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Metformin induces chromosome reorganization and changes in gene expression in normal human fibroblasts

ABSTRACT: We report the effects of metformin treatment on the transcriptome of normal human dermal fibroblasts isolated from foreskin (designated 2DD). We sequenced mRNA from 2 replicates of proliferative (PRO) and 2DD cells treated with two concentrations of metformin (0.5mM and 1.0 mM;5 days exposure). Comparative analyses with PRO transcripts a baseline indicate that fibroblsts exposed to different concentration of metformin result in differnetial transcript profiles.

ORGANISM(S): Homo sapiens

PROVIDER: GSE104458 | GEO | 2018/09/01

REPOSITORIES: GEO

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Project description:Metformin, along with its biotransformation product guanylurea, are commonly observed in municipal wastewaters and subsequent surface waters. Previous studies in fish have identified metformin as a potential endocrine active compound but there are inconsistencies in the literature with regard to effects. To further investigate the potential reproductive toxicity of metformin and guanylurea to fish, a series of experiments were performed with reproductively mature fathead minnows (Pimephales promelas). First, explants of mature fathead minnow ovary tissue were exposed to 0.001-100 µM metformin or guanylurea to investigate whether they can directly perturb steroidogenesis. Second, spawning pairs of fathead minnows were exposed to metformin (0.41, 4.1, 41 µg/L) or guanylurea (1.0, 10, 100 µg/L) for 23 d to assess impacts on reproduction. Lastly, male fathead minnows were exposed to 41 µg/L metformin, 100 µg/L guanylurea, or a mixture of both compounds, with samples collected over a 96 h time course to investigate potential impacts to the hepatic transcriptome or metabolome. Neither metformin or guanylurea effected estradiol or testosterone by ovary tissue exposed in vitro. In the 23 d exposure, neither compound significantly impacted transcription of endocrine-related genes in male liver or gonad, circulating steroid concentrations in male or female fish, or fecundity of spawning pairs. In the 96 h time course, 100 µg guanylurea/L elicited more differential gene expression than 41 µg metformin/L , and showed the greatest impacts after 96 h. A number of DEGs up-regulated after 24 h were subsequently down-regulated after 96 h, demonstrating time-dependent impacts of guanylurea on the liver. Overall, metformin and guanylurea did not elicit effects consistent with reproductive toxicity in adult fathead minnows at environmentally relevant concentrations. Where effects were identified using ‘omics approaches, guanylurea induced greater impacts than metformin.

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Metformin induces chromosome reorganization and changes in gene expression in normal human fibroblasts

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