Citation:

Blackwell, B., G. Ankley, A. Biales, J. Cavallin, A. Cole, T. Collette, D. Ekman, R. Hofer, W. Huang, K. Jensen, M. Kahl, A. Kittelson, S. Romano, M. See, Q. Teng, C. Tilton, AND D. Villeneuve. Effects of Metformin and its Metabolite Guanylurea on Fathead Minnow (Pimephales promelas) Reproduction (FY22 Manuscript). ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, 41(11):2708-2720, (2022). https://doi.org/10.1002/etc.5450

Impact/Purpose:

Metformin is a commonly used pharmaceutical that is now ubiquitous in surface waters. During wastewater treatment, metformin is also converted to a metabolite guanylurea. Prior studies on the effects of metformin identified fish reproduction and sexual development as potential ecological effect of concern. Here, we sought to test if metformin or guanylurea could directly impact fish steroidogenesis, impact fecundity, or interact with additional biological pathways as measured using ‘omics approaches. Exposures were performed at environmentally relevant concentrations. Neither metformin or guanylurea caused effects in steroidogenesis at concentrations up to 100 uM. No effects on reproduction were observed from either metformin or guanylurea at concentrations up to 41 ug metformin/L or 100 ug guanylurea/L. Metformin induced no effects in male fish as determined using metabolomics and transcriptomics, but guanylurea did have a modest impact on the liver transcriptome at 96 h and the liver metabolome at 23 d. Overall, these results suggest fish reproduction is not an ecological endpoint of concern for metformin or guanylurea.

Description:

Metformin, along with its biotransformation product guanylurea, is commonly observed in municipal wastewaters and subsequent surface waters. Previous studies in fish have identified metformin as a potential endocrine-active compound, but there are inconsistencies with regard to its effects. To further investigate the potential reproductive toxicity of metformin and guanylurea to fish, a series of experiments was performed with adult fathead minnows (Pimephales promelas). First, explants of fathead minnow ovary tissue were exposed to 0.001–100 µM metformin or guanylurea to investigate whether the compounds could directly perturb steroidogenesis. Second, spawning pairs of fathead minnows were exposed to metformin (0.41, 4.1, and 41 µg/L) or guanylurea (1.0, 10, and 100 µg/L) for 23 days to assess impacts on reproduction. Lastly, male fathead minnows were exposed to 41 µg/L metformin, 100 µg/L guanylurea, or a mixture of both compounds, with samples collected over a 96-h time course to investigate potential impacts to the hepatic transcriptome or metabolome. Neither metformin nor guanylurea affected steroid production by ovary tissue exposed ex vivo. In the 23 days of exposure, neither compound significantly impacted transcription of endocrine-related genes in male liver or gonad, circulating steroid concentrations in either sex, or fecundity of spawning pairs. In the 96-h time course, 100 µg guanylurea/L elicited more differentially expressed genes than 41 µg metformin/L and showed the greatest impacts at 96 h. Hepatic transcriptome and metabolome changes were chemical- and time-dependent, with the largest impact on the metabolome observed at 23 days of exposure to 100 µg guanylurea/L. Overall, metformin and guanylurea did not elicit effects consistent with reproductive toxicity in adult fathead minnows at environmentally relevant concentrations. Environ Toxicol Chem 2022;41:2708–2720. © 2022 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

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