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Epigenome modulated xenobiotic detoxification pathways control DMBA-induced breast cancer in agouti A^vy/a mice.

ABSTRACT: Environmental xenobiotics with genotoxic activity are carcinogenic. However, individual differences in the susceptibility to xenobiotic-induced breast cancer remain unclear. Since epigenetic modifications could control the expression of metabolic enzymes, our goal was to determine whether epigenome modulated metabolic networks determine susceptibility to xenobiotic-induced breast cancer. The effect of epigenetic background on predisposition to carcinogen 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer development and progression was assessed using the A^vy/a mouse model. In a randomized block design, 22 isogenic A^vy/a (8 yellow, 7 slightly mottled, 7 pseudoagouti) and 8 wild type non-agouti (a/a black) age matched female mice were subjected to DMBA (30 mg/kg per mouse weight) once a week for 6 weeks to induce breast cancer. Compared to pseudoagouti littermates, a significant decrease in tumour latency with increased tumour burden was observed in slightly mottled and yellow littermates (p ? 0.05). However, tumour latency and tumour burden were similar in non-agouti a/a mice and A^vy/a cohorts. Network analysis of differentially expressed liver genes identified altered metabolic gene networks among agouti phenotypes. Consequently, in HPLC analyses, DMBA metabolites were significantly increased in A^vy/a pseudoagouti mice (p ? 0.05). Relative to A^vy/a slightly mottled, A^vy/a yellow and non-agouti a/a black mice, DMBA metabolites increased nine-, eight-, and four-fold, respectively, in A^vy/a pseudoagouti mice. In agreement with this, seven phase 2 xenobiotic detoxification genes were significantly upregulated in A^vy/a pseudoagouti mice (p ? 0.05). The Results from this study suggest that epigenome modulation of xenobiotic detoxification pathways may control xenobiotic-induced breast cancer susceptibility in A^vy/a mice.

SUBMITTER: Mazambani S

PROVIDER: S-EPMC6557611 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Epigenome modulated xenobiotic detoxification pathways control DMBA-induced breast cancer in agouti A<sup>vy</sup>/a mice.

Mazambani Simbarashe S Morris Madeleine M Cheriyath Venugopalan V

Epigenetics 20190509 7

Environmental xenobiotics with genotoxic activity are carcinogenic. However, individual differences in the susceptibility to xenobiotic-induced breast cancer remain unclear. Since epigenetic modifications could control the expression of metabolic enzymes, our goal was to determine whether epigenome modulated metabolic networks determine susceptibility to xenobiotic-induced breast cancer. The effect of epigenetic background on predisposition to carcinogen 7,12-dimethylbenz(a)anthracene (DMBA)-ind ...[more]

PMID: 31070092

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Project description:Fungi are known to utilize transcriptional regulation of genes that encode efflux transporters to detoxify xenobiotics; however, to date it is unknown how fungi transcriptionally regulate and coordinate different phases of detoxification system (phase I, modification; phase II, conjugation; and phase III, secretion). Here we present evidence of an evolutionary convergence between the fungal and mammalian lineages, whereby xenobiotic detoxification genes (phase I coding for cytochrome P450 monooxygenases [CYP450s] and phase III coding for ATP-binding cassette [ABC] efflux transporters) are transcriptionally regulated by structurally unrelated proteins. Following next-generation RNA sequencing (RNA-seq) analyses of a filamentous fungus, Sclerotinia homoeocarpa, the causal agent of dollar spot on turfgrasses, a multidrug resistant (MDR) field strain was found to overexpress phase I and III genes, coding for CYP450s and ABC transporters for xenobiotic detoxification. Furthermore, there was confirmation of a gain-of-function mutation of the fungus-specific transcription factor S. homoeocarpa XDR1 (ShXDR1), which is responsible for constitutive and induced overexpression of the phase I and III genes, resulting in resistance to multiple classes of fungicidal chemicals. This fungal pathogen detoxifies xenobiotics through coordinated transcriptional control of CYP450s, biotransforming xenobiotics with different substrate specificities and ABC transporters, excreting a broad spectrum of xenobiotics or biotransformed metabolites. A Botrytis cinerea strain harboring the mutated ShXDR1 showed increased expression of phase I (BcCYP65) and III (BcatrD) genes, resulting in resistance to fungicides. This indicates the regulatory system is conserved in filamentous fungi. This molecular genetic mechanism for xenobiotic detoxification in fungi holds potential for facilitating discovery of new antifungal drugs and further studies of convergent and divergent evolution of xenobiotic detoxification in eukaryote lineages.IMPORTANCE Emerging multidrug resistance (MDR) in pathogenic filamentous fungi is a significant threat to human health and agricultural production. Understanding mechanisms of MDR is essential to combating fungal pathogens; however, there is still limited information on MDR mechanisms conferred by xenobiotic detoxification. Here, we report for the first time that overexpression of phase I drug-metabolizing monooxygenases (cytochrome P450s) and phase III ATP-binding cassette efflux transporters is regulated by a gain-of-function mutation in the fungus-specific transcription factor in the MDR strains of the filamentous plant-pathogenic fungus Sclerotinia homoeocarpa This study establishes a novel molecular mechanism of MDR through the xenobiotic detoxification pathway in filamentous fungi, which may facilitate the discovery of new antifungal drugs to control pathogenic fungi.

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Epigenome modulated xenobiotic detoxification pathways control DMBA-induced breast cancer in agouti A^vy/a mice.

Publications

Epigenome modulated xenobiotic detoxification pathways control DMBA-induced breast cancer in agouti A<sup>vy</sup>/a mice.

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Epigenome modulated xenobiotic detoxification pathways control DMBA-induced breast cancer in agouti Avy/a mice.

Publications

Epigenome modulated xenobiotic detoxification pathways control DMBA-induced breast cancer in agouti A<sup>vy</sup>/a mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Epigenome modulated xenobiotic detoxification pathways control DMBA-induced breast cancer in agouti A^vy/a mice.