| Oral Exposure to Bisphenol A Increases Dimethylbenzanthracene-Induced Mammary Cancer in Rats Sarah Jenkins,1 Nandini Raghuraman,1 Isam Eltoum,2,3 Mark Carpenter,4 Jose Russo,5 and Coral A. Lamartiniere1,2 1Department of Pharmacology and Toxicology, 2UAB Comprehensive Cancer Center, and 3Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA; 4Department of Mathematics and Statistics, Auburn University, Auburn, Alabama, USA; 5Breast Cancer Research Laboratory, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA Abstract
Background: Bisphenol A (BPA) is widely used in the manufacture of polycarbonate plastics, including infant formula bottles. Objectives: Based on the reported endocrine disruptor activity of this polyphenol, we hypothesized that exposure to BPA early in life would elicit developmental changes in the mammary tissue and cause a predisposition for mammary cancer. Methods: We exposed neonatal/prepubertal rats to BPA via lactation from nursing dams treated orally with 0, 25, and 250 µg BPA/kg body weight/day. For tumorigenesis studies, female offspring were exposed to 30 mg dimethylbenzanthracene (DMBA) /kg body weight at 50 days of age. Results: The combination of DMBA treatment with lactational exposure to BPA demonstrated a dose-dependent increase in mammary tumor multiplicity and reduced tumor latency compared with controls. In the absence of DMBA treatment, lactational BPA exposure resulted in increased cell proliferation and decreased apoptosis at 50 but not 21 days postpartum (shortly after last BPA treatment) . Using Western blot analysis, we determined that steroid receptor coactivators (SRCs) 1–3, Akt, phosphorylated Akt, progesterone receptor A (PR-A) , and erbB3 proteins were significantly up-regulated at 50 days of age. Conclusions: The data presented here provide the first evidence that maternal exposure to BPA during lactation increases mammary carcinogenesis in a DMBA-induced model of rodent mammary cancer. Changes in PR-A, SRC 1–3, erbB3, and Akt activity are consistent with increased cell proliferation and decreased apoptosis playing a role in mammary cancer susceptibility. These alterations provide an explanation of enhanced mammary carcinogenesis after lactational BPA exposure. Key words: apoptosis, bisphenol A, mammary cancer, proliferation, steroid receptor coactivators. Environ Health Perspect 117:910–915 (2009) . doi:10.1289/ehp.11751 available via http://dx.doi.org/ [Online 7 January 2009]
Address correspondence to C. Lamartiniere, Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 1670 University Blvd., Volker Hall 124, Birmingham, AL 35294 USA. Telephone: (205) 934-7139. Fax: (205) 934-8240. E-mail: Coral@uab.edu Supplemental Material is available online at http://www.ehponline.org/members/2009/11751/suppl.pdf We thank J. Ritchie for tumor palpations and necropsies. This research was supported by grant 1U01 ES012771 from the National Institutes of Health (NIH) /National Institute of Environmental Health Sciences. S.J. is supported through a predoctoral fellowship from the NIH/National Cancer Institute Cancer Prevention and Control Training Program, University of Alabama at Birmingham (R25 CA47888) . The authors declare they have no competing financial interests. Received 2 June 2008 ; accepted 6 January 2009.
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