Male Reproductive Health and Environmental Chemicals
Epidemiological observations in man, animal exposure studies and the effects of ecological disasters on the wildlife generated the hypothesis of a possible connection between the decline in human male reproductive health and the widespread use of environmental chemicals with unexpected hormonal -disrupting activities. The main objective of this multinational project was to investigate whether or not there is a problem with the male reproductive health, and to test the environmental hypothesis by a multidisciplinary approach employing epidemiological, clinical, toxicological and basic mechanistic studies. Over a limited period of 2 to 5 years, the consortium succeeded in setting up large systematic studies of semen quality and prevalence of genital malformations in several European countries, These studies are still ongoing but the preliminary data demonstrates that there are real differences in sperm counts between European countries, wit Denmark and Finland positioned as the two extremes. In addition, the differences in semen quality were confirmed by serum levels of inhibin-B, a newly developed biochemical marker for testicular function. Preliminary results from the study of newborns indicate that the prevalence of genital malformations may be markedly higher in Denmark than in Finland, thus implicating that the adverse trends in male reproduction are interrelated, influenced by factors acting during fetal life and associated with geographical location. Retrospective studies of semen quality in France and Finland also demonstrate regional differences and confirmed the birth-cohort effect, with decline in sperm counts concerning mainly men born after the late 1940s these results will serve as the basis for further studies seeking to establish likely casual factors. Parallel studies in animal models explored the in vivo effects of synthetic oestrogens on the male reproductive system. Among the observed endpoints, adverse changes in final testis size, sperm production and Sertoli cell number and function, including decreased secretion of inhihib-B, can most probably be applied to humans. Studies in vitro employing organotypic cultures and cell lines are still ongoing, but the first results have provided additional evidence on the pathways affected by selected chemicals. A systematic study of gene expression in an oestrogen-dependant cell line using differential display, detected a number of novel oestrogen regulated genes, some of which appear promising as bio-markers for both oestrogens and their antagonists. In addition, three practical and useful short-term assays for detecting oestrogenicity (fish vitellogenin assay, the E-screen in breast cancer cell line and a recombinant yeast assay wit the human oestrogen receptor) have been validated and optimized in a large inter-laboratory effort, providing data on sensitivity and reproducibility. One or more of these assays have been used to screen for new potential endocrine-disrupting chemicals, and several new compounds (e.g. parabens, benzophenones), to which there is significant human exposure, have been identified. The fish vitellogenin assay has proven extremely useful for detecting oestrogenic compounds in the aquatic environment. Importantly, studies of bioactivity of selected environmental chemicals reveled that they can have multiple hormonal activities, for example several oestrogens are also anti-androgenic.