Antidiabetic drug metformin disrupts the embryogenesis in zebrafish through an oxidative stress mechanism

Elizalde-Velázquez, Gustavo Axel; Gómez-Oliván, Leobardo Manuel; García-Medina, Sandra; Islas-Flores, Hariz; Hernández-Navarro, María Dolores; Galár-Martínez, Marcela

doi:10.1016/j.chemosphere.2021.131213

Cited by 41 publications

(10 citation statements)

References 41 publications

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“…At 20 dpf, a significant decrease in survival was also observed for larvae exposed to 2 929 and 14 423 ng/L MET, when compared to the control (45.2 and 24.4% survival, respectively) (Table ). As expected, after 20 dpf, mortality was very low until adulthood, since even under normal raising conditions, zebrafish are more sensitive up to 20 dpf, considering that during this period they develop from one cell stage into a swimming larvae and change from vitellogenic reserves to external feeding. , Other recent studies with zebrafish are in agreement with the present findings, reporting that MET at concentrations from 1 to 10 μg/L significantly impacts zebrafish survival at the early phases of development. , However, these effects in mortality are not supported by other studies examining the effects of MET in other fish species, such as brown trout ( Salmo trutta ) and fathead minnows ( Pimephales promelas ), where MET exposure did not impact mortality at different development phases, including the larval stage. ,, Analyzing the few available studies, we hypothesize that zebrafish, at least in the early life stages of development, are potentially more sensitive than the other few fish species tested so far that present longer periods of embryonic development.…”

Section: Resultssupporting

confidence: 83%

“…We hypothesize that the stimulating effects on zebrafish growth parameters (length, weight, and K), observed at 60 dpf and 9 mpf, by environmentally relevant concentrations of MET, could be associated with a phenomenon called hormesis. Hormesis is an adaptive response well documented in aquatic organisms in response to long-term exposure to low concentrations of a variety of environmental stressors, , that results from an overcompensation of the homeostatic regulatory mechanisms, leading to stimulatory effects (e.g., improved growth and/or reproduction). ,, This hormesis phenomenon induced by MET was also suggested by Elizalde-Velazquez et al (2021) in early developmental phases of zebrafish. Despite the potential hormetic effect here observed in zebrafish growth and weight (F 0 60 dpf and 9 mpf males), other key ecological end points revealed severe signs of toxicity, such as increased mortality at early stages of development and disruption of reproductive processes (discussed in sections and ).…”

Section: Resultssupporting

confidence: 82%

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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: Resultssupporting

confidence: 83%

Section: Resultssupporting

confidence: 82%

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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“…Exposing fathead minnows ( Pimephales promelas ) to metformin with a concentration equivalent to that in wastewater led to the development of intersex gonads in males and reduced the size of male fish and the fertility of treated pairs [ 5 ]. Metformin induced several morphological alterations such as malformation of a tail, scoliosis, pericardial edema, and yolk deformation on zebrafish embryos [ 6 ]. Japanese medaka could significantly reduce growth metrics, alter metabolomes, and change the expression of genes associated with cell growth in the early life stage when exposed to a range of relevant concentrations of metformin [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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

Yin

Feng

et al. 2022

BioMed Research International

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Objective. To investigate the genotoxicity of metformin on planarian with different concentrations and exposure times. Methods. The planarians were treated, respectively, with 10 mmol/L and 50 mmol/L metformin for 1, 3, and 5 days, and then, the comet assay and random amplified polymorphic DNA (RAPD) analysis were performed. 13 random primers were used for PCR amplification with the genomic DNAs as templates. Planarians cultured in clear water were used as the control. Genomic template stability (GTS) was calculated by comparing and analyzing the RAPD patterns of the control group and the treatment groups. Results. In the comet assay, DNA damage of planarians treated with 10 mmol/L metformin for 1, 3, and 5 days was 10.2%, 25.4%, and 36.8%, respectively, and that of planarians treated with 50 mmol/L metformin was 40.6%, 62.8%, and 65.4%, respectively. GTS values of planarians exposed to 10 mmol/L metformin for 1, 3, and 5 days were 64.1%, 62.8%, and 52.6%, respectively, and those of planarians exposed to 50 mmol/L metformin for 1, 3, and 5 days were 52.6%, 51.3%, and 50%, respectively. DNA damage increased and GTS values decreased with the increasing metformin exposure concentration and exposure time. Conclusion. Metformin has certain genotoxicity on planarian in a dose- and time-related manner. The comet assay and RAPD analysis are highly sensitive methods for detecting genotoxicity with drugs.

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“…Antioxidant activity levels changed in a timedependent manner, as there was an increase in 15 days, followed by an activation peak in 30 days and gradual inhibition at 45 and 60 days. The induction of an antioxidant response has also been evaluated in Danio rerio embryos exposed to environmentally relevant concentrations of metformin with increased markers of oxidative damage (ELIZALDE-VELÁZQUEZ et al, 2021). The authors show that this response may have been caused by an inhibition of the mitochondrial complex I of the electron transport chain and a consequent increase in superoxide production and triggering of apoptosis mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Tissue damage, mutagenic effect and alteration in antioxidant defense in Danio rerio (Cypriniformes: Cyprinidae) after chronic exposure to Metformin hydrochloride.

Demarco

Zanardini

Zazula

et al. 2022

Preprint

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Metformin hydrochloride (MET) is an oral medication very prescribed for patients with diabetes, with a large part of its metabolites being eliminated in the urine. Basic sanitation systems are not fully effective in removing all the contaminants, promoting contamination to rivers and supply reservoirs. The objective of this study was to test the potential acute and chronic effects of MET on the antioxidant system, mutagenicity effects and tissue damages in the bioindicator D. rerio. The animals were acclimatized and separated into six groups and exposed to different concentrations of MET (0.00, 0.25, 0.50, 0.75, 1.25 g.L− 1) over a 96 hour period to determine the LC50. In another experiment, five groups of ten animals were separated as follows: four groups for evaluation of the chronic effect of 0.45 g.L− 1 of metformin hydrochloride (15, 30, 45 and 60 days) and, a negative control group (NC). The antioxidant system and the tissue damages of the muscle samples and, the mutagenicity in the blood samples were evaluated. The presence of oxidative stress and mutagenicity, together with the activation of the antioxidant system, can be visualized up to 30 days of treatment, with intense tissue damages in 60 days and the emergence of apoptotic cells, which is evidence of the toxic potential of this drug to non-target aquatic populations.

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Antidiabetic drug metformin disrupts the embryogenesis in zebrafish through an oxidative stress mechanism

Cited by 41 publications

References 41 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

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

Tissue damage, mutagenic effect and alteration in antioxidant defense in Danio rerio (Cypriniformes: Cyprinidae) after chronic exposure to Metformin hydrochloride.

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