摘要：Background: Bisphenol A (BPA) is known to be biologically active in experimental models even at low levels of exposure. However, its impact on endometrial cancer remains unclear. Objectives: This study aimed to investigate whether lifelong exposure to different doses of BPA induced uterine abnormalities and molecular changes in a rat model. Methods: Sprague-Dawley rats were exposed to 5 doses of BPA [0, 25, 250, 2,500, or 25,000 μ g / kg body weight (BW)/d] or 2 doses of 17 α − ethynylestradiol (EE2) (0.05 and 0.5 μ g / kg BW/d) starting from gestational day 6 up to 1 y old according to the CLARITY-BPA consortium protocol. The BW, uterus weight, and histopathology end points of the uteri were analyzed at postnatal (PND) day 21, 90, and 365. Estrous cycling status was evaluated in PND90 and PND365 rats. Transcriptomic analyses of estrus stage uteri were conducted on PND365 rats. Results: Based on the analysis of the combined effects of all testing outcomes (including immunohistological, morphological, and estrous cycle data) in a semiblinded fashion, using statistical models, 25 μ g / kg BW/d BPA [BPA(25)], or 250 μ g / kg BW/d BPA [BPA(250)] exerted effects similar to that of EE2 at 0.5 μ g / kg BW/d in 1-y-old rats. Transcriptome analyses of estrus stage uteri revealed a set of 710 genes shared only between the BPA(25) and BPA(250) groups, with 115 of them predicted to be regulated by estradiol and 57 associated with female cancers. An interesting finding is that the expression of 476 human orthologous genes in this rat BPA signature robustly predicted the overall survival ( p = 1.68 × 10 − 5 , hazard ratio = 2.62 ) of endometrial cancer patients. Discussion: Lifelong exposure of rats to low-dose BPA at 25 and 250 μ g / kg BW/d altered the estrous cycle and uterine pathology with similarity to EE2. The exposure also disrupted a unique low-dose BPA-gene signature with predictive value for survival outcomes in patients with endometrial cancer.
