Dataset Information

Low-Dose Bisphenol A in a Rat Model of Endometrial Cancer: A CLARITY-BPA Study.

ABSTRACT: 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?g/kg body weight (BW)/d] or 2 doses of 17?-ethynylestradiol (EE2) (0.05 and 0.5?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?g/kg BW/d BPA [BPA(25)], or 250?g/kg BW/d BPA [BPA(250)] exerted effects similar to that of EE2 at 0.5?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?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. https://doi.org/10.1289/EHP6875.

SUBMITTER: Leung YK

PROVIDER: S-EPMC7725436 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

Low-Dose Bisphenol A in a Rat Model of Endometrial Cancer: A CLARITY-BPA Study.

Leung Yuet-Kin YK Biesiada Jacek J Govindarajah Vinothini V Ying Jun J Kendler Ady A Medvedovic Mario M Ho Shuk-Mei SM

Environmental health perspectives 20201209 12

<h4>Background</h4>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.<h4>Objectives</h4>This study aimed to investigate whether lifelong exposure to different doses of BPA induced uterine abnormalities and molecular changes in a rat model.<h4>Methods</h4>Sprague-Dawley rats were exposed to 5 doses of BPA [0, 25, 250, 2,500, or 25,000μg/kg body weight (BW)/d] or 2 doses of 17α-ethyn ...[more]

PMID: 33296240

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Project description:BackgroundPrevious work determined that early life exposure to low-dose Bisphenol A (BPA) increased rat prostate cancer risk with aging. Herein, we report on prostate-specific results from CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity), which aims to resolve uncertainties regarding BPA toxicity.ObjectivesWe sought to a) reassess whether a range of BPA exposures drives prostate pathology and/or alters prostatic susceptibility to hormonal carcinogenesis, and b) test whether chronic low-dose BPA targets prostate epithelial stem and progenitor cells.MethodsSprague-Dawley rats were gavaged daily with vehicle, ethinyl estradiol (EE) or [Formula: see text] BPA/kg-BW during development or chronically, and prostate pathology was assessed at one year. One developmentally exposed cohort was given testosterone plus estradiol ([Formula: see text]) implants at day 90 to promote carcinogenesis with aging. Epithelial stem and progenitor cells were isolated by prostasphere (PS) culture from dorsolateral prostates (DLP) of rats continuously exposed for six months to [Formula: see text] BPA/kg-BW. Gene expression was analyzed by quantitative real time reverse transcription polymerase chain reaction (qRT-PCR).ResultsExposure to BPA alone at any dose did not drive prostate pathology. However, rats treated with EE, 2.5, 250, or [Formula: see text] BPA/kg-BW plus [Formula: see text] showed greater severity of lateral prostate intraepithelial neoplasia (PIN), and DLP ductal adenocarcinoma multiplicity was markedly elevated in tumor-bearing rats exposed to [Formula: see text]-BW. DLP stem cells, assessed by PS number, doubled with chronic EE and [Formula: see text] exposures. PS size, reflecting progenitor cell proliferation, was greater at 25 and [Formula: see text] BPA doses, which also shifted lineage commitment toward basal progenitors while reducing luminal progenitor cells.ConclusionsTogether, these results confirm and extend previous evidence using a rat model and human prostate epithelial cells that low-dose BPA augments prostate cancer susceptibility and alters adult prostate stem cell homeostasis. Therefore, we propose that BPA exposures may contribute to the increased carcinogenic risk in humans that occurs with aging. https://doi.org/10.1289/EHP3953.

Dataset Information

Low-Dose Bisphenol A in a Rat Model of Endometrial Cancer: A CLARITY-BPA Study.

Publications

Low-Dose Bisphenol A in a Rat Model of Endometrial Cancer: A CLARITY-BPA Study.

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