Environmental xenoestrogens, antiandrogens and disorders of male sexual differentiation

Over the past 20 years, the documented increase in the disorders of male se xual differentiation, such as hypospadias, cryptorchidism, and micropenis, has led to the suspicion that environmental chemicals are detrimental to no rmal male genital development in utero. Male sexual differentiation is crit ically dependent on the normal action of androgens, and unbalanced androgen /estrogen ratios can disturb it. Environmental xenoestrogens (such as herbi cides, pesticides, PCBs, plasticizers. and pp'DDE) that disturb endocrine b alance, cause demasculinizing effects in the male foetus. These environment al chemicals are often referred to as endocrine disrupters: they are though t to mimic endogenous estrogens by entering the cell, binding to the recept or and activating transcription, they may also antagonize normal androgen a ction. We have established numerous cell lines to assess the estrogenicity and antiandrogenicity of compounds found in the environment and to identify new products present in wastewater effluents that are able to disrupt endo crine functions. Several cell lines responding to estrogens have been obtai ned in our group, including cells with different enzymatic equipment and ce lls expressing chimeric receptor or natural estrogen receptors alpha and be ta. These cell lines have proved to be useful for assessing the biological activity of pesticides, fungicides, and chemicals found in plastic or disca rded in the environment. In order to generate a powerful tool for the inves tigation of androgen action and the rapid screening of potential antagonist s, we developed a new stable prostatic cell line. The PALM cell line is an original cellular model to characterize the response of hAR, and it provide s an easy and rapid bioluminescent test to identify new antagonists. We als o developed a model based on a fusion protein between the androgen receptor (AR) and the green fluorescent protein (GFP) to study the intracellular dy namics of AR. The GFP-AR model was applied to define the ability of several xenoestrogens and antiandrogens to inhibit the nuclear transfer of AR. The ubiquitous presence of endocrine disrupters in the environment and the inc reased incidence of neonatal genital malformation support the hypothesis th at disturbed male sexual differentiation may in some cases be caused by inc reased exposure to environmental xenoestrogens and/or antiandrogens. (C) 20 01 Elsevier Science Ireland Ltd. All rights reserved.