Endocrine disruptors and falling sperm counts: lessons learned or not!

BACKGROUND My research program in the 1970–1990 period was primarily focused on the chemistry, toxicology and mechanisms of action of highly persistent organochlorine environmental contaminants including the polychlorinated biphenyls (PCBs), dibenzofurans and dibenzop-dioxins (Figure 1). Since environmental samples and human residues of these organohalogen compounds (OCs) (or persistent organic pollutants) are complex mixtures of PCB, polychlorinated dibenzofuran and polychlorinated dibenzo-p-dioxin isomers and congeners, my laboratory initially focused on structure–activity and quantitative structure– activity relationships among these compounds. 2,3,7,8-tetrachlorodibenzo-p-dioxin was identified as the most toxic OC, and Poland and co-workers initially hypothesized and demonstrated that 2,3,7,8tetrachlorodibenzo-p-dioxin and related compounds induce their toxic responses through activation of the aryl hydrocarbon receptor (AHR). Our quantitative structure–activity relationship studies contributed to development of the toxic equivalence factor approach for hazard assessment of OC mixtures which has been adopted by the World Health Organization and regulatory agencies worldwide to regulate and decrease emissions of OCs from multiple sources. In the early 1990s, we began to investigate the molecular biology and toxicology of AHR-mediated inhibition of estrogen receptor (ER) signalling and the complex mechanisms of inhibitory AHR– ER cross-talk were determined. These studies were an example of antiestrogenic endocrine disruption by AHR agonists.