Benzo[a]pyrene and Caenorhabditis elegans: defining the genotoxic potential in an organism lacking the classical CYP1A1 pathway

Abstract

Benzo[a]pyrene (BaP) is bioactivated in most organisms by the cytochrome P450 (CYP) enzymes, mainly CYP1A1, ultimately resulting in the reactive metabolite BaP-7,8-dihydrodiol-9,10-epoxide (BPDE) capable of covalently binding to DNA and forming adducts. This step has been defined as the key process in cancer initiation in humans. However, limited knowledge is available about the consequences of BaP exposure in organisms lacking this classical CYP1A1 pathway, one example is the model nematode Caenorhabditis elegans. The aim of this study was to define the genotoxic potential of BaP in C. elegans and to advance our understanding of xenobiotic processing in the absence of the CYP1A1 pathway. Exposure to high concentrations of BaP (0–40 µM) significantly affected life cycle endpoints of C. elegans, which were manifested by a reduced reproductive output and shortened life span. An optimised comet assay revealed that DNA damage increased in a dose-dependent manner; however, no bulky DNA adducts (dG-N2-BPDE) were observed by 32P-postlabelling. Global transcriptomic analysis by RNA-Seq identified responsive transcript families, most prominently members of the cyp-35 and UDP-glucuronosyltransferases (UGTs) enzyme families, both of which are linked to xenobiotic metabolism. Strains harbouring mutations in the cyp-35A2 and cyp-35A3 genes were notably less prone to BaP-mediated toxicity, and BaP led to longevity in cyp-35A5 mutants. In summary, BaP induces transcriptional, genotoxic and phenotypic responses in C. elegans, despite the absence of the classical CYP1A1 bioactivation pathway. This provides first evidence that parallel pathways are implicated in BaP metabolism in C. elegans and this seems to be mediated via the cyp-35 pathway.

Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based onRNA‐seq

“…The GO and KEGG functional enrichment analysis showed that these differentially expressed genes were mainly involved in tumor‐related biological processes and signaling pathways, including transcriptional dysregulation in cancer, the TNF signaling pathway, metabolism of xenobiotics by cytochrome P450, the MAPK signaling pathway, and so forth, which is consistent with the results of previous studies 55 . These bioinformatics data indicated that BaP promoted the malignant biological behavior of OSCC possibly based on these signaling pathways.…”

“…13 The GO and KEGG functional enrichment analysis showed that these differentially expressed genes were mainly involved in tumor- pathway, and so forth, which is consistent with the results of previous studies. 55 These bioinformatics data indicated that BaP promoted the malignant biological behavior of OSCC possibly based on these signaling pathways.…”

Cytochromes P450 of Caenorhabditis elegans: Implication in Biological Functions and Metabolism of Xenobiotics

“…The toxic effects of fenitrothion for C. elegans also appear to derive from the formation of reactive metabolites mainly by P450 35A2 [79] (Table 6). Quite recent data have shown that the genotoxic effects of benzo(a)pyrene, B(a)P on C. elegans do not depend on P450s equivalent to those of human family 1A that do not seem to exist in C. elegans but depend on P450s 35A2, 35A3, and 35A5 [99].…”

Benzo(a)pyrene and cardiovascular diseases: An overview of pre-clinical studies focused on the underlying molecular mechanism

“…Properly speaking, BaP is a procarcinogen. Its carcinogenic effects depend on the activity of the detoxification enzymes cytochrome P450 1A1 (CYP1A1) and CYP1B1, which enzymatic metabolism BaP to BPDE ( 21 , 22 ). Furthermore, BaP induces the CYP1A1 gene expression by activating the AhR nuclear translocation signal pathway ( 23 , 24 ).…”