Good Estrogen Bad Estrogen

Estrogen is a term used for a variety of natural and synthetic hormones that influence the growth and function of many tissues, particularly those of the male and female reproductive systems. Estrogen plays a role in several cancers, especially breast and endometrial cancers and possibly prostate and colon cancers. The human diet contains estrogenic compounds that can bind to estrogen receptors in the body, and much research has focused on whether dietary estrogens can influence the development of cancer. Phytoestrogens—estrogen-like compounds produced by plants—have received attention owing to epidemiologic and experimental evidence that they prevent cancer, guard against bone loss, and reduce menopausal symptoms. Mycoestrogens (mold-produced estrogens) have have deleterious effects on livestock health and reproduction. In this month’s issue, Georgi N. Nikov of Tulane University in New Orleans, Louisiana, and colleagues examine the activity of dietary estrogens in humans [EHP 108: 867–872]. They confirm that dietary estrogens have different affinities for human estrogen receptors. They also found that, once bound, each estrogen can also alter a receptor’s shape and size. When estrogen binds to a receptor, the resulting complex interacts with a site within a target gene’s regulatory region. That interaction may either promote or inhibit gene transcription. Alterations in the receptor’s shape may affect how well the estrogen receptor complex can initiate or inhibit gene transcription. Nikov and his colleagues focused on four phytoestrogens—genistein, coumestrol, daidzein, and glyceollin—and the mycoestrogen zearalenone. Genistein and daidzein are normal components of soybeans, which also produce glyceollin when subjected to certain stresses. Coumestrol is produced by clover, and zearalenone is generated by Fusarium molds, which infect grains. The team first measured the estrogens’ affinities for two estrogen receptors, ERα and ERβ, as compared to estradiol, the form of estrogen normally found in the body. But knowing that an estrogen binds to a receptor is only half the story; what follows is perhaps even more important. Therefore, the researchers also investigated how receptor complexes interact with estrogen response element (ERE) sequences, regulatory sites that turn genes off or on. The researchers prepared dilutions of each estrogen and used fluorescence polarization, a relatively new approach, to study estrogen binding. This method employs fluorescent labeling of key molecules to reveal shifts in molecular size and shape; such alterations expose binding, dissociation, and conformational changes. Each estrogen’s ability to displace fluorescently labeled estradiol from ERα and ERβ was determined. This information revealed the affinity with which the plant estrogens bind to the receptors; it also permitted calculation of how much of each is needed to saturate a known amount of receptors. Following these affinity calculations, the team investigated the interactions of receptor complexes with ERE sequences. To this end, Nikov and his team conducted parallel experiments using two types of fluorescently labeled ERE sequences, one from the Xenopus vitellogenin (vit) A2 gene, the other from the human pS2 gene. The researchers found that, except for glyceollin, all of the tested estrogens had a greater affinity for ERβ than ERα; glyceollin had the opposite preference. However, the glyceollin–receptor complexes, unlike the other complexes, did not interact with either ERE sequence. The interactions that did occur varied according to the specific estrogen and which receptor and ERE sequence were involved; however, none were stronger than those involving estradiol. The researchers concluded that just knowing the affinity of the estrogen for the receptor is not enough. Equally important is the way the estrogen–receptor complexes interact with ERE sequences. These interactions may in turn affect transcription of target genes and thus affect the myriad functions of estrogen in the body. –Julia R. Barrett