Developmental programming by xenoestrogens

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Xenoestrogens (XE) are chemicals in the environment that mimic the body's natural steroidal estrogens. Developmental exposure to XE may interfere with normal hormonal signaling and result in altered disease susceptibility in adulthood. I used mouse models to examine the effects on three disease endpoints of developmental exposure to three relevant XE: bisphenol A, a ubiquitous chemical found in many food packaging and plastic products; ethinyl estradiol, the primary component of most oral contraceptive pills; and diethylstilbestrol, a former pharmaceutical that has been linked to increased cancer incidence in women exposed in utero. Endometriosis is an estrogen-dependent, benign gynecological disease. First, using a model of surgically-induced endometriosis, I demonstrated that the altered gene expression profile in mice closely mirrors what is observed in women with the disease. I then used this model to explore the effects of developmental XE exposure on endometriosis. Developmental XE exposure was found to alter the expression of immunomodulatory genes. Second, I examined the effects of developmental XE exposure on adult femoral shape and strength. I found that developmental XE exposure increased femoral length and decreased femoral strength, causing bones to fracture more easily. Third, I found that developmental XE exposure increased mammary gland density and tended to increase intraductal hyperplasia. Importantly these effects were seen within the range of current human exposure. Overall my research demonstrates that developmental programming by XE is linked to increased disease susceptibility in adulthood; exposure to low-environmentally relevant levels of XE may increase the risk of endometriosis, bone fractures, and breast cancer.