Integrated metabolomics and transcriptomics analysis reveals new biomarkers and mechanistic insights on atrazine exposures in MCF‑7 cells

Atrazine (ATZ) is a widely used herbicide worldwide and is a long-suspected endocrine-disrupting chemical. However, most endocrine-disrupting toxicity studies on ATZ have been based on animal models and those investigating inner mechanisms have only focused on a few genes. Therefore, the possible link between ATZ and endocrine-disrupting toxicity is still unclear. In this study, multi-omics and molecular biology techniques were used to elucidate the possible molecular mechanisms underlying the effect of ATZ exposure on MCF-7 proliferation at environmentally relevant concentrations. Our study is the first report on ATZ-induced one carbon pool by folate metabolic disorder in MCF-7 cells. A concentration of 1 μM ATZ yielded the highest cell viability and was selected for further mechanistic studies. A total of 34 significantly changed metabolites were identified based on metabolomic analysis, including vitamins, amino acids, fatty acids, and corresponding derivatives. Folate and pyridoxal have potential as biomarkers of ATZ exposure. One carbon pool by folate metabolic pathway was identified based on metabolic pathway analysis of the significantly altered pathways. Moreover, FTCD and MTHFD related to this pathway were further identified based on transcriptomic analysis and protein assays. Folate and different forms of 5,6,7,8-tetrahydrofolate, which participate in purine synthesis and associate with methyl groups (SOPC, arachidonic acid, and L-tryptophan) in one carbon pool by the folate metabolic pathway, potentially promote MCF-7 cell proliferation. These findings on the key metabolites and regulation of the related differentially expressed genes in folate metabolism will shed light on the mechanism of MCF-7 cell proliferation after ATZ exposure. Overall, this study provides new insights into the mechanistic understanding of toxicity caused by endocrine-disrupting chemicals.