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

Content Provider	Europe PMC
Author	Abbass, Mustafa Chen, Yuzhi Arlt, Volker M. Stürzenbaum, Stephen R.
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.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00204-020-02968-z.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC7904753&blobtype=pdf
ISSN	03405761
Journal	Archives of Toxicology [Arch Toxicol]
Volume Number	95
DOI	10.1007/s00204-020-02968-z
PubMed Central reference number	PMC7904753
Issue Number	3
PubMed reference number	33420596
e-ISSN	14320738
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2021-01-09
Publisher Place	Berlin/Heidelberg
Access Restriction	Open
Rights License	Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2021
Subject Keyword	Caenorhabditis elegans Benzo[a]pyrene DNA adducts Xenobiotics
Content Type	Text
Resource Type	Article
Subject	Health, Toxicology and Mutagenesis Medicine Toxicology