1 Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center - New Orleans, LA 70112, USA.
2 Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Exp Biol Med (Maywood). 2018 May;243(8):695-707. doi: 10.1177/1535370218771333.
The isoflavone phytoestrogens found in the soy protein isolate used in soy infant formulas have been shown to have estrogenic actions in the developing male reproductive tract resulting in reproductive toxicity. However, few studies have examined potential estrogenicity of soy protein isolate as opposed to that of pure isoflavones. In this study, we fed weanling male Sprague-Dawley rats a semi-purified diet with casein or soy protein isolate as the sole protein source from postnatal day 21 to 33. Additional groups were fed casein or soy protein isolate and treated s.c. with 10 µg/kg/d estradiol via osmotic minipump. Estradiol treatment reduced testis, prostate weights, and serum androgen concentrations ( P < 0.05). Soy protein isolate had no effect. Estradiol up-regulated 489 and down-regulated 1237 testicular genes >1.5-fold ( P < 0.05). In contrast, soy protein isolate only significantly up-regulated expression of 162 genes and down-regulated 16 genes. The top 30 soy protein isolate-up-regulated genes shared 93% concordance with estradiol up-regulated genes. There was little overlap between soy protein isolate down-regulated genes and those down-regulated by estradiol treatment. Functional annotation analysis revealed significant differences in testicular biological processes affected by estradiol or soy protein isolate. Estradiol had major actions on genes involved in reproductive processes including down-regulation of testicular steroid synthesis and expression of steroid receptor activated receptor (Star) and cytochrome P450 17α-hydroxylase/(Cyp17a1). In contrast, soy protein isolate primarily affected pathways associated with macromolecule modifications including ubiquitination and histone methylation. Our results indicate that rather than acting as a weak estrogen in the developing testis, soy protein isolate appears to act as a selective estrogen receptor modulator with little effect on reproductive processes. Impact statement Soy protein isolate (SPI) is the sole protein used to make soy-based infant formulas. SPI contains phytoestrogens, which are structurally similar to estradiol. These phytoestrogens, daidzein, genistein, and equol, fit the definition of endocrine-disrupting compounds, and at high concentrations, have estrogenic actions resulting in reproductive toxicity in the developing male, when provided as isolated chemicals. However, few animal studies have examined the potential estrogenicity of SPI as opposed to pure isoflavones. In this study, SPI feeding did not elicit an estrogenic response in the testis nor any adverse outcomes including reduced testicular growth, or androgen production during early development in rats when compared to those receiving estradiol. These findings are consistent with emerging data showing no differences in reproductive development in males and female children that received breast milk, cow's milk formula, or soy infant formula during the postnatal feeding period.
大豆婴儿配方奶粉中使用的大豆分离蛋白中的异黄酮植物雌激素已被证明对发育中的雄性生殖道具有雌激素作用，导致生殖毒性。然而，很少有研究检查大豆分离蛋白的潜在雌激素与纯异黄酮的雌激素作用。在这项研究中，我们从出生后第 21 天到 33 天，用半纯化饮食喂养断奶雄性 Sprague-Dawley 大鼠，其中酪蛋白或大豆分离蛋白作为唯一的蛋白质来源。其他组用酪蛋白或大豆分离蛋白喂养，并通过皮下渗透微型泵以 10μg/kg/d 的雌二醇处理。雌二醇处理降低了睾丸、前列腺的重量和血清雄激素浓度（P<0.05）。大豆分离蛋白没有影响。雌二醇上调了 489 个和下调了 1237 个睾丸基因 >1.5 倍（P<0.05）。相比之下，大豆分离蛋白仅显著上调了 162 个基因的表达，并下调了 16 个基因的表达。大豆分离蛋白上调的前 30 个基因与雌二醇上调的基因有 93%的一致性。大豆分离蛋白下调的基因与雌二醇处理下调的基因之间几乎没有重叠。功能注释分析显示，受雌二醇或大豆分离蛋白影响的睾丸生物学过程存在显著差异。雌二醇对生殖过程中涉及的基因有主要作用，包括睾丸类固醇合成的下调和类固醇受体激活受体（Star）和细胞色素 P450 17α-羟化酶/（Cyp17a1）的表达。相比之下，大豆分离蛋白主要影响与大分子修饰相关的途径，包括泛素化和组蛋白甲基化。我们的结果表明，大豆分离蛋白在发育中的睾丸中不是作为一种弱雌激素，而是作为一种选择性雌激素受体调节剂，对生殖过程几乎没有影响。
大豆分离蛋白（SPI）是用于制造大豆配方奶粉的唯一蛋白质。SPI 含有植物雌激素，其结构与雌二醇相似。这些植物雌激素，如大豆苷元、染料木黄酮和黄豆苷元，符合内分泌干扰化合物的定义，并且在高浓度下，当作为单独的化学物质提供时，对发育中的雄性具有雌激素作用，导致生殖毒性。然而，很少有动物研究检查 SPI 的潜在雌激素与纯异黄酮的区别。在这项研究中，与接受雌二醇的大鼠相比，SPI 喂养在睾丸中没有引起雌激素反应，也没有任何不良后果，包括睾丸生长减少或雄激素产生减少，在大鼠早期发育期间。这些发现与新兴数据一致，即接受母乳喂养、牛奶配方奶粉或大豆婴儿配方奶粉的男性和女性儿童在产后喂养期间的生殖发育没有差异。
