Reproductive consequences of developmental phytoestrogen exposure

Abstract

Phytoestrogens, estrogenic compounds derived from plants, are ubiquitous in human and animal diets. These chemicals are generally much less potent than estradiol but act via similar mechanisms. The most common source of phytoestrogen exposure to humans is soybean-derived foods that are rich in the isoflavones genistein and daidzein. These isoflavones are also found at relatively high levels in soy-based infant formulas. Phytoestrogens have been promoted as healthy alternatives to synthetic estrogens and are found in many dietary supplements. The aim of this review is to examine the evidence that phytoestrogen exposure, particularly in the developmentally sensitive periods of life, has consequences for future reproductive health.

Figure 1. Maturation index of vaginal wall cells over time in infants fed breast milk, cow-based formula, or soy-based formula

Maturation index is expressed as the percent of superficial cells plus half of the percent of intermediate cells on a Papanicolau smear of vaginal introitus cells from female infants. Curves extrapolated from data obtained from 11 or 12 infants per group. Dotted line segments connect observations from multiple visits by the same child at different ages. Figure adapted with permission from Environ Health Perspect (Bernbaum et al. 2008).

Figure 2. Serum circulating levels of genistein following neonatal exposure by different routes

Data plotted are mean serum genistein levels at the indicated times after dosing. Blue lines, oral genistin 37.5 mg/kg in corn oil, data from Jefferson et al. 2009a; Red lines, subcutaneous (SQ) genistein 50 mg/kg in corn oil, data from Doerge et al. 2002; Green lines, oral genistein 50 mg/kg in soy formula/corn oil mixture, data from Cimafranca et al. 2010. Total serum genistein shown in solid lines; aglycone fraction shown in dotted lines. Single orange points on right side of graph are the 25^th, 50^th, 75^th percentiles and highest level of total serum genistein in human infants on soy formula at random time points after feeding, data from Cao et al. 2009.

Figure 3. Representative confocal images depicting the plexus of kisspeptin (Kiss) neuronal fibers surrounding GnRH neurons in the anterior hypothalamus

The density of Kiss projections is reduced by approximately half in postnatal day 28 female rats following neonatal exposure for 4 days to 10 mg/kg body weight genistein as described previously (Losa et al. 2011). A, Control; B, Genistein-treated.

Figure 4. Schematic representation of posteriorization of the female reproductive tract after neonatal genistein exposure

Upper panels: Neonatal genistein exposure alters expression of Hoxa genes along anterior-posterior axis of the postnatal day 5 uterus. In addition, hedgehog family secreted signaling factors and other transcription factors normally expressed in the cervix and vagina are abnormally expressed in the oviduct after 5 days of genistein treatment. Lower panels: Alterations in expression of Hoxa genes and other transcription factors persist in the adult female reproductive tract following neonatal genistein exposure. Hoxa gene expression depicted on right side of each schematic; line thickness and font size indicate relative expression levels. Expression of other genes indicated in boxes to left of each schematic; font size and direction of red arrows indicate relative expression levels compared to controls. Ovid, oviduct; Ut, uterus; Cx, cervix; Vg, vagina. Information presented is from Jefferson et al. 2011.

Figure 5. Embryo loss during transit through the oviduct in adult mice treated neonatally with genistein

Embryos were flushed from the oviduct and uterus of control (white bars) and neonatal genistein-treated (black bars) superovulated mice at the indicated times after human chorionic gonadotropin (hCG) administration and mating. Graph shows mean number ± SEM of embryos per mouse. Asterisks, p<0.05 compared to control at same time point. Schematic above graph indicates expected embryo stage and location within the female reproductive tract at the different time points. Modified from Jefferson et al. 2009b.