Caracterização da tríade exposição-gene-doença: impacto dos desreguladores endócrinos no microambiente prostático

Abstract

Endocrine disruptors (EDs) are chemical substances widely distributed in the environment, recognized for their ability to mimic or inhibit the action of natural hormones, leading to adverse health outcomes. The prostate, as a hormone-responsive organ, demonstrates a significant vulnerability to the exposure of these compounds, making the investigation of their effects under prolonged exposure conditions crucial. In this context, the present research explored the impacts of ED exposure on the prostatic microenvironment through two complementary studies. The first study, a systematic review with meta-analysis, evaluated the influence of perinatal exposure to Bisphenol A (BPA) on the incidence of preneoplastic lesions in the prostate of Sprague-Dawley rats, based on four preclinical studies. The results indicated that the lateral lobe of the prostate is particularly sensitive to the induction of prostatic intraepithelial neoplasia (PIN), especially after low doses of BPA (0.1 to 2.5 µg/kg), suggesting a non-monotonic response. The meta-analysis showed a combined Odds Ratio of 20.25, indicating a significantly increased risk of prostatic lesions in animals perinatally exposed to BPA, particularly under hormonal stimulation in adulthood. The second study analyzed continuous exposure to a mixture of 12 EDs from the gestational period until adulthood (postnatal day 220) in Sprague-Dawley rats. Histological analyses revealed significant prostatic lesions, including low-grade prostatic intraepithelial neoplasia (LGPIN), focal hyperplasia, and dysplasia, indicating a continuous susceptibility throughout development. At the molecular level, changes in the transcriptional profile were observed, with pathway enrichment related to RNA splicing, protein folding, nucleocytoplasmic transport, and immune response, reflecting cellular adaptive mechanisms to environmental stress as well as processes favoring dysregulated cell proliferation. Survival analysis highlighted that the genes ARCN1, CD55, CRIP2, and MFSD4A are associated with a worse prognosis in prostate cancer patients, suggesting their potential as biomarkers for tumor progression. In conclusion, the findings from these two studies provide compelling evidence that prolonged exposure to EDs, particularly during critical periods of development, compromises prostatic homeostasis, favoring the formation of precancerous lesions and increasing the risk of progression to prostate cancer.