Chronic Di(2-ethylhexyl) Phthalate and Diisononyl Phthalate Exposure Impairs Uterine Endometrial Glycogen Metabolism in Mice

Phthalates are associated with several reproductive disorders in women and reduce fertility in mice. They are also known to impair hepatic glycogen metabolism. Glucose is a crucial nutrient for the uterus, and glycogen buffers glucose concentration in the endometrium. The objective of this study was to investigate how long-term exposure to di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) alters glycogen metabolism in the murine endometrium. Six-week-old female mice were fed chow containing vehicle or DEHP or DiNP at 0.15, 1.5, and 1500 parts per million (ppm) ad libitum for 9 months. Uteri were collected at diestrus. DEHP significantly reduced glycogen levels in the glandular epithelium (GE) and luminal epithelium (LE). In the stroma, both 1.5 and 1500 ppm groups had significantly lower glycogen. In the DiNP-treated mice, all three concentrations significantly decreased glycogen in GE, LE, and stroma. Neither phthalate altered mRNA levels of hexokinase1 (Hk1), glycogen synthase 1 (Gys1), glycogen phosphorylase M (Pygm), or glucose-6-phosphatase 3 (G6pc3). Immunohistochemistry showed that both phthalates increased HK1 levels in the stroma but not the epithelium. DEHP and DiNP (1500 ppm) increased PYGM in GE, LE, and stroma. DiNP (1500 ppm) significantly lowered G6PC3 in LE compared to all other groups. In the GE, both 1.5 and 1500 ppm DiNP decreased the immunostaining of G6PC3 compared to control and 0.15 ppm DiNP. Our results show that phthalates alter endometrial glycogen levels and expression of key enzymes. These findings are consistent with altered glycogen metabolism, which could alter endometrial glucose metabolism.