Exposure to environmentally relevant levels of DEHP during development modifies the distribution and expression patterns of androgen receptors in the anterior pituitary in a sex-specific manner.

DEHP is a prevalent phthalate with wide industrial applications and well-documented endocrine-disrupting effects, including the potential disruption of AR signaling in different tissues. The present study aimed to investigate the effects of gestational and lactational exposure to environmentally relevant DEHP concentrations on AR expression and subcellular localization in the pituitary gland, the master endocrine organ, with a focus on gonadotroph cells by in vivo and in vitro approaches. After DEHP exposure during gestation and lactation, a sex-specific modulation was detected in AR-positive pituitary cells and AR protein expression as assessed through flow cytometry and western blot. In male rats, DEHP increased AR-positive cells at postnatal day (PND) 21, with this effect persisting at PND75. In females, DEHP elevated AR-expressing cells at PND21, but this increase was followed by a reduction in adulthood. Furthermore, DEHP altered AR subcellular localization by reducing nuclear AR expression and increasing its cytoplasmic expression in gonadotrophs, and modified LH content in secretory granules, indicating enhanced secretory activity. In primary pituitary cell cultures DEHP exposure regulated AR subcellular localization by decreasing nuclear AR levels, and disrupting the testosterone effect on AR cytoplasmic-nuclear shuttling in a dose-dependent manner. In conclusion, our study shows alteration of pituitary AR expression and subcellular localization following gestational and lactational DEHP exposure in a sex specific manner, and indicates that DEHP retains AR in the cytoplasm, interfering with testosterone activity in pituitary cells.