Endocrine Disruption

This topic was developed beginning in the late 1980s as a consequence of the accidental finding in our laboratory that plasticware used in routine experimental procedures leached estrogenic chemicals. This initial finding plus the research program they generated had numerous ramifications, from the very emergence of the concept of ENDOCRINE DISRUPTION and a field of research devoted to it, to legislation banning the use of BPA in baby bottles.

This research is designed to identify possible links between the increasing incidence in humans of diseases and conditions like reproductive impairment, cancer, obesity, diabetes and altered behaviors and environmental estrogens. To achieve these ends, we used three approaches, namely:

a) The identification of estrogenic xenobiotics by assessing their ability to induce proliferation of breast cancer cells and of androgenic xenobiotics by assessing their ability to inhibit proliferation of MCF7-AR1 cells, a stable androgen receptor transfectant developed by us. So far, we have identified novel environmental estrogens that may have a causal role in the reproductive health effects mentioned above: among them, i) nonyl phenol, a widely used antioxidant and detergent, ii) plasticizers such as dibutylphthalate and benzylbutylphthalate and iii) pesticides such as dieldrin, toxaphene and endosulfan. The bioassay we developed for the identification of estrogens (E-SCREEN assay) is now used worldwide for screening xenobiotics.

b) The development of novel technology to measure the total environmental estrogen burden in tissues and/or body fluids from wildlife and humans. These methods are being used to assess the hypothesis that xenoestrogen exposure increases the risk of breast cancer.

c) Developmental origins of adult disease: We have shown that in utero exposure to minute, environmentally relevant quantities of xenoestrogens irreversibly alters the development of the female genital tract and the mammary gland, induces obesity and alters sex dimorphic behaviors and brain structures. These effects comprise several levels of organization, from molecular events such as extemporaneous gene expression, altered DNA methylation patterns, the histoarchiecture of organs and their functions. Our findings indicate that environmentally relevant levels of BPA affect the regulation of the estrous cycle probably at the central level (hypothalamic-hypophyseal-gonadal axis), induce early cessation of ovarian cycles, alter the development and histoarchitecture of the mammary gland, and induce preneoplastic and neoplastic lesions in the mammary gland. We are currently exploring the processes that may explain these effects, which include biochemical (altered gene expression, altered DNA methylation) and biophysical components (altered collagen fiber organization, altered biophysical properties of the extracellular matrix).

BPA rat mammary gland ductal hyperplasia ductal carcinoma in situ
PND50 rat mammary glands show ductal hyperplasia (DH) and ductal carcinoma in situ (DCIS) on perinatal exposure to BPA (Murray et al 2007 (top); Acevedo et al 2013 (bottom))

Multi-stage effects of BPA on mammary gland development soto sonnenschein

Recommended Readings –¬†

Soto et al. 1995. The E-SCREEN assay as a tool to identify estrogen: an update on estrogenic environmental pollutants. Environ Health Perspect 103(7):113-22.