Emerging wastewater contaminant metformin causes intersex and reduced fecundity in fish

Abstract

The occurrence of intersex fish, where male reproductive tissues show evidence of feminization, have been found in freshwater systems around the world, indicating the potential for significant endocrine disruption across species in the ecosystem. Estrogens from birth control medications in wastewater treatment plant effluent have been cited as the likely cause, but research has shown that endocrine disruption is not solely predictable based on hormone receptor interactions. Many other non-hormone pharmaceuticals are found in effluent at concentrations orders of magnitude higher than estrogens, yet there is little data indicating the impacts of these other medications. The widely prescribed anti-diabetic metformin is among the most abundant of pharmaceuticals found in effluent and is structurally dissimilar from hormones. However, we show here that exposing fathead minnows (Pimephales promelas) to a concentration of metformin found in wastewater effluent causes the development of intersex gonads in males, reduced size of treated male fish, and reduction in fecundity for treated pairs. Our results demonstrate that metformin acts as an endocrine disruptor at environmentally relevant concentrations.

Determining potential adverse effects in marine fish exposed to pharmaceuticals and personal care products with the fish plasma model and whole-body tissue concentrations

“…Another study (Huerta et al 2016) found effects in fish exposed to oxazepam when plasma concentrations were about one third of the Cmax value. Other studies reported significant effects on growth, fertility, and behavioral effects in fish with observed or predicted plasma concentrations similar to the human Cmax value (Niemuth and Klaper 2015; Valenti et al 2012). …”

Contaminants of emerging concern in a large temperate estuary

“…The high metformin concentration observed in sculpin from the Nisqually estuary (27.8 ng/g) was surprising given the very low K ow for this compound. A recent study (Niemuth and Klaper 2015) demonstrated reduced growth in male fathead minnow ( Pimephales promelas ) and extensive disruption of reproductive parameters in both sexes of this species exposed to metformin at 40,000 ng/L. Another recent study demonstrated significant increases in mRNA transcripts for vitellogenin, estrogen receptor-alpha, gonadotropin releasing hormone 3, and cytochrome P450 3A4-like isoform in juvenile fathead minnow exposed to concentrations in water as low as 1 ng/mL (Crago et al, 2016).…”

The insulin sensitiser metformin regulates chicken Sertoli and germ cell populations

“…Thus, there is data indicating that metformin administration in adult obese rats fed high-fat diet restores reproductive parameters (testosterone, E 2 , semen quality and testis weight; Yan et al 2015). In addition, there is a recent report of an increase in the percentage of intersex fish after metformin exposure during developmental stages at environmental doses, without clear effects on testosterone levels and gonad appearance (Niemuth et al 2015). These data are complemented by those of Tartarin et al (2012a), who observed decreased testosterone production in vitro and decreases in testis size in mice exposed to metformin during foetal development of animals unaffected by type 2 diabetes.…”