Comparative metabolism of xenobiotic chemicals by cytochrome P450s in the nematode Caenorhabditis elegans

Harlow, Philippa H.; Perry, Simon J.; Stevens, Alexander J.; Flemming, Anthony J.

doi:10.1038/s41598-018-31215-w

Cited by 38 publications

(33 citation statements)

References 19 publications

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“…The cyp-35s are thought to be part of the first stage xenobiotic detoxification response in C. elegans and were shown to be induced by β-naphthoflavone, PCB52, atrazine and lansoprazole. (Menzel et al 2001(Menzel et al , 2005(Menzel et al , 2007Lindblom and Dodd 2006;Harlow et al 2018). BaP is metabolised in Homo sapiens mainly by the action of CYP1′s (CYP1A1, CYP1A2, and CYP1B1) (Shimada et al 1997;Gotoh 1998;Xue and Warshawsky 2005;Shimada 2006;Luch and Baird 2010).…”

Section: Transcriptional Analysis Of C Elegans Exposed To Bapmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Transcriptional Analysis Of C Elegans Exposed To Bapmentioning

confidence: 99%

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

et al. 2021

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“…The C. elegans cuticle is known to be a barrier against absorption of toxicants (Hunt 2017). The nematode is known to possess CYP 450 enzymes, although their repertoire is not as extensive as in mammals (Harlow et al 2018).…”

Section: Elegans: Analysis Of Lc-hrms Data and Overlapmentioning

confidence: 99%

Cross-species metabolomic analysis of DDT and Alzheimer’s disease-associated tau toxicity

Kalia

et al. 2021

Preprint

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Background. The formation of hyperphosphorylated tau (p-tau) protein tangles in neurons is a pathological marker of Alzheimer's disease (AD). Exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) has been associated with an increased risk of AD. Objectives. To determine if there was a connection between DDT exposure and tau toxicity we investigated whether exposure to DDT can exacerbate tau protein toxicity in C. elegans. In addition, we examined the association between p-tau protein and metabolism in a human population study and in a transgenic C. elegans strain neuronally expressing a mutant tau protein fragment that is prone to aggregation. Methods. In the human population study, we used a metabolome-wide association framework to determine the association between p-tau measured in the cerebrospinal fluid (CSF) and metabolomic features measured in both plasma (n = 142) and CSF (n = 78) using high-resolution metabolomics (HRM). Using the same HRM method, we determined changes in metabolomic features in the transgenic C. elegans strain compared to its control strain. Metabolites associated with p-tau in both species were analyzed for overlap. We also examined the effect of DDT and aggregating tau protein on growth, swim behavior, mitochondrial function, metabolism, learning, and lifespan in C. elegans. Results. Plasma and CSF-derived features associated with p-tau level were related to drug, amino acid, fatty acid, and mitochondrial metabolism pathways. Five metabolites overlapped between plasma and C. elegans, and 4 between CSF and C. elegans. DDT exacerbated the inhibitory effect of aggregating tau protein on growth and basal respiration. In the presence of aggregating tau protein, DDT induced more curling and was associated with reduced levels of amino acids but increased levels of uric acid and adenosylselenohomocysteine. Developmental exposure to DDT blunted the lifespan reduction caused by aggregating tau protein. Conclusion. The model organism C. elegans can complement human studies by providing a means to study mechanisms of environmental toxicants. Specifically, our C. elegans data show that DDT exposure and tau protein aggregation both inhibit mitochondrial function and DDT exposure can exacerbate the mitochondrial inhibitory effects of tau protein aggregation providing a plausible explanation for the observed human associations.

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“…(Qin and Powell-Coffman 2004;Kuzin et al 2014). Furthermore, the C. elegans homologue of the mammalian nuclear factor erythroid 2-related (NRF2) transcription factor, protein skinhead-1 (SKN-1), functions in the p38 MAPK pathway in parallel to the DAF-2-mediated insulin/IGF-1-like signaling pathway (IIS) in order to regulate oxidative stress responses and longevity (Harlow et al 2018). In addition, differences in xenobiotic metabolizing enzymes between fish and human have to be taken into account.…”

Section: Resultsmentioning

confidence: 99%

Alternative model organisms for toxicological fingerprinting of relevant parameters in food and nutrition

Sandner

König

Wallner

et al. 2021

Critical Reviews in Food Science and Nutrition

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In the field of (food) toxicology, there is a strong trend of replacing animal trials with alternative methods for the assessment of adverse health effects in humans. The replacement of animal trials is not only driven by ethical concerns but also by the number of potential testing substances (food additives, packaging material, contaminants, and toxicants), which is steadily increasing. In vitro 2D cell culture applications in combination with in silico modeling might provide an applicable first response. However, those systems lack accurate predictions of metabolic actions. Thus, alternative in vivo models could fill the gap between cell culture and animal trials. In this review, we highlight relevant studies in the field and spotlight the applicability of alternative models, including C. elegans, D. rerio, Drosophila, HET-CAM and Lab-on-a-chip.

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Comparative metabolism of xenobiotic chemicals by cytochrome P450s in the nematode Caenorhabditis elegans

Cited by 38 publications

References 19 publications

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

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

Cross-species metabolomic analysis of DDT and Alzheimer’s disease-associated tau toxicity

Alternative model organisms for toxicological fingerprinting of relevant parameters in food and nutrition

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