An ‘omics approach to investigate the growth effects of environmentally relevant concentrations of guanylurea exposure on Japanese medaka (Oryzias latipes)

Abstract

Metformin is a widely prescribed pharmaceutical used in the treatment of numerous human health disorders, including Type 2 Diabetes, and as a results of its widespread use, metformin is thought to be the most prevalent pharmaceutical in the aquatic environment by weight. The removal of metformin during the water treatment process is directly related to the formation of its primary degradation product, guanylurea, generally present at higher concentrations in surface waters relative to metformin. Growth effects observed in 28-day early life stage (ELS) Japanese medaka exposed to guanylurea were found to be similar to growth effects in 28-day ELS medaka exposed to metformin; however, effect concentrations were orders of magnitude below those of metformin. The present study uses a multi-omics approach to investigate potential mechanisms by which low-level, 1 ng · L−1 nominal, guanylurea exposure may lead to altered growth in 28-day post hatch medaka via shotgun metabolomics and proteomics and qPCR. Specifically, analyses show 6 altered metabolites, 66 altered proteins and 2 altered genes. Collectively, metabolomics, proteomics, and gene expression data (using qPCR) indicate that developmental exposure to guanylurea exposure alters a number of important pathways related to the overall health of ELS fish, including biomolecule metabolism, cellular energetics, nervous system function/development, cellular communication and structure, and detoxification of reactive oxygen species, among others. To our knowledge, this is the first study to both report the molecular level effects of guanylurea on non-target aquatic organisms, and to relate molecular-level changes to whole organism effects.