Of the antiandrogenic EDCs, the cellular and molecular mechanisms of action of the fungicide vinclozolin is one of the most thoroughly characterized (see elsewhere in this volume).Vinclozolin metabolites, M1,and M2 but not vinclozolin itself, competitively inhibit the binding of androgens to the mammalian AR. M1 and M2 also inhibit DHT-induced transcriptional activity in cells transfected with the human AR. More recently, Kelce et al.  demonstrated that vinclo-zolin treatment altered gene expression in vivo in an antiandrogenic manner. In contrast to their ability to bind to the AR, neither vinclozolin nor its antiandro-genic metabolites display affinity for the ER, although they do have weak affinity for the progesterone receptor. Vinclozolin, M1, and M2 do not inhibit 5 «-reductase activity in vitro, the enzyme required for the conversion of testosterone to the more active androgen DHT. Androgen-induced gene expression is a multistep process. Agonist-bound AR undergoes conformational changes, loses heat-shock proteins, forms homodimers, is imported from a perinuclear region into the nucleus, and binds androgen response elements on regulatory sequences on the DNA "upstream" from androgen-responsive genes, activating mRNA synthesis. Binding of antagonists to AR results in conformations that differ from that obtained with the natural ligands such that AR-DNA binding and gene expression are blocked. In addition, vinclozolin inhibits growth of androgen-dependent tissues in the castrate-immature-testosterone treated and pubertal male rat. In the intact pubertal and adult male rat, vinclozolin treatment also alters hypothala-mic-pituitary-gonadal function. Oral treatment with vinclozolin causes elevations of serum LH and testosterone. In contrast to vinclozolin, treatment with some other antiandrogens like p,p'-DDE  and methoxychlor [107,108] fail to induce any significant change in serum LH or testosterone levels.
Was this article helpful?