Phytoestrogens modulate prostaglandin production in bovine endometrium: Cell type specificity and intracellular mechanisms

Prostaglandins (PGs) are known to modulate the proper cyclicity of bovine reproductive organs. The main luteolytic agent in ruminants is PGF _2α, whereas PGE₂ has luteotropic actions. Estradiol 17β (E₂) regulates uterus function by influencing PG synthesis. Phytoestrogens structurally resemble E₂ and possess estrogenic activity; therefore, they may mimic the effects of E₂ on PG synthesis and influence the reproductive system. Using a cell-culture system of bovine epithelial and stromal cells, we determined cell-specific effects of phytoestrogens (i.e., daidzein, genistein), their metabolites (i.e., equol and para-ethyl-phenol, respectively), and E₂ on PGF_2α and PGE₂ synthesis and examined the intracellular mechanisms of their actions. Both PGs produced by stromal and epithelial cells were significantly stimulated by phytoestrogens and their metabolites. However, PGF _2α synthesis by both kinds of cells was greater stimulated than PGE₂ synthesis. Moreover, epithelial cells treated with phytoestrogens synthesized more PGF_2α than stromal cells, increasing the PGF_2α to PGE₂ ratio. The epithelial and stromal cells were preincubated with an estrogen-receptor (ER) antagonist (i.e., ICI), a translation inhibitor (i.e., actinomycin D), a protein kinase A inhibitor (i.e., staurosporin), and a phospholipase C inhibitor (i.e., U73122) for 0.5 hrs and then stimulated with equol, para-ethyl-phenol, or E₂. Although the action of E₂ on PGF_2α synthesis was blocked by all reagents, the stimulatory effect of phytoestrogens was blocked only by ICI and actinomycin D in both cell types. Moreover, in contrast to E₂ action, phytoestrogens did not cause intracellular calcium mobilization in either epithelial or stromal cells. Phytoestrogens stimulate both PGF_2α and PGE₂ in both cell types of bovine endometrium via an ER-dependent genomic pathway. However, because phytoestrogens preferentially stimulated PGF_2α synthesis in epithelial cells of bovine endometrium, they may disrupt uterus function by altering the PGF _2α to PGE₂ ratio.