Acute exposure to diethylhexyl phthalate (DEHP) and diisononyl phthalate (DiNP) impacts pituitary hormones and inflammatory markers, suggesting altered reproductive aging in adult female mice

Phthalates are ubiquitous endocrine-disrupting chemicals whose exposure is associated with accelerated reproductive aging in humans. We focused on the pituitary gland, the source of the gonadotropins: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH). We hypothesized that the common phthalates di-(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) modulate inflammation in the pituitary and impact gonadotropin expression acutely and during aging. To test this, female CD-1 mice were orally dosed with corn oil or varying concentrations of DEHP and DiNP for 10 days. Pituitary tissues were collected immediately after dosing or 15 months post-dosing, processed, and analyzed by quantitative real-time PCR (qPCR) and immunohistochemistry. We found that acute phthalate exposure did not alter Fshb and Lhb mRNA expression compared with controls, but both DEHP and DiNP reduced FSH immunopositive cell number. Phthalate exposure also decreased Il1b, and increased Il18 and Tnf mRNA levels compared with controls, suggesting an inflammatory imbalance. At 15 months post-dosing, DiNP exposure increased Lhb and Il1b mRNA levels, but repressed Fshb and Nlrp3 mRNA levels compared with controls. Next, using dissociated cultures, we investigated the impact of phthalates and the proinflammatory stimulus lipopolysaccharide (LPS) on inflammation and gonadotropin gene expression directly at the pituitary. Both the DEHP metabolite MEHP and LPS decreased Fshb, but not Lhb mRNA relative to control. MEHP also repressed the induction of Il1b by LPS. Together, these findings suggest that acute exposure to phthalate alters mRNA expression of inflammatory markers and gonadotropins in the pituitary, which could alter the process of reproductive aging.