Early Exposure to DES Causes Genetic Reprogramming Leading to Increases in Benign Uterine Tumors

Cheryl Lyn Walker, Ph.D.
University of Texas M.D. Anderson Cancer Center
R01ES008263 and P30ES007784

Background: Uterine fibroids are common benign tumors in the muscle tissues of the uterus. They occur in up to 77% of women, can cause severe menstrual bleeding and pelvic discomfort, and account for over 200,000 hysterectomies each year in the United States alone. Lesions causing symptoms range in size from 10 millimeters up to 20 centimeters. Data indicate that 25% of white women have problematic lesions. African-American women have a higher risk of developing fibroids and, in general, their clinical symptoms are worse. Previous research has suggested a link between environmental exposures and uterine fibroids.

Advance: Diethylstilbestrol (DES) is one such exposure. NIEHS funded scientists at the University of Texas M.D. Anderson Cancer Center were interested in why and how DES has this effect. To determine the actions of DES, they used rats with a genetic predisposition to developing uterine fibroids and exposed some of them to DES during their first week of life. The DES exposed animals had almost a 95% incidence of tumor formation while the unexposed animals that only had the genetic alteration had about a 50% incidence. There were more tumors in the DES exposed animals and the tumors were larger in size and more invasive. Additional probing enabled the researchers to determine that the difference is due to how the gene responded to the estrogen stimulation. DES did not cause a mutation in the gene, but it caused the gene to become ”reprogrammed” so that it responded differently to the natural estrogen stimulation later in life.

Implications: Results from these findings indicate that reprogramming of genes during the developmental period as a consequence of an early life exposure to an artificial estrogen can interact with a preexisting genetic condition to increase tumor formation and the severity of the disease. This study differs from traditional carcinogenicity studies that have shown that environmental exposures lead to genetic mutations that are part of multiple events leading to carcinogenesis. If additional research confirms these results, this study’s findings could have implications for other hormonally-mediated cancers such as those of the breast and prostate.

Citation: Cook JD, Davis BJ, Cai SL, Barrett JC, Conti CJ, Walker CL. Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8644-9.

Walker CL, Stewart EA. Uterine fibroids: the elephant in the room. Science. 2005 Jun 10;308(5728):1589-92. Review.