Prenatal and Postnatal Exposures to Bisphenol A Alter the Mammary Proteome and Predispose for Chemically-induced Mammary Cancer in Rats

Coral A. Lamartiniere1, 2 Angela Betancourt1, Sarah Jenkins1, Mark Carpenter3, Isam Eltoum4, James Mobley5, Jose Russo6 and Jun Wang1, 1Department of Pharmacology and Toxicology, University of Alabama at Birmingham (UAB); 2UAB Comprehensive Cancer Center; 3Department of Mathematics and Statistics, Auburn University; 4Department of Pathology, UAB; 5Department of Surgery, UAB; 6Breast Cancer Research Laboratory, Fox Chase Cancer Center, Philadelphia

Bisphenol A (BPA) is found as a polymer in food containers such as baby bottles, lining of food and soft drink cans, designer drinking bottles, office water cooler bottles, dental sealents, etc. It is even found in children’s toys. BPA has been measured in greater than 90% of urine of young girls. Our goal is to determine if early exposure to BPA can alter puberty and the ontogeny of mammary protein expression as the offspring matures and if it predisposes for mammary cancer development. Rats were exposed during pregnancy only or during lactation only to 0, 25 and 250 µg BPA/Kg BW orally.

Prenatal only and prepubertal only exposures to BPA did not alter vaginal opening (a marker of puberty). Mammary glands were investigated for protein expression using 2-D gel separation and mass spectrometry (MALDI-TOF-TOF) identification. In offspring of rats exposed prenatally to BPA, 23, 21 and 16 proteins were identified as differentially regulated at 21, 50 and100 days, respectively. Included in these are 14-3-3 proteins and SPARC (secreted protein acidic and rich in cysteine), proteins that are associated with cell signaling, and mammary and cancer development.

In mammary glands of 50 day old rats, but not in 21 day old rats, exposed prepubertally to BPA, we found increased rate of cell proliferation and decreased apoptosis. Using western blot analysis, steroid receptor co-activators 1-3, Akt, phospho-Akt, progesterone receptor A, and erbB3 proteins were determined to be significantly up-regulated at 50 days. In adult rats exposed prepubertally to BPA and then to the carcinogen, dimethylbenzanthracene, we found a dose dependent increase in tumor multiplicity and decreased latency compared to controls.

We conclude that at very low doses, prenatal and postnatal BPA exposures do not significantly alter puberty in rats, but do alter key protein expressions in the mammary of developing rats. Furthermore, we demonstrate that, at a minimum, prepubertal BPA exposure predisposes for increased susceptibility to chemically-induced mammary cancer in rats. If these effects found in rodents carry over to humans, even small, seemingly harmless exposures of BPA early in life could play a role in increased breast cancer susceptibility later in life.

(Supported by NCI/NIEHS Grant UO1 ES012771).