Acute exposure to di(2-ethylhexyl) phthalate or diisononyl phthalate leads to increased inflammation and oxidative stress in the uteri of mice

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 (20 μg/kg/day, 200 μg/kg/day, or 200 mg/kg/day), or DiNP (20 μg/kg/day, 100 μg/kg/day, or 200 mg/kg/day). Uteri were collected during diestrus for histological and gene expression analyses. Quantitative PCR (qPCR) showed that DEHP (20 and 200 μg/kg/day) and DiNP (200 mg/kg/day) increased expression of inflammasome-related genes (Il18, Il1β, and Nlrp3). DiNP at 200 mg/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 20 μg/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 200 μg/kg/day) and all doses of DiNP. while cell proliferation was only changed in DEHP (200 μg/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.