Bisphenol A (BPA) Exposure In Utero Leads to Immunoregulatory Cytokine Dysregulation in the Mouse Mammary Gland: A Potential Mechanism Programming Breast Cancer Risk
- 774 Downloads
Bisphenol-A (BPA) is a ubiquitous estrogen-like endocrine disrupting compound (EDC). BPA exposure in utero has been linked to breast cancer and abnormal mammary gland development in mice. The recent rise in incidence of human breast cancer and decreased age of first detection suggests a possible environmental etiology. We hypothesized that developmental programming of carcinogenesis may involve an aberrant immune response. Both innate and adaptive immunity play a role in tumor suppression through cytolytic CD8, NK, and Th1 T-cells. We hypothesized that BPA exposure in utero would lead to dysregulation of both innate and adaptive immunity in the mammary gland. CD1 mice were exposed to BPA in utero during gestation (days 9–21) via osmotic minipump. At 6 weeks, the female offspring were ovariectomized and estradiol was given at 8 weeks. RNA and protein were extracted from the posterior mammary glands, and the mRNA and protein levels were measured by PCR array, qRT-PCR, and western blot. In mouse mammary tissue, BPA exposure in utero significantly decreased the expression of members of the chemokine CXC family (Cxcl2, Cxcl4, Cxcl14, and Ccl20), interleukin 1 (Il1) gene family (Il1β and Il1rn), interleukin 2 gene family (Il7 receptor), and interferon gene family (interferon regulatory factor 9 (Irf9), as well as immune response gene 1 (Irg1). Additionally, BPA exposure in utero decreased Esr1 receptor gene expression and increased Esr2 receptor gene expression. In utero exposure of BPA resulted in significant changes to inflammatory modulators within mammary tissue. We suggest that dysregulation of inflammatory cytokines, both pro-inflammatory and anti-inflammatory, leads to a microenvironment that may promote disordered cell growth through inhibition of the immune response that targets cancer cells.
KeywordsMammary Gland Breast Cancer Risk Mammary Tissue Interferon Regulatory Factor Estradiol Treatment
Compliance with Ethical Standards
Human and Animal Rights and Informed Consent
All animal experiments were conducted in accordance with the Yale University Animal Care Committee Guidelines.
This work was supported by NIH Grant RO1 HD076422.
Conflict of Interest
The authors declare that they have no conflicts of interests.
- 9.Gerona RR, Woodruff TJ, Dickenson CA, Pan J, Schwartz JM, Sen S, Friesen MW, Fujimoto VY, Hunt PA (2013) Bisphenol-A (BPA), BPA glucuronide, and BPA sulfate in mid gestation umbilical cord serum in a northern and central California population. Environ Sci Technol 47:12477–12485CrossRefPubMedGoogle Scholar
- 13.Horstman KA, Naciff JM, Overmann GJ, Foertsch LM, Richardson BD, Daston GP (2012) Effects of transplacental 17-alpha-ethynyl estradiol or bisphenol A on the developmental profile of steroidogenic acute regulatory protein in the rat testis. Birth Defects Res B Dev Reprod Toxicol 95:318–325CrossRefPubMedGoogle Scholar
- 26.Pupo M, Pisano A, Lappano R, Santolla MF, De Francesco EM, Abonante S, Rosano C, Maggiolini M (2012) Bisphenol A induces gene expression changes and proliferative effects through GPER in breast cancer cells and cancer-associated fibroblasts. Environ Health Perspect 120:1177–1182CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Lamartiniere CA, Jenkins S, Betancourt AM, Wang J, Russo J (2011) Exposure to the endocrine disruptor Bisphenol A alters susceptibility for mammary cancer. Horm Mol Biol Clin Invest 5:45–52Google Scholar
- 39.Barr A, Manning D (1999) G Proteins Techniques of Analysis, Manning DR, ed. Boca Raton, FL: CRC Press, Inc. 227–245. 48. Mi H, Dong Q, Muruganujan A, Gaudet P, Lewis S, Thomas PDGoogle Scholar
- 47.Shurin GV, Ferris R, Tourkova IL, Perez L, Lokshin A, Balkir L, Collins B, Chatta GS, Shurin MR (2005) Loss of new chemokine CXCL14 in tumor tissue is associated with low infiltration by dendritic cells (DC), while restoration of human CXCL14 expression in tumor cells causes attraction of DC both in vitro and in vivo. J Immun 174:5490–5498CrossRefPubMedGoogle Scholar
- 70.Doherty LF, Bromer JG, Zhou Y, Aldad TS, Taylor HS (2010) In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer. Horm Cancer 1:146–155CrossRefPubMedPubMedCentralGoogle Scholar
- 75.Block K, Kardana A, Igarashi P, Taylor HS (2000) In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing müllerian system. FASEB J 200014:1101–1108Google Scholar