Dose‐Related Gastric Toxicity of Diethyl Phthalate in Female Wistar Rats

Diethyl phthalate (DEP) is commonly used in cosmetics, personal care products, and pharmaceutical formulations as a low-molecular-weight phthalate. Despite its widespread use, information on its effects on the gastric mucosa remains limited. This study examined the dose-related effects of DEP on inflammation, oxidative stress, gastric mucosal defense, DNA damage, apoptosis, and histopathological changes in rat gastric tissue. Twenty-eight female Wistar rats were randomly assigned to four groups (n = 7 per group): control and DEP (100, 300, or 600 mg/kg/day). These experimental toxicological doses were administered by oral gavage for 21 days. Gastric tissue levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), superoxide dismutase (SOD), malondialdehyde (MDA), trefoil factor family 1 (TFF1), and mucin-5AC (MUC5AC) were determined by ELISA. Histopathological examination, Bax/Bcl-2 immunohistochemistry, and comet assay were performed. Dose-response relationships were assessed using polynomial trend analysis. DEP exposure resulted in significant dose-dependent increases in IL-6, TNF-α, COX-2, MDA, Bax expression, Bax/Bcl-2 ratio, histopathological damage, and DNA damage (all p < 0.001), whereas SOD levels and Bcl-2 expression significantly decreased (all p < 0.001). TFF1 and MUC5AC levels were significantly increased at 100 mg/kg but significantly decreased at 600 mg/kg compared with controls. Histopathological examination showed progressive gastric mucosal injury with increasing DEP doses. DEP exposure induced dose-related changes in gastric inflammation, oxidative stress, mucosal protective factors, histopathology, DNA damage, and apoptosis-related protein expression. The findings suggest that oxidative stress and inflammation are associated with altered mucosal defense, DNA damage, and apoptosis following DEP exposure.