Developmental phenotypic and transcriptomic effects of exposure to nanomolar levels of metformin in zebrafish

Comparative Effects of Embryonic Metformin Exposure on Wild and Laboratory-Spawned Fathead Minnow (Pimephales promelas) Populations

“…31−34 Exposure to nM concentrations of metformin also led to an increase in the occurrence of various morphological abnormalities in ELS zebrafish, along with behavioral alterations and changes in the proportion of unhatched eggs remaining at 5-DPF. 52 The deformities observed in that study mirrored those observed in the present study, including skeletal abnormalities, cardiac edema, and yolk sac edema, with cardiac edema as the most frequently observed adverse outcome. 52 In light of the aforementioned variability, the cohortdependent responses observed in the present study were not entirely surprising, with one notable exception.…”

“…Metformin is one of the most prevalent pharmaceuticals found in surface waters globally, and there is a growing body of evidence to suggest that current environmental exposure scenarios may adversely impact the reproduction and development of small-bodied fish. However, the nature and magnitude of effects appears to differ between species, timing of exposure, and study duration. ,,,,,− , For example, the growth of 28-DPF Japanese medaka (Oryzias latipes) was found to be significantly reduced by developmental exposure to environmentally relevant concentrations of metformin. , Similar effects were not observed in 21-DPF FHM exposed to comparable concentrations of metformin as embryos; however, other researchers have found that the growth and reproduction of FHM are affected by environmentally relevant concentrations of metformin at later life stages. − Exposure to nM concentrations of metformin also led to an increase in the occurrence of various morphological abnormalities in ELS zebrafish, along with behavioral alterations and changes in the proportion of unhatched eggs remaining at 5-DPF . The deformities observed in that study mirrored those observed in the present study, including skeletal abnormalities, cardiac edema, and yolk sac edema, with cardiac edema as the most frequently observed adverse outcome …”

“…Previous laboratory studies have found that growth effects in metformin and guanylurea exposed ELS medaka are accompanied by metabolome and proteome changes that are consistent with dysregulated biomolecule metabolism and energy homeostasis. ,, Moreover, transcriptomic responses observed in 5-DPF zebrafish exposed to nM concentrations of metformin indicated changes in the expression of genes associated with metabolic processes, in addition to disruption of pathways involved in cardiovascular, neurological, and immune system development . The findings of those studies support energetic dyshomeostasis as a plausible explanation for the adverse effects on yolk sac energy stores observed herein.…”

“…While metformin exposure did not appear to significantly affect the size at hatch of wild-spawned FHM, there was a significant positive effect on the fish length at hatch in the lab-spawned cohort. To the best of our knowledge, this has not been reported in metformin-exposed fish from other laboratory exposure studies, which typically report no effect or negative effects on the length. ,− ,, …”

Genotoxicity Evaluation of Metformin in Freshwater Planarian Dugesia japonica by the Comet Assay and RAPD Analysis

“…Low-dose metformin exposure for a long time could cause a significant upregulation of numerous endocrine-related genes in FHM [ 28 ]. Metformin affected the expression of genes related to neurological and cardiovascular development and the expression of CYP3A65, GSTM1, p53, and DNMT1 genes in the liver in zebrafish [ 29 , 30 ]. It was also found that metformin could induce oxidative stress and the two-generation endocrine disruption in Oryzias latipes [ 31 ].…”