Zearalenones: Characterization of the estrogenic potencies and receptor interactions of a series of fungal β-resorcylic acid lactones

This study investigates the direct estrogen receptor interactions and the character of the biological activities of three estrogenic resorcylic acid lactones in the immature rat uterus. These compounds are fungal metabolites (P-1492; zearalenone) or derivatives thereof (P-1496 and P-1560; epimeric zearalanols) that have been associated with estrogenizing syndromes in cattle fed mold-infected grain. The compounds compete with estradiol for binding to the cytoplasmic receptor (P- 1496, 13.6%; P-1492, 1.8%; P-1560, 0.8% that of estradiol), and they translocate estrogen receptor sites to the nucleus, with P- 1496 showing the most prolonged nuclear receptor interaction. The three compounds induce the synthesis of the uterine induced protein (P-1496 > P-1560 > P-1492) and increase uterine weight. Direct binding studies with the most potent compound P-1496, in tritium-labeled form indicates a K_d of 1.8 nM (compared to 0.12 nM for estradiol) for interaction with uterine cytoplasmic receptor. Cytoplasmic receptor complexes with [³H]P-1496 sediment at 8S on low salt sucrose density gradients, as do [ HJestradiol receptor complexes. After uterine uptake of [³H]P-1496, salt-extracted nuclear receptor complexes sediment at 5.4S on 0.4 M KC1 sucrose density gradients, as do the nuclear [³H]estradiol receptor complexes. These studies document that despite the unique chemical nature of these resorcylic acid lactones, they interact directly with the estrogen receptor and evoke many of the same biological and biochemical responses that are evoked by the natural estrogen estradiol.