle, Denton, TX, 76203, USA.
Aquat Toxicol. 2018 Dec;205:58-65. doi: 10.1016/j.aquatox.2018.10.003. Epub 2018 Oct 9.
Metformin is one of the most prevalent pharmaceuticals in both surface and waste waters, yet little is known about the bioavailability and/or effects of developmental exposure on early life stage (ELS) fish. Here, we demonstrate that embryo-larval stages of medaka are capable of taking up metformin from the aquatic environment, provided exposure occurs prior to chorion hardening (∼6-hpf). Once transferred to clean water, ELS medaka are able to completely depurate metformin in <24-hours. Furthermore, ELS medaka exposed to a range of relevant concentrations of waterborne metformin (from 6 hpf through 28-days post hatch) had significantly reduced growth metrics, altered metabolomes, and changes in the expression of genes associated with cell growth. The range of concentrations investigated were 1.0, 3.2, 10, 32, and 100 μg·L. To examine effects of chronic, low level metformin exposure across the full medaka life-cycle, we exposed newly fertilized embryos to 3.2 μg L waterborne metformin for 165-days. The weight and length of adult fish were examined, as were effects on the production of some steroid hormones, specifically a significant increase (control females: 0.161 ± 0.023 pg/mg; metformin treated females: 3.42 ± 0.543) in the production of 11-ketotestosterone was observed in adult female medaka. Collectively, these results suggest that current environmental exposure scenarios may be sufficient to cause effects on developing fish.
二甲双胍是地表和废水中最常见的药物之一，但对于其在发育早期阶段（ELS）鱼类中的生物利用度和/或暴露效应知之甚少。在这里，我们证明了在卵壳变硬之前（约 6 小时pf），胚胎 - 幼虫阶段的斑马鱼能够从水生环境中摄取二甲双胍。一旦转移到清洁水中，ELS 斑马鱼能够在<24 小时内完全清除二甲双胍。此外，暴露于一系列相关浓度的水传播二甲双胍（从 6 小时pf 到孵化后 28 天）的 ELS 斑马鱼的生长指标显著降低，代谢组发生改变，与细胞生长相关的基因表达发生变化。研究的浓度范围为 1.0、3.2、10、32 和 100μg·L。为了研究慢性、低水平的二甲双胍暴露对整个斑马鱼生命周期的影响，我们将新受精的胚胎暴露于 3.2μg·L 水传播的二甲双胍中 165 天。检查了成年鱼的体重和长度，以及对某些类固醇激素产生的影响，特别是在成年雌性斑马鱼中观察到 11-酮睾酮的产生显著增加（对照组雌性：0.161±0.023pg/mg；二甲双胍处理组雌性：3.42±0.543）。总的来说，这些结果表明，当前的环境暴露情况可能足以对发育中的鱼类产生影响。
