Oral exposure to di(2-ethylhexyl) phthalate alters the expression of GATA6, OCT4, and CDX2 in blastocysts and decreases the rate of implantation in a mouse model.

Abstract

Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer ubiquitously found in the environment. Due to its biological activity, it is classified as an endocrine-disrupting chemical and reproductive toxicant. DEHP and its metabolites have been detected in women with various infertility-related pathologies, and their concentrations have been associated with reduced embryo quantity and quality, implantation failure, and miscarriage in humans. The formation of the inner cell mass and trophectoderm in blastocysts is a critical fate decision for continued development and cellular differentiation, accompanied by the expression of GATA6, OCT4, and CDX2. This study tested whether DEHP induces deleterious conformational changes in blastocysts, potentially leading to reduced implantation rates. Adult female CD-1 mice were exposed to vehicle (corn oil) or DEHP (0, 20, 200, or 2,000 μg/kg/day) orally for 1 mo. The 2,000 μg/kg/day dose induced oocyte and embryo fragmentation. Embryo developmental arrest was evident at DEHP doses of 200 and 2,000 μg/kg/day. DEHP affected the levels and expression patterns of GATA6, OCT4, and CDX2 at doses of 200 and 2,000 μg/kg/day. These doses also impacted the number and functionality of blastocysts. Furthermore, DEHP doses of 200 and 2,000 μg/kg/day impaired endometrial implantation capacity, as evidenced by the failure to implant normal blastocysts from untreated females using transcervical embryo transfer. Collectively, these data suggest that oral exposure to DEHP for 1 mo affects the expression of GATA6, OCT4, and CDX2, consequently reducing implantation capacity.