Authors
Maffini MV, Rubin BS, Sonnenschein C, Soto AM.

Title
Endocrine disruptors and reproductive health: The case of bisphenol A

Source
Molecular and Cellular Endocrinology 2006, 25:179-186

Summary
In recent years, scientific reports have emphasized the potential role of environmental pollutants in increasing the incidence of breast, prostate and testicular cancer, diminishing male reproductive capacity and compromising the neural development of infants and children. Recent experimental data has demonstrated that exposure to bisphenol A (BPA) may exert adverse health effects. However, despite extensive experimental data, there has been controversy regarding the low dose effects of BPA on human reproductive health. The objective of this paper was to review the most recent reports published on the effects of BPA on the male and female reproductive system and the mammary gland with a particular focus on low dose effects that might be relevant to actual human exposure.

After a short overview of the controversy surrounding the hypothesis of “low dose effects” in general, and particularly in relation to BPA, a review of the widespread exposure to BPA caused by ubiquitous use of compound is presented showing that permanent adverse effects in human offspring might be induced by low doses of the BPA present in mother’s blood, placenta, milk. The mechanism of action of low doses of BPA on morphological structure and physiological function of male and female genital tracts, the reproductive system and mammary gland are then discussed and the relationships between the compound and later neoplastic development are highlighted.

The authors have focused attention on recent findings that demonstrated that fetal exposure to low doses of BPA induced a decrease in uterine weight associated with increased DNA synthesis within the endometrial glandular epithelium and an endometrial expression of both estrogen receptors (ERa) and progesterone receptors (PR). The authors suggest that the consequences of these changes may appear in the future as an alteration of the responsiveness of the uterus to endogenous hormones under different physiological or pathological conditions or the predisposition of the tissue to disease and carcinogenesis.

A number of other findings indicated that the development of the mouse mammary gland can also be affected by perinatal exposure to environmentally relevant doses of BPA. After fetal exposure to low doses of BPA, significant increase in the percentage of ducts, terminal ducts, number of alveolar buds and altered remodeling of terminal end buds, as well as altered response to estradion were observed at different times after exposure. Maffini et al. concluded that the observed BPA-induced changes may contribute to the likelihoods of neoplastic development in the mammary gland since the expansion of terminal end buds and terminal ducts have been associated with increased carcinogenesis in both rodents and humans.

Numerous studies have shown that animals exposed to low doses of BPA exhibited
significant weight gain in both female and male offspring, advanced sexual maturation, disruption of the regularity of the estrous cycle and an altered sexual differentiation process. An increase in body weight and altered estrous cycle patterns observed in the female offspring persisted after BPA administration ceased and occurred for a long time after the exposure had ended. While the underlying mechanisms are not fully understood, these findings might be explained by disturbances in gene development processes and/or an alteration in the hypothalamic-pituitary-gonadal axis in BPA exposed females. Recent published data revealed that a compound interaction with the brain specific regions responsible for sexual dimorphism during critical periods of sexual development might lead to disruption in sexual development and differentiation. During the discussion of these findings, it was stressed that the permanent alterations in estrous cyclicity in BPA exposed females might limit future reproductive fertility and overall reproductive success.

A number of development studies in male rodents have shown that prenatal exposure to low dose BPA increased ano-genital distance and prostatic size in the newborn male, caused malformation in the urethra, as well as decreased epididymal weight. Furthermore, in adulthood these animals exhibited decreased sperm quality and production and enlarged prostates. There is some evidence to suggest that these effects were mediated through increased expression of androgen receptor in the prostate stroma and BPA induced disruption of cell differentiation in the peritubular stroma. A recent study also revealed that BPA induced an overall increase in prostate duct volume due to an increase in the proliferation of basal epithelial cells. The authors postulated that the reported findings may impact on fertility, and may have led to changes in the age of male reproductive maturity, and to the onset of disease later in life.

In summary, Maffini et al. suggested that, according to new findings, low dose BPA exposure during the early stages of development have long-lasting differential effects on the mammary gland and a variety of reproductive parameters that could impact male and female reproductive health and contribute to the earlier onset or higher incidence of disease, altered sexual maturity, fertility and fecundity. Scientific evidence has associated low dose BPA exposure with increased risk of breast, prostate and testicular cancer. These findings support the controversial theory that exposure to low, environmentally relevant doses of BPA (and other contaminants that mimic sex hormones) during early stages of human development might contribute to negative effects in male and female reproductive health and human infertility.
This research paper has focused attention on an import point in endocrine disruption studies that humans are exposed to a variety of endocrine disruptors acting through many different pathways at different times during their development. This posed several research needs that must be addressed: 1)new scientific methods and tools can and should be developed to further scientific understanding of endocrine disruptor contributions to the process of deteriorating reproductive health in humans and wildlife; 2) a need for chemical and biochemical approaches aimed at a better understanding of the mechanism of action of xenoestrogens with regard to the low-dose effects; 3) examination of exposure should be provided at different developmental periods in order to reveal specific windows of vulnerability to specific endocrine disruptors and their mixtures. It is clear that the mechanisms by which exposure in utero to BPA elicits the deleterious effects observed in various studies remain to be determined.