Neonatal Exposure to the Phytoestrogen Genistein Alters Ovarian Differentiation and Development

Abstract

Genistein, the primary phytoestrogen in soy, was investigated for potential adverse effects on the developing female reproductive system with particular focus on the ovary. Mice were treated with genistein at doses that span the range of human exposure including vegetarian mothers during pregnancy and lactation to infants on soy based infant formulas. Neonatal genistein exposure caused the formation of multi-oocyte follicles (MOFs) in the ovary. This effect is mediated by ERβ as mice lacking this receptor do not develop MOFs while mice lacking ERβ do. Further study of genistein's effects on the ovary revealed inhibition of neonatal oocyte nest breakdown; oocytes were still attached by intercellular bridges and the normal progression of apoptosis was attenuated. Mechanistic studies of MOF formation revealed alterations in cell adhesion molecules. In addition, genistein is not unique in its ability to cause ovarian disruption; other environmental estrogens caused MOFs as well as altered cell adhesion molecule expression. Further, these effects appear to be exacerbated by preferential binding to ERβ. Assessment of reproductive function showed that mice treated with genistein (0.5 and 5 mg/kg) showed signs of early reproductive senescence while mice treated with genistein (50 mg/kg) exhibited infertility characterized by fewer, smaller, implantation sites as well as reabsorptions; ovaries from these mice had no corpora lutea. Stimulation with exogenous gonadotropins restored ovulation, suggesting problems with the hypothalamic-gonadal axis. These data taken together demonstrate that neonatal exposure to genistein at environmentally relevant doses causes adverse effects on the developing reproductive system and in particular on the ovary.