Developmental and Full‐Life Cycle Exposures to Guanylurea and Guanylurea–Metformin Mixtures Results in Adverse Effects on Japanese Medaka (Oryzias latipes)

Abstract

Metformin is currently thought to be the highest drug by weight released into the aquatic environment, as a direct result of its widespread use in the treatment of a number of human health disorders. The removal of metformin from wastewaters is directly related to the formation of guanylurea (metformin's only known persistent degradation product), which is generally present at higher concentrations in surface waters than the parent compound. With metformin use rising steadily, it is important to characterize the effects of guanylurea on nontarget aquatic organisms. We recently demonstrated the effects of developmental exposure to environmentally relevant concentrations of metformin on the growth of early life stage (ELS) medaka as well as effects on the body weight of adult male fish following full‐life cycle exposures. In the present study, we describe similar effects of guanylurea exposure on these endpoints and life stages. Guanylurea led to effects on growth in a 28‐d ELS assessment that were similar to those of metformin; however, these effects occurred at concentrations in the ng/L range compared with the μg/L range for metformin. A possible sex‐dependent association with body weight changes was also observed in adults following a 165‐d full‐life cycle exposure to guanylurea alone or in a mixture with metformin. To our knowledge, the present is the first study to report the toxicity of guanylurea to nontarget aquatic organisms. Environ Toxicol Chem 2019;00:1–6. © 2019 SETAC

Does the antidiabetic drug metformin affect embryo development and the health of brown trout (Salmo trutta f. fario)?

“…In this report, no effects of metformin on hatching rate, time to hatch and mortality in an early-life stage test with zebrafish could be displayed leading to a no observed effect concentration (NOEC) of ≥ 10 mg/L for metformin. Ussery [73] showed that metformin did not influence mortality, hatch success or time to hatch of Japanese medaka exposed to 1–100 µg/L metformin for 28 days. Likewise, an effect of the drug on the body length could not be observed in our experiment whereas the weight of brown trout larvae was found to be reduced when exposed to 10 and 100 µg/L metformin at 7 °C and 1 µg/L at 11 °C.…”

“…Niemuth and Klaper [50] showed that fathead-minnows weighed less when exposed to 40 µg/L metformin. Ussery [73] demonstrated that metformin decreased the weight and length of 28 days old Japanese medaka at concentrations of 1–100 µg/L. In contrast, in the assessment report mentioned above [19] the growth of zebrafish was not influenced by metformin.…”

“…In a further study, Niemuth et al [49] demonstrated that a concentration of 40 µg/L metformin increased the vitellogenin mRNA in adult fathead minnow exposed for 28 days. Ussery [73] showed that metformin reduced the growth of Japanese medaka ( Oryzias latipes ) exposed to 1–100 µg/L metformin for 28 days. In contrast, in a report [19] cited by Moermond and Smit [45], a NOEC ≥ 10 mg/L metformin was derived for hatching rate, time to hatch, survival, length and weight in an early-life stage toxicity test with zebrafish ( Danio rerio ).…”

Peer Review #2 of "Effects of guanylurea, the transformation product of the antidiabetic drug metformin, on the health of brown trout (Salmo trutta f. fario) (v0.1)"

“…Mortality, time to hatch, and hatching success were not influenced by the chemical. In the same study of Ussery et al (2019), growth was not significantly reduced in adult medaka exposed to 1 ng/L and 7.5 µg/L guanylurea in a full life cycle test. In addition, the authors reported that the hormonal system seemed to be influenced by guanylurea, since enhanced estradiol production was measured in the liver of male adult medaka exposed to 7.5 µg/L guanylurea.…”

Multi-region assessment of pharmaceutical exposures and predicted effects in USA wadeable urban-gradient streams

“…Metformin is excreted essentially unchanged in human urine [160], poorly removed by wastewater treatment technologies [161], considered environmentally recalcitrant [161,162], and increasingly reported in environmental samples [7,9,163]. Environmentally-relevant [161,164,165] metformin exposures in the μg/L range have recently been shown to induce biological responses in fish [166][167][168][169], including up-regulation of vitellogenin mRNA [170,171] and other gene targets [169,171,172], male intersex in fathead minnow (Pimephales) [170], and behavioral modifications in Siamese fighting fish (Betta splendens) [167]. Guanylurea, metformin's only currently recognized persistent environmental degradate, is often observed in surface waters at higher concentrations than metformin [155,[163][164][165] and, importantly, has been recently reported to cause growth effects in Japanese medaka (Oryzias latipes) similar to metformin but at low (<10) ng/L concentrations [166].…”