Association of the Endosomal TLR4 Pathway with Dorsolateral Prostatic Remodeling Induced by Perinatal Phthalate Mixture Exposure in Rats

Phthalates are endocrine disruptors that alter the homeostasis of hormone-dependent organs. Perinatal exposure to endocrine disruptors can program different organs and promote morphological and metabolic alterations, increasing susceptibility to diseases later in life, as proposed by the Developmental Origins of Health and Disease (DOHaD) hypothesis. This study evaluated the effects of perinatal exposure to a six-phthalate mixture on prostatic structure and molecules related to inflammation and oxidative stress. Pregnant Sprague-Dawley rats received the mixture from gestational day 10 to postnatal day 21 and were divided into: Control (corn oil), T1 (20 µg/kg/day), and T2 (200 mg/kg/day) groups. At postnatal day 120, offspring dorsolateral prostates were analyzed by morphology, RT-qPCR, immunohistochemistry, and oxidative profiling. Results showed that the mixture induced glandular disorganization, proliferative lesions, and increased collagen deposition in T2. Both doses of the mixture increased mast cell recruitment and activation compared to controls. Molecular analysis revealed that mixture exposure upregulated genes and proteins associated with inflammation and the endosomal TLR4 pathway, potentially as a deregulated anti-inflammatory response. Elevated glutathione S-transferase activity in T2 suggested increased reactive oxygen species. In conclusion, perinatal exposure to the phthalate mixture compromises prostatic integrity, promoting histological remodeling and triggering dysregulation in anti-inflammatory mechanisms. These findings suggest that early-life exposure to plasticizers may predispose the dorsolateral prostate to lesions through dysregulation of the TLR4–IFN-β axis.