Comparative Effects of Embryonic Metformin Exposure on Wild and Laboratory-Spawned Fathead Minnow (Pimephales promelas) Populations

Abstract

Metformin is routinely detected in aquatic ecosystems because of its widespread use as a treatment for Type 2 diabetes. Laboratory studies have shown that exposure to environmentally relevant concentrations of metformin can alter metabolic pathways and impact the growth of early life stage (ELS) fish; however, it is unknown whether these effects occur in wild populations. Herein, we evaluate whether findings from laboratory studies are representative and describe the relative sensitivities of both populations. Duplicate exposures (0, 5, or 50 μg/L metformin) were conducted using wild- and lab-spawned fathead minnow (Pimephales promelas) embryos. Apart from the water source, exposure conditions remained constant. Wild embryos were exposed to previously dosed lake water to account for changes in bioavailability, while reconstituted freshwater was used for the laboratory study. Developmental metformin exposure differentially impacted the growth and morphology of both cohorts, with energy dyshomeostasis and visual effects indicated. The fitness of wild-spawned larvae was impacted to a greater extent relative to lab-spawned fish. Moreover, baseline data reveal important morphological differences between wild- and lab-spawned ELS fatheads that may diminish representativeness of lab studies. Findings also confirm the bioavailability of metformin in naturally occurring systems and suggest current exposure scenarios may be sufficient to negatively impact developing fish.

Are Fish Populations at Risk? Metformin Disrupts Zebrafish Development and Reproductive Processes at Chronic Environmentally Relevant Concentrations

“…For example, 28-day and 57-day MET exposures at concentrations of 1–100 μg/L and 1 μg/L have been shown to induce decreased weight and length in the early life stages of the Japanese medaka ( Oryzias latipes ) and S. trutta , respectively. Yet, an increase in length or no effects on growth parameters were observed when embryos/larvae of fathead minnow ( P. promelas) were exposed to similar MET concentrations for 5 or 21 days, respectively. A similar increase in length was reported for P. promelas larvae exposed to 31 μg/L MET at day 30 and an increase in the condition factor after MET exposure of 322 μg/L at day 64 …”

“…Apart from the present work, there is a paucity of data assessing long-term effects of environmentally relevant concentrations of MET in different time-points during the fish life cycle. Most of the studies available tested MET concentrations above those reported in surface waters, and/or fish were exposed for short time periods, covering only one stage of the life cycle. ,,, …”

Is the Environmental Risk of Metformin Underestimated?

“…However, several works performed by distinct institutions using different fish species point mostly to negative effects at ranges from nanograms per liter to low micrograms per liter. Thus, even if some contrasting findings were reported by different teams for fathead minnows ( Pimephales promelas ), − with the latest study by Nielsen et al showing the impact on embryonic development at 5 μg/L, particularly in wild-spawned fathead minnows, most studies support effects in the range of environmental concentrations. The reported effects include the disruption of embryonic development in zebrafish and fathead minnows at concentrations as low as 0.39–5 μg/L; − vitellogenin (VTG) induction and disruption of reproduction-associated signaling pathways in fathead minnows, zebrafish, and Japanese rice fish ( Oryzias latipes ) − at concentrations ranging from 0.39 to 40 μg/L; and changes in the metabolism of lifelong-exposed zebrafish and in processes related to the cell cycle, DNA repair, and steroid hormone biosynthesis, concomitantly to alterations in apical end points such as growth, hepatosomatic index, and fertilization rate , at concentrations ranging from 0.39 to 14.4 μg/L.…”

Water Analysis: Emerging Contaminants and Current Issues

“…In another interesting study on metformin, Nielsen et al found that exposure to metformin during development has a more harmful effect on wild fish larvae compared to those raised under laboratory conditions, suggesting reduced representativeness of lab studies. 161 Physiologically based kinetic (PBK) models, which offer a mechanistic understanding of how chemicals affect organisms, are crucial risk assessment tools but are limited to a few fish species and rarely account for the ionization of many pharmaceuticals. A study by Wang et al introduced a generalized PBK model for fish, estimating parameters based on fish and chemical properties, and enhancing its applicability across various species.…”