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Transcriptomic analysis of hepatotoxicity induced by pesticides imazalil, thiacloprid and clothianidin alone or in binary mixtures in a 28-day study in female Wistar rats

ABSTRACT: Co-occurrence of pesticide residues in food commodities raises a safety issue as their mixture effects on human health is largely unknown and need to be investigated. In a previous study, we reported the toxicological effects (pathology & histopathology) of imazalil (IMZ), thiacloprid (THI), and clothianidin (CTD) alone and in binary mixtures in a 28-day gavage study in female Wistar rats. Here, we undertook a transcriptomic analysis by means of total RNA sequencing (RNA-Seq). Ingenuity pathway analysis (IPA) was used to gain mechanistic information on the hepatotoxic pathways affected after treatment with pesticides, alone and in mixtures. Our data shows that 2986 genes were deregulated by CTD while IMZ and THI had effect on 194 and 225 genes, respectively. All three compounds share a common subset of genes whose network is associated with xenobiotic metabolism and nuclear receptors. Additionally, DNA repair process was predicted for CTD. The same networks were retrieved for the mixtures. Dose addition was indicated for the evaluated gene expressions. Our results bring new insight in the hepatotoxicity mechanisms of IMZ, THI, and CTD.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE153986 | GEO | 2020/12/31

REPOSITORIES: GEO

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Project description:The recent development of a custom cDNA microarray platform for one of thé standard organisms in aquatic toxicology, Daphnia magna, opened up new ways to mechanistic insights of toxicological responses. In this study, gene expression and (sub)organismal responses (Cellular Energy Allocation, growth) were assayed after short-term waterborne metal exposure. Microarray analysis of Ni-exposed daphnids revealed several affected functional gene classes, of which the largest ones were involved in different metabolic processes (mainly protein and chitin related processes), cuticula turnover, transport and signal transduction. Furthermore, genes involved in oxygen transport and heme metabolism (hemoglobin, δ-aminolevilunate synthase) were down-regulated. Applying a Partial Least Squares regression on nickel fingerprints and biochemical (sub)organismal parameters revealed a set of co-varying genes (hemoglobin, RNA terminal phosphate cyclase, a ribosomal protein and an “unknown” gene fragment). An inverse relationship was seen between the mRNA expression levels of different cuticula proteins and available energy reserves. In addition to the nickel exposure, daphnids were exposed to binary mixtures of nickel and cadmium or nickel and lead. Using multivariate analysis techniques, the mixture gene expression fingerprints (Ni2++Cd2+, Ni2++Pb2+) were compared to those of the single metal treatments (Ni2+, Cd2+, Pb2+). It was hypothesized that the molecular fingerprints of the mixtures would be additive combinations of the gene expression profiles of the individual compounds present in the mixture. However, our results clearly showed additionally affected pathways after mixture treatment (e.g. additional affected genes involved in carbohydrate catabolic processes and proteolysis), indicating interactive molecular responses which are not merely the additive sum of the individual metals. These findings, although indicative of the complex nature of mixture toxicity evaluation, underline the potential of a toxicogenomics approach in gaining more mechanistic information on the effects of single compounds and mixtures.

Dataset Information

Transcriptomic analysis of hepatotoxicity induced by pesticides imazalil, thiacloprid and clothianidin alone or in binary mixtures in a 28-day study in female Wistar rats

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