Chronic exposure to environmentally relevant levels of simvastatin disrupts zebrafish brain gene signaling involved in energy metabolism

Barros, Susana; Coimbra, Ana M.; Alves, Nélson; Pinheiro, M.F.; Quintana, José Benito; Santos, Miguel M.; Neuparth, Teresa

doi:10.1080/15287394.2020.1733722

Cited by 20 publications

(10 citation statements)

References 86 publications

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“…Pharmaceuticals pose serious health risks to aquatic organisms and public health since they are produced to maximise biological activities at low concentrations [12,13]. Some of these risks include DNA damage, immunomodulation, disruption of energy metabolism, endocrine disruptions and formation of antibiotic resistant microbial strains [14][15][16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Occurrence and risk assessment of selected pharmaceuticals in water and sediments of Usuma Dam, Abuja, Nigeria

Ilechukwu

Okonkwo

Olusina

et al. 2021

International Journal of Environmental Analytical Chemistry

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The occurrence and ecological risk associated with nine pharmaceuticals; Ciprofloxacin, Metronidazole, Amoxycillin, Trimethoprim, Tetracycline, Sulfamethoxazole, Ibuprofen, Diclofenac and Paracetamol were investigated in water and sediments of Usuma Dam, Abuja, Nigeria. The samples were extracted with solid phase extraction and analysed with high performance liquid chromatography coupled with UV/VIS detector (HPLC-UV/VIS). Metronidazole with a concentration range of 191.11-572.73 ng/L and Trimethoprim with a concentration range of 0.27-0.42 µg/g d.w. were the predominant antibiotics in the water and sediments respectively. Ibuprofen was the only analgesics detected in the samples. The ecological risk assessed with the worst observed data for each pharmaceutical in the samples showed that Amoxycillin and Ibuprofen pose a high toxic risk to aquatic life in the dam while Trimethoprim and Ciprofloxacin could result in medium ecological risk. The results of this study draw attention to the occurrence and ecological risks of pharmaceuticals to aquatic life.

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Section: Introductionmentioning

confidence: 99%

Occurrence and risk assessment of selected pharmaceuticals in water and sediments of Usuma Dam, Abuja, Nigeria

Ilechukwu

Okonkwo

Olusina

et al. 2021

International Journal of Environmental Analytical Chemistry

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“…The reduction of ATP levels led to the selection of two genes involved in the cellular respiration. idh3a , a gene encoding isocitrate dehydrogenase (IDH) which is a rate-limiting enzyme in the tricarboxylic acid cycle, and cox5aa (cytochrome c oxidase subunit 5Aa), which is part of the complex IV of the electron transport chain and plays a key role in the aerobic mitochondrial energy metabolism (Arnold, 2012; Barros et al, 2020; Kadenbach et al, 2000). Once AMPK is activated, catabolic processes are stimulated (e.g.…”

Section: Methodsmentioning

confidence: 99%

“…lipogenesis, gluconeogenesis and fatty acid synthesis). The fatty acids ß-oxidation can be carried out by the medium-chain acyl-CoA dehydrogenase ( acadm ) (Barros et al, 2020). The gene encoding acetyl-CoA carboxylase alpha ( acaca ) was selected, since the cytosolic enzyme ACC catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, an essential substrate in the regulation of fatty acids synthesis (Alves-Bezerra & Cohen, 2017; Harwood, 2005).…”

Section: Methodsmentioning

confidence: 99%

“…lipogenesis, gluconeogenesis and fatty acid synthesis). The fatty acids ß-oxidation can be carried out by the medium-chain acyl-CoA dehydrogenase (acadm) (Barros et al, 2020). The gene encoding acetyl-CoA carboxylase alpha (acaca) was selected, since the cytosolic enzyme ACC catalyzes the The qRT-PCR zebrafish primers for the genes acaca, acadm, cox5aa, idh3a and hmgcra were obtained in other published studies (Table 1).…”

Section: Qrt-pcr: Gene Selection and Primer Designmentioning

confidence: 99%

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Metformin disrupts Danio rerio metabolism at environmentally relevant concentrations: A generational study

Barros

Ribeiro

Coimbra

et al. 2022

Preprint

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Metformin (MET) is an anti-diabetic pharmaceutical with a large-scale consumption, which is increasingly detected in surface waters. However, current knowledge on the generational effects of MET exposure in the metabolism of non-target organisms is limited. The present study aimed at investigating the effects of MET in the model freshwater teleost Danio rerio, following a generational exposure (from egg up to 9 months exposure) to environmentally relevant concentrations ranging from 361 ng/L to 13 000 ng/L. Biochemical markers were used to determine cholesterol and triglycerides levels, as well as mitochondrial complex I activity in males and females zebrafish liver. mRNA transcript changes were also assessed in the liver of both sexes by means of an exploratory RNA-seq analysis and expression levels of key genes involved in the energy metabolism and lipid homeostasis, i.e. acaca, acadm, cox5aa, idh3a, hmgcra, prkaa1, were determined using qRT-PCR analysis. The findings here reported revealed that MET was able to significantly disrupt critical biochemical and molecular processes involved in zebrafish metabolism, such as cholesterol and fatty acid biosynthesis, the mitochondrial electron transport chain and the tricarboxylic acid cycle, concomitantly to changes on the hepatosomatic index. Non-monotonic dose response curves were frequently detected in the gene expression profile, with higher effects observed for 361 ng/L and 2 166 ng/L concentrations. Collectively, the obtained results suggest that environmentally relevant concentrations of MET are able to severely disrupt D. rerio metabolism, with potential impacts at the ecological level, supporting the need to update the environmental quality standard (EQS) and predicted no-effect concentration (PNEC) for MET.

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“…All samples were assessed in duplicate. PCR reactions efficiency was determined by standard curves performed with six serial dilutions of the cDNA pool of all samples (from 0.0064 to 20 ng of cDNA) [41,108] was normalized to gapdh and clathrin and calculated using the Livak method [109]. Expression levels were normalized to solvent control mean and data were expressed as fold changes relative to this group.…”

Section: Real Time Quantitative-polymerase Chain Reaction (Qrt-pcr)mentioning

confidence: 99%

The anti-lipidemic drug simvastatin modulates Epigenetic Biomarkers in the AmphipodGammarus locusta

Alves¹,

Neuparth²,

Barros³

et al. 2020

Preprint

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The adverse effects of certain environmental chemicals have been recently associated with epigenome´s modulation. Although the changes in the epigenetic signature are still not integrated into hazard and risk assessment, they are interesting candidates for linking environmental exposures to altered phenotypes given that these changes may be passed across multiple non-exposed generations. Here, we addressed the effects of simvastatin (SIM), one of the most prescribed human pharmaceuticals, in epigenetic regulators of the amphipod Gammarus locusta, as a proxy to support its integration in hazard and environmental risk assessment. SIM is a known modulator of epigenome in mammalian cell lines, and has been reported to impact G. locusta ecological endpoints at environmentally relevant levels. G. locusta juveniles were exposed to three SIM concentrations (0.32, 1.6 and 8 µg.L -1 ), for 15 days. The basal expression of selected epigenetic regulators was determined, along with the quantification of DNA methylation levels and the assessment of key ecological endpoints. Exposure to 0.32 and 8 µg.L -1 SIM induced significant downregulation of DNA methyltransferase1 (dnmt1), concomitantly with Global DNA hypomethylation and impact on growth. Overall, this work is the first to validate the basal expression of key epigenetic regulators in a keystone marine crustacean, supporting the integration of epigenetic biomarkers into hazard assessment frameworks.

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Chronic exposure to environmentally relevant levels of simvastatin disrupts zebrafish brain gene signaling involved in energy metabolism

Cited by 20 publications

References 86 publications

Occurrence and risk assessment of selected pharmaceuticals in water and sediments of Usuma Dam, Abuja, Nigeria

Occurrence and risk assessment of selected pharmaceuticals in water and sediments of Usuma Dam, Abuja, Nigeria

Metformin disrupts Danio rerio metabolism at environmentally relevant concentrations: A generational study

The anti-lipidemic drug simvastatin modulates Epigenetic Biomarkers in the AmphipodGammarus locusta

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