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The effects of environmentally relevant concentrations of aqueous atorvastatin on Xenopus laevis

ABSTRACT: Numerous studies report active pharmaceutical compounds detected in both wastewater effluent and surface waters. Exposure to statin drugs in general, and atorvastatin in particular, is likely to be a concern. We hypothesized that chronic exposure to low concentrations of atorvastatin in water would result in an adverse effect on production of steroids regulating growth and development of the model amphibian Xenopus laevis. To assess the potential for impacts we used three experimental assays. The FETAX assay was used to evaluate the effects of a range of doses of atorvastatin on developing embryos. A 60 day metamorphosis assay assessed the effects of aqueous atorvastatin exposure at environmentally concentrations on metamorphosing tadpoles. A 60 day chronic flow-through exposure evaluated the effects of chronic low concentrations of atorvastatin on adults. The data from the FETAX assay confirmed uptake, activity, and effect of atorvastatin in X. laevis tadpoles. The results of the 60-day flow-through exposure on metamorphosing tadpoles showed significant evidence of altered cholesterol biosynthesis. The dose-dependent increase in cyp19a1 expression also indicated that the steroidogenesis pathway was affected. The RNAseq analysis confirmed that exposure to environmentally relevant concentrations of atorvastatin does cause significant alterations to global transcriptional profiles in a manner consistent with dysregulation of the cholesterol biosynthesis pathway, both through the downregulation of many genes involved in that pathway, but also in the impacts to other, related pathways. The qPCR data for both adult males and adult females indicated only slight changes in expression with the exception that hmgcr was significantly downregulated in males, and cyp3a4 expression was significantly downregulated in females. The data we present here indicated that chronic exposure to environmentally relevant concentrations of atorvastatin does have the potential to impact early life stage frogs, particularly by altering expression of genes involved in critical molecular pathways.

ORGANISM(S): Xenopus laevis

PROVIDER: GSE236279 | GEO | 2023/07/07

REPOSITORIES: GEO

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Project description:Hydroxylated polychlorinated biphenyls are the metabolites produced from polychlorinated biphenyls (PCBs) by drug-metabolizing enzyme cytochrome P450 1A1. These compounds are bound to transthyretin, a major plasma thyroid hormone-binding protein in amphibian tadpoles. The compounds-transthyretin complexes are transferred into the brain across the blood brain barrier in mammals. Thus these compounds are suspected to disrupt neural development in brain. We studied about the effects of hydroxylated PCBs on the thyroid system in brain using metamorphosing tadpoles of African clawed toad, Xenopus laevis. The metamorphosis assay revealed that these compounds had inhibitory effects on the thyroid hormone-induced metamorphosis. This in vivo assay was a powerful tool to detect thyroid-disrupting activities, because we were not able to detect the inhibitory effects of these compounds using thyroid hormone-responsive reporter gene assay in a cultured Xenopus cell line. A genome-wide gene expression analysis in brain following short-term exposure to these compounds demonstrated that the delay of metamorphosis and the morphological thyroid-disrupting changes could be caused partially by disruption of the thyroid hormone-induced gene expression by hydroxylated PCBs. Furthermore, we associated functional ontology terms with the transcripts whose expression were altered by thyroid hormone alone, or thyroid hormone and hydroxylated PCBs. We suggested that these approachs using a technique of bioinformatics revealed molecular mechanism of thyroid-disrupting activities in vivo. Thyroid hormones induce amphibian metamorphosis and alter a lot of thyroid hormone-responsive gene expression. We studied about the effects of hydroxylated PCBs on TH-induced gene expression. Premetamorphic tadpoles were treated with 500 nM hydroxylated PCBs in the presence of 1 nM thyroid hormone for 4 days. After exposure period total RNA was extracted from brain. Study included at least three replicate of each treatment.

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The effects of environmentally relevant concentrations of aqueous atorvastatin on Xenopus laevis

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