Dioxins are widespread by-products of many industrial processes. Exposure to these environmental contaminants can cause cancer and infertility. In particular, dioxins are known to either promote or antagonize the effects of estrogens—steroid hormones that regulate the function of reproductive tissues and other organs—although the molecular details of these estrogen-related actions remain unclear. In the May 29 Nature, Fumiaki Ohtake and colleagues at the University of Tokyo describe how dioxins alter cellular responses to estrogens in cultured cells and mice (Nature, 423:545-550, May 29, 2003).

Ohtake et al. first looked at dioxin estrogen-related action in cultured breast and uterine cancer cells. Estrogens act by binding to specific receptors present in the cell nucleus: ER-α and ER-β, The activated receptors in turn dock to control regions of target genes and trigger their transcription, initiating a cascade of molecular and cellular events.

Dioxins and related pollutants normally bind to another class of nuclear receptor, of which the aryl hydrocarbon receptor (AhR) is an example. When AhR is activated by dioxin, it recruits a chaperone protein, the aryl hydrocarbon nuclear translocator (Arnt), and this complex can induce the expression of genes involved in the detoxification of xenobiotic compounds.

Ohtake and colleagues found that when estrogen is absent the dioxin-activated AhR–Arnt complex can associate directly with estrogen receptors, leading to activation of transcription and estrogenic effects. The same estrogenic actions of dioxins were observed when researchers injected the toxins in ovariectomized mice, which lack circulating estrogens, but were absent in ovariectomized mice which also lacked the gene encoding either AhR or ER-α. The AhR–Arnt complex was also found to repress the estrogen receptor function when estrogens are present and bound to the receptors, thus providing an explanation for previous reports of anti-estrogenic activities of dioxins.

In an accompanying News and Views article, Jan Brosens and Malcolm Parker of Imperial College London note "From a molecular viewpoint, this study reveals another way in which a member of the steroid-receptor family can be activated in the absence of its ligand. Other such mechanisms have been described." Both the estrogen receptors and AhR appeared on the evolutionary scene well before industrial pollution, note the authors, and their interaction under natural conditions "may be important during development and perhaps in adult life."