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.
Phthalates are a class of synthetic compounds, known as endocrine-disrupting chemicals, widely used as plasticizers in consumer products, including personal care items, medical devices, and food packaging. Two common phthalates, di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP), have been associated with adverse effects on female reproductive health. This study investigated the effects of acute DEHP and DiNP exposure on uterine inflammation and oxidative stress in adult female CD-1 mice. Mice were orally dosed for 10 days with vehicle control, DEHP (20μg/kg/day, 200μg/kg/day, or 200mg/kg/day), or DiNP (20μg/kg/day, 100μg/kg/day, or 200mg/kg/day). Uteri were collected during diestrus for histological and gene expression analyses. Quantitative PCR (qPCR) showed that DEHP (20 and 200μg/kg/day) and DiNP (200mg/kg/day) increased expression of inflammasome-related genes (Il18, Il1β, and Nlrp3). DiNP at 200mg/kg/day also increased Il10 expression. Oxidative stress genes revealed DEHP increased Prdx2 expression at all doses without affecting Sod1, Cat, or Gpx1. However, DiNP increased Prdx2 at 20μg/kg/day but reduced Sod1, Cat, and Gpx1 at higher doses. Histological analysis revealed that high-dose DiNP reduced outer myometrium thickness and luminal epithelial cell height, while DEHP only affected the cell height at the highest dose. Macrophage and other mononuclear phagocytic cell infiltration increased with DEHP (20 and 200μg/kg/day) and all doses of DiNP. while cell proliferation was only changed in DEHP (200μg/kg/day). Together, these findings demonstrate that acute exposure to DEHP and DiNP induces uterine inflammatory and oxidative stress responses, with distinct dose-dependent effects for each phthalate.
Adriana Andrus, L. Y. Parra-Forero, Coba N Sexton et al.· Reproductive Toxicology· 1 citation