Disruption of the developing female reproductive system by phytoestrogens: Genistein as an example

Abstract

Studies in our laboratory have shown that exposure to genistein causes deleterious effects on the developing female reproductive system. Mice treated neonatally on days 1-5 by subcutaneous injection of genistein (0.5-50 mg/kg) exhibited altered ovarian differentiation leading to multioocyte follicles (MOFs) at 2 months of age. Ovarian function and estrous cyclicity were also disrupted by neonatal exposure to genistein with increasing severity observed over time. Reduced fertility was observed in mice treated with genistein (0.5, 5, or 25 mg/kg) and infertility was observed at 50 mg/kg. Mammary gland and behavioral endpoints were also affected by neonatal genistein treatment. Further, transgenerational effects were observed; female offspring obtained from breeding genistein treated females (25 mg/kg) to control males had increased MOFs. Thus, neonatal treatment with genistein at environmentally relevant doses caused adverse consequences on female development which is manifested in adulthood. Whether adverse effects occur in human infants exposed to soy-based products such as soy infant formulas is unknown but the neonatal murine model may help address some of the current uncertainties since we have shown that many effects obtained from feeding genistin, the glycosolated form of genistein found in soy formula, are similar to those obtained from injecting genistein.

Dietary genistein stimulates mammary hyperplasia in gilts

“…Current findings showed a decrease in BW at puberty onset and a tendency for an increase in duration of first estrus in gilts fed the diet without soya compared with gilts fed the commercial soya diet, but there was no effect of added genistein. This is contrary to our expectation because mice treated neonatally with genistein generally show an increased length of the estrous cycle (review by Jefferson et al, 2007) and accelerated onset of puberty (Lewis et al, 2003). This discrepancy between our results and those reported in mice could be due to the difference in age at treatment (i.e.…”

“…It is well documented that neonatal exposure of mice to genistein disrupts ovarian function during adulthood and reduces fertility (review by Jefferson et al, 2007). To the best of our knowledge, only two studies looked at the effects of phytoestrogens on reproduction in swine.…”

“…Indeed, advanced mammary gland development and differentiation were observed with exposure to genistein, moreover, the dose and timing of exposure has an impact on these effects (review by Jefferson et al, 2007). Mice injected s.c. with lower doses of genistein (0.5 and 5 mg/kg) showed advanced mammary gland morphogenesis at puberty, whereas stunted mammary development was observed at the highest dose (50 mg/kg; Padilla-Banks et al, 2006).…”

“…In rodents, it was shown that neonatal exposure to genistein stimulates mammary development and differentiation (review by Jefferson et al, 2007) and there is one report in swine suggesting that postpubertal exposure to genistein also enhances mammogenesis (Ford, 2003). Because of its structural similarity to estradiol-17b, many of the actions of genistein are mediated through estradiol receptors alpha (ERa) and ER beta (ERb; Nilsson et al, 2001).…”

The ovary: basic biology and clinical implications

“…This effect of estrogen underscores the need for further research on the effect of endocrine disruptors - environmental and dietary compounds that act like hormones - in reproductive diseases. Along these lines, increasing evidence from rodent studies indicates that neonatal exposure to genistein, the phytoestrogen found in soy, disrupts normal reproduction (30)(31)(32)(33)(34)(35)(36). The effects of phytoestrogens and other estrogen-like compounds on the reproductive tract, fertility, and reproductive cancers are not well understood.…”