Our paper concerned the adverse effects on development of the prostate and urethra in male mouse fetuses as a result of fetal exposure to drugs and chemicals in the environment that are potent estrogens.

We fed pregnant mice a chemical, bisphenol A (BPA), at a dose 5 times lower than the dose that the US-EPA currently states is a safe daily intake amount for humans (called the reference dose). According to findings from the Centers for Disease Control and Prevention and other research, the amount of BPA in 95% of people in the USA exceeds the amount of BPA that would result from the dose we administered in this study.

We also fed pregnant mice a dose of the estrogenic drug used in birth control pills, ethinylestradiol, and our dose was approximately 5-times below the dose in birth control pills. Approximately two million women using birth control pills are estimated to become pregnant each year in the USA and Europe, and these women continue taking the pills until they finally realize that they are pregnant. Human fetuses are thus commonly exposed to this drug at doses higher than those we used in this study.

We found that the estrogenic drug ethinylestradiol and the chemical used to make polycarbonate plastic, BPA, caused an identical malformation of the urethra at the bladder-urethra junction (a marked constriction), suggesting that fetal exposure to these chemicals could result in bladder outlet obstruction disease.

We also showed that the chemicals stimulated an increase in prostate size due to stimulation of a type of cell—the basal epithelial cell—which is implicated in the development of prostate cancer later in life.

The method used in this study was developed by Dr. Barry Timms, Professor of Biomedical Sciences at the University of South Dakota School of Medicine, who was the first author of the published article.

This technique involves removing the fetal prostate and urethra, sectioning the tissue, and then scanning each section into a computer while providing a unique code for each region being examined. The computer program then reconstructs the organ, and we can conduct analyses of the size and shape of the different structures.

Subsequently, we also conduct histochemical analysis on the sections to determine which types of cells and which genes and proteins in the cells are being altered. This is an extremely powerful approach, since you can actually see the changes in fetal cells and organs at the molecular through the entire organ level.

The chemical BPA was found to be able to be linked together to create polycarbonate plastic and the resin lining of metal cans in the early 1950s. However, BPA was shown to be an estrogen-mimicking endocrine-disrupting chemical many years prior to the discovery that it could be used to make plastic.

BPA was first considered for use as an estrogenic drug by Sir Charles Edward Dodds in the 1930s, prior to his synthesis of the drug diethylstilbestrol (DES), which is structurally and functionally similar to BPA. This is important because DES is a known human carcinogen and, in addition to causing cancer, DES caused reproductive system abnormalities in millions of people whose mothers were administered this drug during pregnancy (due to the mistaken assumption that it would prevent miscarriage; this use was banned in 1972).

We used the drug DES as our "positive control" estrogen, since there is a large published literature describing the virtually identical harm it causes in mice and humans due to exposure during fetal life. The fact that BPA and DES, as well as ethinylestradiol, all caused the same abnormalities in prostate and urethra development thus should not be surprising, but now that this has been clearly demonstrated, the level of concern about exposure of human fetuses to BPA and ethinylestradiol has increased.

Dr. Timms and I met a number of years ago and began collaborating due to our mutual interest in examining the potential for the disrupting effects of estrogenic chemicals and drugs on development of the prostate, as well as the rest of the male reproductive and urogenital system.

Bisphenol A is now produced in excess of 6 billion pounds per year and is one of the highest volume chemicals in worldwide production. The chemical bond linking BPA molecules in polycarbonate plastic and resins is unstable, particularly when exposed to heat. The amount of leaching of BPA into the environment from numerous common household products and into food and beverages from containers (that are typically described as microwave safe) is great enough to lead to significant levels of exposure of virtually everyone in the world who has been examined, including high levels in pregnant women and fetuses.

Over the past few years a wide range of adverse effects in laboratory animals due to exposure to BPA has been reported in peer-reviewed published studies conducted by scientists not associated with chemical corporations. In response, chemical corporations have engaged in a strategy referred to as "manufactured uncertainty," originally developed by the tobacco industry, and 100% of chemical industry-funded studies report that BPA causes no adverse effects.

The approach by corporations of producing "science" that always shows your product to be safe has been successful in blocking attempts to restrict the uses of BPA by governments and regulatory agencies. Exposure of fetuses and babies to BPA is of special concern, since developmental abnormalities are permanent.

Regarding birth control pills, millions of women taking birth control pills are not diligent about taking the pills regularly, and thus become pregnant (taken regularly, the pills are effective in most women). Physicians are not adequately warning women about the need to be diligent with regard to taking birth control pills, due to the potential dangers associated with fetal exposure to estrogenic drugs, even though the harm to human fetuses due to exposure to DES is well known.

Because women taking birth control pills do not expect to become pregnant, they often continue taking the pills for an extended period of time. Our findings in mice reveal a significant adverse consequence for male mouse fetuses of exposure to a very low dose of the estrogenic drug in birth control pills. The fact that DES caused the same harm in mouse and human fetuses, and our finding that ethinylestradiol and DES (as well as BPA) caused the same effects in mice, suggests that there should be a greater level of concern with exposure of human fetuses to the chemicals in birth control pills and plastic.

Frederick S. vom Saal, Ph.D.
Professor of Biology
Division of Biological Sciences
University of Missouri-Columbia
Columbia, Missouri, USA
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