Endocrine disrupting compounds (EDCs), including phthalates (PAEs), are chemicals that interfere with human hormone system to cause cancerous tumors, birth defects, and other developmental disorders. Phthalates are a group of related compounds that are very widely used as plasticizers and solvents. Our previous study demonstrated estrogen down regulate microRNA 34b (mir-34b) and indicated that miR-34b is an oncosuppressor and targets cyclin D1 and Jagged-1 (JAG1) to inhibit tumor growth and cell proliferation in an ER + /wild-type p53 breast cancer cell line (MCF-7). In this 3-year study, we will investigate the reproductive effect of Di-(2-ethylhexyl) phthalate (DEHP), Di-n-butyl phthalate (DBP) and their primary metabolites, Mono-(2-ethylhexyl) phthalate (MEHP) and mono-n-butyl phthalate (MBP) and clarify the molecular mechanism of EDCs toxicity. There are at least four major and specific aims will be accomplished in this research: (1) The effects of phthalates on mouse embryonic development and median lethal dose (LD50) and related gene expression profiles by transcriptome and microRNA analysis. (2) The impacts of epigenetic regulation (i.e., DNA methylation and histone acetylation, including Dnmt1, Dnmt2, Dnmt3a, Dnmt3b, HD-1, SIN3a and SIN3b) by phthalates and their metabolites. (3) The interference of phthalates and the metabolites in embryo, placental and fetal development, including telomerase activity will be examined. (4) To verify the possible role of phthalates on human reproduction and their signaling pathway. In conclusion, the integration of these findings will improve our ability to understand phthalates in human reproduction and provide therapeutic strategies to target the complex estrogenic pathway in embryonic development and fertility protection.
|Effective start/end date||8/1/13 → 7/31/14|
- Di-(2-ethylhexyl) phthalate (DEHP)
- Di-n-butyl phthalate (DBP)
- epigenetic regulation
- reproductive toxicity
- embryonic development