Odum J, Tinwell H, Jones K, Van Miller J P, Joiner R L, Tobin G, Kawasaki H, Deghenghi R, Ashby J
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, United Kingdom.
Toxicol Sci. 2001 May;61(1):115-27. doi: 10.1093/toxsci/61.1.115.
Five rodent diets have been evaluated for their possible effect on the sexual development of the rat. Groups of 12 pregnant Alpk rats were fed one of the following combinations of diets during pregnancy and postnatally: RM3/RM1, AIN-76A/AIN-76A, RM3/AIN-76A, Teklad Global 2016 (Global)/Global and Purina 5001/Purina 5001. AIN-76A is phytoestrogen-free while the other diets contained varying amounts of phytoestrogens. The phytoestrogens genistein and daidzein were determined in the diets studied, and the concentrations found agreed with earlier estimates. RM3/RM1 was selected as the control group, as this has been used routinely in this laboratory for the past decade. Determinations were made in offspring of the times of vaginal opening and first estrus among the females, and of prepuce separation and testes descent among the males. At postnatal day (PND) 26 the females from 6 of the 12 litters were terminated and tissue weights measured. Males from 6 of the 12 litters were similarly studied at PND 68. Animals from the remaining litters were transferred to RM1 diet at PND 70. Termination of the study was at PND 128 (males) and PND 140 (females) when body weights and tissue weights were determined. Marked differences in body weight, sexual development, and reproductive tissue weights were observed for rats maintained on AIN-76A or Purina 5001, with only minimal effects among rats maintained on the Global diet. These comparisons were against RM3/RM1 as the reference diet. However, using Purina 5001 as the reference diet reversed the direction of the differences seen when using RM3/RM1 as the reference diet. The differences observed when using RM3/RM1 as reference diet occurred mainly postnatally. In addition, the fact that similar differences were seen for the phytoestrogen-free diet, AIN-76A, and the phytoestrogen-rich diet, Purina 5001, indicate that these effects are more likely to be caused by nutritional differences between the diets that then have centrally mediated effects on rodent sexual development, rather than individual dietary components affecting peripheral estrogen receptors (ER). This proposal is supported by abolition of the uterotrophic activity of AIN-76A and Purina 5001 (relative to RM3/RM1) in the immature rat by coadministration of the gonadotrophin-releasing hormone (GnRH) antagonist ANTARELIX: The present data indicate that choice of diet may influence the timing of sexual development in the rat, and consequently, that when evaluating the potential endocrine toxicity of chemicals, the components of rodent diets used should be known, and as far as is possible, controlled.
已对五种啮齿动物饮食对大鼠性发育的可能影响进行了评估。将12只怀孕的Alpk大鼠分为几组，在孕期和产后分别喂食以下饮食组合之一：RM3/RM1、AIN-76A/AIN-76A、RM3/AIN-76A、Teklad Global 2016（全球）/全球以及普瑞纳5001/普瑞纳5001。AIN-76A不含植物雌激素，而其他饮食含有不同量的植物雌激素。在所研究的饮食中测定了染料木黄酮和大豆苷元这两种植物雌激素，测定结果与先前的估计相符。RM3/RM1被选为对照组，因为在过去十年中该饮食在本实验室中一直被常规使用。对雌性后代的阴道开口时间和首次发情时间以及雄性后代的包皮分离和睾丸下降时间进行了测定。在出生后第26天（PND 26），处死12窝中的6窝雌性大鼠并测量组织重量。在PND 68时对12窝中的6窝雄性大鼠进行了类似研究。其余窝的动物在PND 70时转喂RM1饮食。研究在PND 128（雄性）和PND 140（雌性）结束时测定体重和组织重量。观察到以AIN-76A或普瑞纳5001喂养的大鼠在体重、性发育和生殖组织重量方面存在显著差异，而以全球饮食喂养的大鼠仅有极小影响。这些比较是以RM3/RM1作为参照饮食。然而，以普瑞纳5001作为参照饮食时，所观察到的差异方向与以RM3/RM1作为参照饮食时相反。以RM3/RM1作为参照饮食时观察到的差异主要发生在出生后。此外，不含植物雌激素的饮食AIN-76A和富含植物雌激素的饮食普瑞纳5001出现类似差异这一事实表明，这些影响更可能是由饮食之间的营养差异引起的，这些差异随后对啮齿动物性发育产生中枢介导作用，而不是个别饮食成分影响外周雌激素受体（ER）。共同给予促性腺激素释放激素（GnRH）拮抗剂安他瑞克可消除AIN-76A和普瑞纳5001（相对于RM3/RM1）在未成熟大鼠中的子宫营养活性，这支持了该提议：目前的数据表明饮食选择可能会影响大鼠性发育的时间，因此，在评估化学物质的潜在内分泌毒性时，应了解并尽可能控制所用啮齿动物饮食的成分。
