ORIGINAL ABSTRACT

Pesticide mixture exposure during critical developmental windows is a growing public health concern, given their potential additive or synergistic effects on the male reproductive system. This study aimed to evaluate whether developmental exposure to a mixture of propiconazole (PRO) and glyphosate (GLY) alters the postpubertal rat prostate. Pregnant rats were orally exposed to vehicle (saline) or a mixture of PRO and GLY (4 mg PRO/kg/day and 3.7 mg GLY/kg/day) from gestation day 9 until weaning. On postnatal day 60, male offspring were euthanized, and the prostate and serum samples were collected. PROGLY-exposed rats exhibited changes in the ventral and dorsolateral prostate histoarchitecture, including epithelial and stromal remodeling and increased incidence of prostate lesions. In the ventral prostate, although the relative glandular area remained unchanged, PROGLY exposure exhibited increased epithelial height and decreased luminal acinar area. Also, hyperplastic and atrophic acini were more prevalent in these animals. PROGLY exposure reduced estrogen receptor beta (ESR2) protein level, particularly in hyperplastic and atrophic acini, without affecting androgen or estrogen receptor alpha. ESR2 decrease was associated with an increased cell proliferation index in hyperplastic acini and a reduction in serum testosterone level in PROGLY-exposed rats. Stromal alterations included increased smooth muscle cell layers and reduced vimentin-positive fibroblasts, with no evidence of myofibroblast presence. This study shows that developmental exposure to PROGLY disrupts normal ventral prostate architecture and hormone signaling in postpubertal rats. These findings highlight the potential long-term risks of combined pesticide exposure on male reproductive health and the importance of evaluating mixture effects.