Jefferson Wendy N, Doerge Daniel, Padilla-Banks Elizabeth, Woodling Kellie A, Kissling Grace E, Newbold Retha
Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
Environ Health Perspect. 2009 Dec;117(12):1883-9. doi: 10.1289/ehp.0900923. Epub 2009 Jul 27.
Developmental exposure to environmental estrogens is associated with adverse consequences later in life. Exposure to genistin (GIN), the glycosylated form of the phytoestrogen genistein (GEN) found in soy products, is of concern because approximately 20% of U.S. infants are fed soy formula. High circulating levels of GEN have been measured in the serum of these infants, indicating that GIN is readily absorbed, hydrolyzed, and circulated.
We investigated whether orally administered GIN is estrogenic in neonatal mice and whether it causes adverse effects on the developing female reproductive tract.
Female CD-1 mice were treated on postnatal days 1-5 with oral GIN (6.25, 12.5, 25, or 37.5 mg/kg/day; GEN-equivalent doses), oral GEN (25, 37.5, or 75 mg/kg/day), or subcutaneous GEN (12.5, 20, or 25 mg/kg/day). Estrogenic activity was measured on day 5 by determining uterine wet weight gain and induction of the estrogen-responsive gene lactoferrin. Vaginal opening, estrous cyclicity, fertility, and morphologic alterations in the ovary/reproductive tract were examined.
Oral GIN elicited an estrogenic response in the neonatal uterus, whereas the response to oral GEN was much weaker. Oral GIN altered ovarian differentiation (i.e., multioocyte follicles), delayed vaginal opening, caused abnormal estrous cycles, decreased fertility, and delayed parturition.
Our results support the idea that the dose of the physiologically active compound reaching the target tissue, rather than the administered dose or route, is most important in modeling chemical exposures. This is particularly true with young animals in which phase II metabolism capacity is underdeveloped relative to adults.
发育过程中暴露于环境雌激素与生命后期的不良后果有关。接触染料木苷（GIN），即大豆制品中发现的植物雌激素染料木黄酮（GEN）的糖基化形式，令人担忧，因为约20%的美国婴儿喂养大豆配方奶粉。在这些婴儿的血清中检测到高循环水平的GEN，表明GIN易于吸收、水解和循环。
我们研究了口服GIN对新生小鼠是否具有雌激素活性，以及它是否对发育中的雌性生殖道产生不良影响。
雌性CD-1小鼠在出生后第1至5天接受口服GIN（6.25、12.5、25或37.5mg/kg/天；GEN等效剂量）、口服GEN（25、37.5或75mg/kg/天）或皮下注射GEN（12.5、20或25mg/kg/天）治疗。在第5天通过测定子宫湿重增加和雌激素反应基因乳铁蛋白的诱导来测量雌激素活性。检查阴道开口、发情周期、生育能力以及卵巢/生殖道的形态学改变。
口服GIN在新生小鼠子宫中引发雌激素反应，而口服GEN的反应则弱得多。口服GIN改变卵巢分化（即多卵母细胞卵泡），延迟阴道开口，导致异常发情周期，降低生育能力，并延迟分娩。
我们的结果支持这样一种观点，即在模拟化学物质暴露时，到达靶组织的生理活性化合物的剂量比给药剂量或途径更为重要。对于幼龄动物尤其如此，因为相对于成年动物，它们的II期代谢能力发育不全。
