Lipid dysregulation in mouse ovarian antral follicles after oral exposure to a human relevant mixture of three phthalates.

Dibutyl phthalate, benzyl butyl phthalate, and di-2-ethylhexyl phthalates leach from consumer and medical products, leading to chronic daily exposure in women. Phthalates are associated with impaired ovarian function and metabolic syndrome in women. In mice, oral exposure to human relevant levels of a mixture of these phthalates disrupted the ovarian follicle proteome causing dysregulation of lipid metabolism proteins. This study aimed to establish the consequences of those alterations on the follicular lipid profile and identify relevant systemic impacts of phthalates. Adult CD-1 female mice were pipet fed vehicle (corn oil) or the phthalate mixture (32 µg/kg/day) for 10 days. Antral follicles were isolated and subjected to targeted lipid profiling, neutral lipid and triglyceride quantification, and expression analyses of key lipid homeostasis enzymes. Liver and serum samples were also tested for systemic effects. Lipid profiling revealed that phthalate-treated mice had significantly increased follicular free fatty acid (FFA), acylcarnitine, and lysophospholipid content with some changes also observed in liver and serum. Neutral lipid content was unaffected, but decreased follicle and increased hepatic triglyceride content were observed in phthalate-treated mice. Phthalate exposure increased follicular fatty acid synthase expression, decreased carnitine o-palmitoyltransferase 2 and altered some key triglyceride hydrolysis enzymes. These results strongly suggest that human relevant phthalate mixture exposure leads to lipid, gene and protein changes consistent with increased FFA synthesis, impaired beta oxidation, and decreased triglyceride abundance in antral follicles. These findings add key mechanistic information to the poorly understood associations between phthalate burden, antral follicle function, and metabolic dysfunction in women.