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BACKGROUND: Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women during the mid-1900s, is a potent endocrine disruptor. Previous studies have suggested an association between endocrine-disrupting compounds and secondary sex ratio. METHODS: Data were provided by women participating in the National Cancer Institute (NCI) DES Combined Cohort Study. We used generalized estimating equations to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the relation of in utero DES exposure to sex ratio (proportion of male births). Models were adjusted for maternal age, child&apos;s birth year, parity, and cohort, and accounted for clustering among women with multiple pregnancies. RESULTS: The OR for having a male birth comparing DES-exposed to unexposed women was 1.05 (95% CI, 0.95-1.17). For exposed women with complete data on cumulative DES dose and timing (33%), those first exposed to DES earlier in gestation and to higher doses had the highest odds of having a male birth. The ORs were 0.91 (95% C, 0.65-1.27) for first exposure at = 13 weeks gestation to < 5 g DES; 0.95 (95% CI, 0.71-1.27) for first exposure at = 13 weeks to = 5 g; 1.16 (95% CI, 0.96-1.41) for first exposure at < 13 weeks to < 5 g; and 1.24 (95% CI, 1.04-1.48) for first exposure at < 13 weeks to = 5 g compared with no exposure. Results did not vary appreciably by maternal age, parity, cohort, or infertility history. CONCLUSIONS: Overall, no association was observed between in utero DES exposure and secondary sex ratio, but a significant increase in the proportion of male births was found among women first exposed to DES earlier in gestation and to a higher cumulative dose. KEY WORDS: diethylstilbestrol, estrogens, endocrine-disrupting chemicals, females, sex ratios. Environ Health Perspect 115:1314-1319 (2007). doi:10.1289/ehp.10246 available via http://dx.doi.org/ [Online 28 June 2007], Diethylstilbestrol (DES) is a synthetic estrogen that was prescribed to > 2 million pregnant women in the mid-1900s. In later years, it was discovered to be associated with the occurrence [...]

BACKGROUND: Diethylstilbestrol (DES) is a synthetic estrogen associated with adverse effects on reproductive organs. DES-induced toxicity of the mouse seminal vesicle (SV) is mediated by estrogen receptor α (ERα), which alters expression of seminal vesicle secretory protein IV (Svs4) and lactoferrin (Ltf) genes. OBJECTIVES: We examined a role for nuclear receptor activity in association with DNA methylation and altered gene expression. METHODS: We used the neonatal DES exposure mouse model to examine DNA methylation patterns via bisulfite conversion sequencing in SVs of wild-type (WT) and ERα-knockout (αERKO) mice. RESULTS: The DNA methylation status at four specific CpGs (-160, -237, -306, and -367) in the Svs4 gene promoter changed during mouse development from methylated to unmethylated, and DES prevented this change at 10 weeks of age in WT SV. At two specific CpGs (-449 and -459) of the Ltf gene promoter, DES altered the methylation status from methylated to unmethylated. Alterations in DNA methylation of Svs4 and Ltf were not observed in αERKO SVs, suggesting that changes of methylation status at these CpGs are ERα dependent. The methylation status was associated with the level of gene expression. In addition, gene expression of three epigenetic modifiers--DNMT3A, MBD2, and HDAC2--increased in the SV of DES-exposed WT mice. CONCLUSION: DES-induced hormonal toxicity resulted from altered gene expression of Svs4 and Ltf associated with changes in DNA methylation that were mediated by ERα. Alterations in gene expression of DNMT3A, MBD2, and HDAC2 in DES-exposed male mice may be involved in mediating the changes in methylation status in the SV. 10.1289/ehp.1307351, Introduction Endocrine-disrupting chemicals (EDCs) are substances in the environment, food sources, and manufactured products that can interfere with the normal functioning of the body's endocrine system (Diamanti-Kandarakis et al. 2009). [...]