Changes in the pro/antiproliferative pathways can favor the development of preneoplastic lesions in the female prostate after co-exposure with BPA, E2 and Genistein

Introduction: The female prostate is a urogenital-associated gland regulated by steroid hormones. Alterations in these hormonal profile present deleterious effects, related to activation of pro/antiproliferative pathways, development, and homeostasis. In addition, prostate disorders are associated with aging and exposure to endocrine disruptors (EDs), such as bisphenol A (BPA) that is associated to development of preneoplastic lesions by activation of these pathways. Also, the co-exposure with other agents, like the phytoestrogen genistein and the estrogen 17β-estradiol (E2), could modulate the prostatic microenvironment under endocrine disruption. Objectives: Thus, the aim of this study was to analyze expression of proliferative (PHH3) and cell death (caspase 3 – inactivated and activated) markers in the female prostate of aged gerbils under BPA endocrine disruption and its co-exposure with genistein and E2. Methods: For this work, females were divided into 5 experimental groups (N=40): control (gavage with water); E2 (Gavage with 17β-estradio l – 0.5 mg/kg/day); Phytoestrogen (GIN) (gavage with genistein – 240 mg/kg/day), and BPA group (gavage with 50 µg/kg/day). The gavage of control and BPA groups occurred during gestation (24-26 days) and lactation (21 days), both windows of susceptibility for females. The E2 and GIN groups were exposed to these agents after the BPA exposure, from 12 months of age, for 6 months. Samples were analyzed by immunohistochemistry (IHC) technique to analyze the expression of PHH3 and caspase 3. IHC evaluation was performed to quantify positive cells. Statistical analyses considered p<0.05(ANOVA or Kruskall-Wallis test, followed by Tukey or Dunns post-test). Results:The present study showed an increase of PHH3 expression in the BPA (47.26% ± 6.77), E2 (47.07% ± 5.37) and GIN (53.47% ± 7.32) groups, in comparation to the control group (23.63% ± 4.97), demonstrating the action of BPA in this pathway. However, for the caspase 3 – activated (aCASP3), there was an increase for this marker in the E2 (21.25% ± 4.15) group, compared to the others. In addition, a decrease in aCASP3 in the GIN (1.05% ± 4.15) group compared to the control group, with no significant differences to BPA group, indicating that in this microenvironment, GIN did not influence in the apoptotic pathways. Also, for the caspase 3- inactivated (iCASP3), there was an imbalance among the groups, demonstrating an increase in the E2 (46.54% ± 6.00) group, in comparation with the control (17.14% ± 6.00) and BPA (14.88% ± 5.61) groups. In addition, there was a decrease in the GIN (5.55% ± 6.00) group, in comparation to the E2 (46.54% ± 6.00) group. These results showed the imbalance and disequilibrium in the pro/antiproliferative pathways, which can favor proliferative lesions occurrence. Also, there was possible to realize a balance in these pathways in the E2 group. Conclusions: Thus, this work demonstrated the action of BPA, E2 and genistein like an endocrine disruptors, promoting changes in expression of PHH3 and caspase 3, activating pro/antiproliferative pathways, encouraging the development of preneoplastic lesions.