phytoestrogens and Hypospadias

Experimental data indicate that gestational exposures to estrogenic compounds impact risk of hypospadias. We examined whether risk of hypospadias (i.e., a congenital malformation in which the opening of the penile urethra occurs on the ventral side of the penis) was associated with maternal intake of phytoestrogens, given their potential impact on estrogen metabolism. The analysis included data on mothers of 1,250 hypospadias cases and 3,118 controls who delivered their infants from 1997 to 2005 and participated in the National Birth Defects Prevention Study, a multistate, population-based, case-control study. After adjustment for several covariates, high intakes of daidzein, genistein, glycetin, secoisolariciresinol, total isoflavones, total lignans, and total phytoestrogens were associated with reduced risks; odds ratios comparing intakes ≥90th percentile with intakes between the 11th and 89th percentiles ranged from 0.6 to 0.8. For example, the odds ratio for total phytoestrogen intake was 0.7 (95% confidence interval: 0.5, 1.0). This study represents the first large-scale analysis of phytoestrogen intake and hypospadias. The observed associations merit investigation in additional populations before firm conclusions can be reached.

Topics: Adult; Butylene Glycols; Case-Control Studies; Diet, Vegetarian; Female; Genistein; Humans; Hypospadias; Infant, Newborn; Isoflavones; Lignans; Male; Odds Ratio; Phytoestrogens; Pregnancy; Prenatal Exposure Delayed Effects; Risk Assessment; Risk Factors; Surveys and Questionnaires

Topics: Animals; Animals, Newborn; Endocrine Disruptors; Female; Genistein; Hypospadias; Male; Maternal Exposure; Mice; Phytoestrogens; Pregnancy; Prenatal Exposure Delayed Effects; Urethra; Vulva

Topics: Animals; Diet; Female; Fetus; Genistein; Humans; Hypospadias; Male; Mitogen-Activated Protein Kinase Kinases; Phytoestrogens; Pregnancy; Prenatal Exposure Delayed Effects; Soybean Proteins; Urethra

The increasing incidence of hypospadias is partly attributed to increased gestational exposure to endocrine disruptors. We investigated the effects of genistein, the primary phytoestrogen in soy, on the molecular program of male urethral development.. Female mice were fed diets supplemented with genistein (500 mg/kg diet) or control diets before breeding and throughout gestation. Urethras from embryonic day 17.5 male fetuses were harvested, and RNA was prepared, amplified, labeled and hybridized on whole genome microarrays. Data were analyzed using packages from the R/Bioconductor project. Immunohistochemical analysis and immunoblotting were used to confirm the activity of MAPK and the presence of Ntrk1 and Ntrk2 during urethral development.. Gestational exposure to genistein altered the urethral expression of 277 genes (p <0.008). Among the most affected were hormonally regulated genes, including IGFBP-1, Kap and Rhox5. Differentially expressed genes were grouped into functional pathways of cell proliferation, adhesion, apoptosis and tube morphogenesis (p <0.0001), and were enriched for members of the MAPK (p <0.00001) and TGF-β (p <0.01) signaling cascades. Differentially expressed genes preferentially contained ELK1, Myc/Max, FOXO, HOX and ER control elements. The MAPK pathway was active, and its upstream genistein affected tyrosine kinase receptors Ntrk1 and Ntrk2 were present in the developing male urethra.. Gestational exposure to genistein contributes to hypospadias by altering pathways of tissue morphogenesis, cell proliferation and cell survival. In particular, genes in the MAPK and TGF-β signaling pathways and those controlled by FOXO, HOX and ER transcription factors are disrupted.

Topics: Animals; Animals, Newborn; Blotting, Western; Cell Proliferation; Cell Survival; Extracellular Signal-Regulated MAP Kinases; Female; Fetus; Forkhead Box Protein O1; Forkhead Transcription Factors; Genistein; Homeodomain Proteins; Hypospadias; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; Neoplasm Proteins; Phytoestrogens; Pregnancy; Prenatal Exposure Delayed Effects; Signal Transduction; Transforming Growth Factor beta; Urethra

The phytoestrogen (plant estrogen) genistein, present in soy products, is of interest because in utero exposure to genistein can cause hypospadias in our mouse model and maternal consumption of soy is prevalent in human populations. Another compound of interest is the fungicide vinclozolin, which also causes hypospadias in the mouse and rat and can occur concurrently with genistein in the diet as a residue on exposed foods. A study in the United Kingdom found no relationship between a maternal organic vegetarian diet and hypospadias frequency, but women who consumed nonorganic vegetarian diets had a greater percentage of sons with hypospadias. Because nonorganic diets can include residues of pesticides such as vinclozolin, we sought to assess the interaction of realistic daily exposures to genistein and vinclozolin and their effects on the incidence of hypospadias.. Pregnant mice were fed a soy-free diet and orally gavaged from gestational days 13 to 17 with 0.17 mg/kg/day of genistein, 10 mg/kg/day of vinclozolin, or genistein and vinclozolin together at the same doses, all in 100 microL of corn oil. The controls received the corn oil vehicle. The male fetuses were examined at gestational day 19 for hypospadias, both macroscopically and histologically.. We identified no hypospadias in the corn oil group. The incidence of hypospadias was 25% with genistein alone, 42% with vinclozolin alone, and 41% with genistein and vinclozolin together.. These findings support the idea that exposure to these compounds during gestation could contribute to the development of hypospadias.

Topics: Abnormalities, Drug-Induced; Animals; Diet, Vegetarian; Drug Interactions; Endocrine Disruptors; Female; Fetus; Food Contamination; Fungicides, Industrial; Genistein; Gestational Age; Hypospadias; Male; Mice; Models, Animal; Oxazoles; Pesticide Residues; Phytoestrogens; Pregnancy

To investigate the possible role of the maternal diet, particularly vegetarianism and consumption of phytoestrogens, in the origin of hypospadias, which is reported to be increasing in prevalence.. Detailed information was obtained prospectively from mothers, including previous obstetric history, lifestyle and dietary practices, using structured self-completed questionnaires during pregnancy. Previously recognized associations with environmental and parental factors were examined, focusing particularly on the hypothesized hormonal link. Multivariate logistic regression was used to identify independent associations.. Of 7928 boys born to mothers taking part in the Avon Longitudinal Study of Pregnancy and Childhood, 51 hypospadias cases were identified. There were no significant differences in the proportion of hypospadias cases among mothers who smoked, consumed alcohol or for any aspect of their previous reproductive history (including the number of previous pregnancies, number of miscarriages, use of the contraceptive pill, time to conception and age at menarche). Significant differences were detected for some aspects of the maternal diet, i.e. vegetarianism and iron supplementation in the first half of pregnancy. Mothers who were vegetarian in pregnancy had an adjusted odds ratio (OR) of 4.99 (95% confidence interval, CI, 2.10-11.88) of giving birth to a boy with hypospadias, compared with omnivores who did not supplement their diet with iron. Omnivores who supplemented their diet with iron had an adjusted OR of 2.07 (95% CI, 1.00-4.32). The only other statistically significant association for hypospadias was with influenza in the first 3 months of pregnancy (adjusted OR 3.19, 95% CI 1.50-6.78).. As vegetarians have a greater exposure to phytoestrogens than do omnivores, these results support the possibility that phytoestrogens have a deleterious effect on the developing male reproductive system.

Topics: Diet, Vegetarian; Dietary Supplements; Embryonic and Fetal Development; Estrogens, Non-Steroidal; Female; Humans; Hypospadias; Iron; Isoflavones; Male; Phytoestrogens; Plant Preparations; Pregnancy; Prenatal Exposure Delayed Effects; Prospective Studies