Assessment of aquatic toxicity and endocrine disruption potential of metformin, an anti-diabetic drug

Abstract

Metformin, one of the most prescribed anti-diabetic pharmaceuticals, has been frequently detected in ambient water. However, knowledge of its effects on aquatic organisms is very limited. In this study, acute and chronic toxicity of metformin was evaluated using two freshwater organisms, a crustacean (Daphnia magna) and Japanese medaka fish (Oryzias latipes) following Organization for Economic Co-operation and Development (OECD) test guidelines. Endocrine disruption potential of metformin and its underlying mechanisms were also investigated using adult Japanese medaka. In 21 d chronic D. magna test, no observed effect concentration (NOEC) for survival was determined at 40 mg/L of metformin, but significant changes in reproduction were not observed at this concentration. In early life stage toxicity test with medaka, NOEC for survival was determined at 100 mg/L of metformin. Predicted no effect concentration (PNEC) value of metformin was determined at 4 mg/L, based on D. magna 21 d NOEC. Hazard quotient (HQ) was estimated less than 1 suggesting negligible risk. In adult male Japanese medaka, plasma 17β-estradiol (E2) level and E2 to testosterone (T) ratio were significantly increased following 21 d exposure to metformin. In addition, transcription of steroidogenic genes such as star, cyp11a, hsd3b, cyp19a, hsd11b2, and cyp11b was significantly up-regulated. In female Japanese medaka, 11-ketotestosterone (11-KT) level as well as cyp11b gene transcription level was increased following 21 d exposure to metformin. Our observation suggests that current level of metformin in ambient water is not likely to be of concern among freshwater organisms. However, its endocrine disruption potential through alteration of steroidogenic pathway warrants long-term exposure studies.