Metformin disrupts Danio rerio metabolism at environmentally relevant concentrations: A full life-cycle study

Barros, Susana; Ribeiro, Marta; Coimbra, Ana M.; Pinheiro, M.F.; Morais, Hugo; Alves, Nélson; Montes, Rosa; Rodil, Rosario; Quintana, José Benito; Santos, Miguel M.; Neuparth, Teresa

doi:10.1016/j.scitotenv.2022.157361

Cited by 16 publications

(17 citation statements)

References 56 publications

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“…Taken together the findings of the present study with those of our parallel study, MET appears to deregulate critical biochemical and molecular processes in male zebrafish metabolism, which in turn could affect the steroid hormone biosynthesis and the expression of vtg1 and vtg2 . We hypothesize that this disruption can be linked with the significant decrease in the fertilization rate and the nonactivated eggs reported in the pairwise cross-breeding study.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, a comprehensive transcriptome analysis with biological replication was produced for liver samples of males and females from the control group and from the 14 423 ng/L MET treatment (Supporting Information − Tables S3 and S4) to strengthen the data of our previous exploratory RNA-seq analysis. 3 Importantly, the hierarchical clustering heatmap (Supporting Information − Figure S3) reported that exposed males presented a pattern of gene expression closer to the females (MET exposed and the control) than to the control males. Furthermore, the RNA-seq findings showed multiple metabolic processes significantly disrupted in males.…”

Section: A)mentioning

confidence: 99%

“…This RNA-seq approach, commercially obtained at Novogene (United Kingdom), was used to perform a mechanistic analysis on the genes and pathways involved in steroid biosynthesis and reproductive processes and to validate the genes/pathways related to energy/lipid metabolisms found to be altered in the exploratory RNA-seq analysis of our parallel study. 3 Samples were subjected to sequencing (Illumina Novaseq 6000 paired-end (2 × 150)) and subsequent bioinformatics analysis with parameters set to a false discovery rate (FDR) pvalue (padj) < 0.05 and a Log 2 (FoldChange) > 0. Raw data was submitted to the NCBI SRA database under the BioProject PRJNA906165.…”

Section: Experimental Designmentioning

confidence: 99%

“…1,2 In T2DM patients, MET acts by inhibiting the mitochondrial complex I of the electron transport chain, interfering with several metabolic pathways, such as cholesterol and steroid hormone biosynthesis. 3 Due to the increasing incidence of T2DM, MET is currently one of the most prescribed human pharmaceuticals worldwide. 4−7 As a result, high amounts of this drug are continuously discharged into aquatic environments.…”

Section: Introductionmentioning

confidence: 99%

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Are Fish Populations at Risk? Metformin Disrupts Zebrafish Development and Reproductive Processes at Chronic Environmentally Relevant Concentrations

Barros

Alves

Pinheiro

et al. 2022

Environ. Sci. Technol.

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The antidiabetic drug Metformin (MET), one of the most prevalent pharmaceuticals in the environment, is currently detected in surface waters in the range of ng/L to low μg/L. As current knowledge regarding the long-term effects of environmentally relevant concentrations of MET in nontarget organisms is limited, the present study aimed at investigating the generational effects of MET, in concentrations ranging from 390 to 14 423 ng/L in the model organism Danio rerio (up to 9 mpf), including the effects on its nonexposed offspring (until 60 dpf). We integrate several apical end points, i.e., embryonic development, survival, growth, and reproduction, with qRT-PCR and RNA-seq analyses to provide additional insights into the mode of action of MET. Reproductive-related parameters in the first generation were particularly sensitive to MET. MET parental exposure impacted critical molecular processes involved in the metabolism of zebrafish males, which in turn affected steroid hormone biosynthesis and upregulated male vtg1 expression by 99.78-to 155.47-fold at 390 and 14 432 MET treatment, respectively, pointing to an estrogenic effect. These findings can potentially explain the significant decrease in the fertilization rate and the increase of unactivated eggs. Nonexposed offspring was also affected by parental MET exposure, impacting its survival and growth. Altogether, these results suggest that MET, at environmentally relevant concentrations, severely affects several biological processes in zebrafish, supporting the urgent need to revise the proposed Predicted No-Effect Concentration (PNEC) and the Environmental Quality Standard (EQS) for MET.

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Section: Resultsmentioning

confidence: 99%

Section: A)mentioning

confidence: 99%

Section: Experimental Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Are Fish Populations at Risk? Metformin Disrupts Zebrafish Development and Reproductive Processes at Chronic Environmentally Relevant Concentrations

Barros

Alves

Pinheiro

et al. 2022

Environ. Sci. Technol.

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“…Since it is not naturally degraded, MET is easily reintroduced to humans as they move up the food chain (Meffe et al, 2021). Barros et al (2022) showed that MET behaves as an endocrine disruptor at environmentally relevant quantities. MET is a mobile compound with a low affinity to soils (Mrozik & Stefanska, 2014).…”

Section: Introductionmentioning

confidence: 99%

Determination of metformin and triclosan in sewage sludge using Liquid chromatography-mass spectrometry (LC-MS)

Maheswari²,

Suganya³

et al. 2022

JANS

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Pharmaceuticals and personal care products (PPCPs) are generally neither totally removed by sewage treatment nor completely destroyed in the environment. Metformin (MET) and triclosan (TRI) are two compounds in PPCPs that have the potential to be environmental pollutants. This research aimed to determine MET and TRI in sewage sludge using a liquid chromatograph-mass spectrometer (LCMS-8040) and a sewage sludge extraction method. The Milli-Q water and sewage sludge were also tested at three different MET and TRI concentrations (0.01, 0.02, and 0.03 mg L-1). As a result, the corresponding recoveries of MET and TRI in both matrixes ranged from 85.93 to 116.10 per cent and 90.50 to 116.30 per cent (n = 7, RSD < 10%). Then, the limit of detection (LOD) and the limit of quantification (LOQ) for MET and TRI were found to be 0.005 and 0.01 mg L-1. The amounts of MET and TRI in the sewage sludge samples from the Ukkadam sewage treatment plant (USTP), Coimbatore, ranged from BDL to 0.0587 mg L-1 and 0.0719 to 0.1851 mg L-1, respectively. Consequently, the amounts of MET and TRI in the sewage sludge samples from the Tamil Nadu Agricultural University sewage treatment plant (TSTP), Coimbatore, ranged from BDL to 0.0227 mg L-1 and 0.0393 to 0.1296 mg L-1, respectively. This exclusive use of the highly sensitive LCMS-8040 consumes less time than other analytical methods for measuring the amount of MET and TRI in sewage sludge by overcoming the risk of chemical degradation.

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Exposure to low levels of antidiabetic glibenclamide had no evident adverse effects on intestinal microbial composition and metabolic profiles in amphibian larvae

Liu,

Meng,

Chen

et al. 2023

Environ Sci Pollut Res

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Unmetabolized human pharmaceuticals may enter aquatic environments, and potentially exert adverse effects on the survival of non-target organisms. Here, Pelophylax nigromaculatus tadpoles were exposed to different concentrations of antidiabetic glibenclamide (GLB) for 30 days to evaluate its potential ecotoxicological effects in amphibians. The mortality rate of GLB-exposed groups appeared to be lower than that of the control group. Despite not being statistically signi cant, there was a tendency for a decrease in intestinal microbial diversity after exposure. The abundance of Firmicutes was shown to decrease, but those of other phyla did not in GLB-exposed tadpoles. Some potentially pathogenic bacteria (e.g., Clostridium, Bilophila, Hafnia) decrease unexpectedly, while some bene cial bacteria (e.g., Akkermansia, Faecalibacterium) increased in GLB-exposed tadpoles. Accordingly, GLB-induced changes in intestinal microbial compositions did not seem harmful to animal health. Moreover, minor changes in a few intestinal metabolites were observed after GLB exposure. Overall, our results suggested that exposure to low levels of GLB did not necessarily exert an adverse impact on aquatic organisms.

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Metformin disrupts Danio rerio metabolism at environmentally relevant concentrations: A full life-cycle study

Cited by 16 publications

References 56 publications

Are Fish Populations at Risk? Metformin Disrupts Zebrafish Development and Reproductive Processes at Chronic Environmentally Relevant Concentrations

Are Fish Populations at Risk? Metformin Disrupts Zebrafish Development and Reproductive Processes at Chronic Environmentally Relevant Concentrations

Determination of metformin and triclosan in sewage sludge using Liquid chromatography-mass spectrometry (LC-MS)

Exposure to low levels of antidiabetic glibenclamide had no evident adverse effects on intestinal microbial composition and metabolic profiles in amphibian larvae

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