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Atrazine exposure decreases the activity of DNMTs, global DNA methylation levels, and dnmt expression.

ABSTRACT: Atrazine, a herbicide used on agricultural crops is widely applied in the Midwestern United States as well as other areas of the globe. Atrazine frequently contaminates potable water supplies and is a suspected endocrine disrupting chemical. Previous studies have reported morphological, hormonal, and molecular alterations due to developmental and adulthood atrazine exposure; however, studies examining epigenetic alterations are limited. In this study, the effects of atrazine exposure on DNA methyltransferase (DNMT) activity and kinetics were evaluated. Global DNA methylation levels and dnmt expression in zebrafish larvae exposed to 0, 3, or 30 parts per billion (ppb) atrazine throughout embryogenesis was then assessed. Results indicate that atrazine significantly decreased the activity of maintenance DNMTs and that the inhibition mechanism can be described using non-competitive Michaelis-Menten kinetics. Furthermore, results show that an embryonic atrazine exposure decreases global methylation levels and the expression of dnmt4 and dnmt5. These findings indicate that atrazine exposure can decrease the expression and activity of DNMTs, leading to decreased DNA methylation levels.

SUBMITTER: Wirbisky-Hershberger SE

PROVIDER: S-EPMC5656531 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Atrazine exposure decreases the activity of DNMTs, global DNA methylation levels, and dnmt expression.

Wirbisky-Hershberger Sara E SE Sanchez Oscar F OF Horzmann Katharine A KA Thanki Devang D Yuan Chongli C Freeman Jennifer L JL

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 20170830 Pt 1

Atrazine, a herbicide used on agricultural crops is widely applied in the Midwestern United States as well as other areas of the globe. Atrazine frequently contaminates potable water supplies and is a suspected endocrine disrupting chemical. Previous studies have reported morphological, hormonal, and molecular alterations due to developmental and adulthood atrazine exposure; however, studies examining epigenetic alterations are limited. In this study, the effects of atrazine exposure on DNA meth ...[more]

PMID: 28859886

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Project description:DNA methyltransferase inhibitors (DNMTi) decitabine and azacytidine are approved therapies for myelodysplastic syndrome and acute myeloid leukemia, and their combinations with other anticancer agents are being tested as therapeutic options for multiple solid cancers such as colon, ovarian, and lung cancer. However, the current therapeutic challenges of DNMTis include development of resistance, severe side effects and no or partial treatment responses, as observed in more than half of the patients. Therefore, there is a critical need to better understand the mechanisms of action of these drugs. In order to discover molecular targets of DNMTi therapy, we identified 638 novel CpGs with an increased methylation in response to decitabine treatment in HCT116 cell lines and validated the findings in multiple cancer types (e.g., bladder, ovarian, breast, and lymphoma) cell lines, bone marrow mononuclear cells from primary leukemia patients, as well as peripheral blood mononuclear cells and ascites from platinum resistance epithelial ovarian cancer patients. Azacytidine treatment also increased methylation of these CpGs in colon, ovarian, breast, and lymphoma cancer cell lines. Methylation at 166 identified CpGs strongly correlated (|r|≥ 0.80) with corresponding gene expression in HCT116 cell line. Differences in methylation at some of the identified CpGs and expression changes of the corresponding genes was observed in TCGA colon cancer tissue as compared to adjacent healthy tissue. Our analysis revealed that hypermethylated CpGs are involved in cancer cell proliferation and apoptosis by P53 and olfactory receptor pathways, hence influencing DNMTi responses. In conclusion, we showed hypermethylation of CpGs as a novel mechanism of action for DNMTi agents and identified 638 hypermethylated molecular targets (CpGs) common to decitabine and azacytidine therapy. These novel results suggest that hypermethylation of CpGs should be considered when predicting the DNMTi responses and side effects in cancer patients.

Dataset Information

Atrazine exposure decreases the activity of DNMTs, global DNA methylation levels, and dnmt expression.

Publications

Atrazine exposure decreases the activity of DNMTs, global DNA methylation levels, and dnmt expression.

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