Developmental Health Effects of Metformin and Guanylurea on Larval Zebrafish (Danio rerio)

Abstract

Metformin is the most common first-line oral therapeutic agent used in the treatment of type-2 diabetes. Because of its widespread use, metformin has been increasingly detected in wastewater effluent. It is partially bio-transformed into guanylurea is subsequently released into aquatic environments. Since the literature concerning the effect of metformin and guanyl urea on early life stage of fish is scant, the aim of this research was to understand the potential influence of metformin and guanylurea on developmental, cardiometabolic and behavioral responses in zebrafish embryos, from the 4 cell stage (3 hours post fertilization, hpf) to first feed (120 hpf). To this end, embryos were exposed to environmentally relevant (0.4, 4, 40 μg·L−1) and supra-environmental (400 and 4000 μg·L−1) concentrations of the two chemicals. Metformin caused an increased mortality and spinal abnormalities in all concentrations compared to controls. and increased pericardial and yolk sac edema at the highest tested concentration. Metformin did not cause alterations in hatch or heart rate over the examined developmental stages. In addition, metformin did not cause alterations in general swimming, light-dark movement, startle response or thigmotaxis, irrespective of exposure concentration. Exposure to guanylurea over the same developmental stages caused a significant difference in mortality at 40 μg·L−1 only. Guanylurea did not cause alterations to any of the other tested endpoints. Our data suggests that metformin and guanylurea caused modest impacts to embryonic development of zebrafish at these concentrations.