ZINC DEPRIVATION AND TERATOGENESIS

次优膳食锌缺乏是一个潜在的致病危险因素 妊娠并发症和新生儿发育的治疗。 本实验室 重点研究饮食锌缺乏对妊娠恒河猴的影响 了解导致“营养风险”的机制， 怀孕 我们的数据表明，锌剥夺的影响是最 在生长和发育期间有明显的特征。 未来五 我们将继续使用恒河猴来定义机制 容易导致“营养不良”的怀孕 我们尤其 将研究中度缺锌对青少年恒河猴的作用， 猴子 青少年恒河猴是人类最好的模型之一， 青春期 我们将通过以下方法研究膳食锌缺乏的影响： 关注缺锌对生长的影响程度， 性成熟通过影响生长因子和其他激素。 更 重要的是，利用怀孕的动物，母亲和胎儿都将 进行研究，以确定基本的生化和细胞病变相关 锌缺乏症。 我们假设青春期女性的健康 将被同时发生的膳食锌缺乏严重破坏， 将涉及释放、分布、结合或/或组织中的缺陷 对生长因子的反应。 我们还假设， 在免疫和行为功能中会发现异常。 此外，我们认为，胚胎和胎儿缺锌可能会出现 由于急性期反应破坏母体锌， 体内平衡 我们建议，急性期反应，如介导的 通过施用重组TNF α，将导致所谓的 “母体毒性综合征”，并将包括螯合锌， 母体肝脏由于急性时相蛋白的产生增加 金属硫蛋白加上锌进入肝脏的吸收增加， 血浆α 2巨球蛋白升高。 这些后果 事件将减少锌转移到胚胎/胎儿。 的 发生的异常是由于许多因素，包括锌 缺乏引起细胞脂质的速率和程度的改变， 核酸和蛋白质氧化以及DNA甲基化的改变。 支持 因为这些假设将对健康产生重大影响， 在母体毒性/急性期反应期间补充，以及 提供了一个统一的假设， 多种外源性损伤、锌缺乏和 发育异常

Suboptimal dietary zinc deficiency is a potential etiological risk factor for pregnancy complications and neonatal development. Our laboratory has focused on the role of dietary zinc deficiency in pregnant rhesus monkeys to understand the mechanisms that lead to a "nutritionally-at-risk" pregnancy. Our data indicate that the effects of zinc deprivation are most marked during periods of growth and development. During the next five years we will continue our use of the rhesus monkey to define mechanisms that predispose to a "nutritionally-at-risk" pregnancy. In particular, we will study the role of moderate zinc deprivation in adolescent rhesus monkeys. Adolescent rhesus monkeys are amongst the best models for human adolescence. We will investigate the effects of dietary zinc deficiency by focusing on the extent to which zinc deficiency influences growth and sexual maturation via effects on growth factors and other hormones. More importantly, utilizing pregnant animals, both the mother and conceptus will be studied to identify basic biochemical and cellular lesions associated with zinc deficiency. We postulate that the health of adolescent females will be significantly disrupted by concurrent dietary zinc deficiency and will involve defects in the release, distribution, binding, or/or tissue response to growth factors. We also postulate that concurrent abnormalities will be seen in immunological and behavioral function. Additionally, we believe that embryonic and fetal zinc deficiency can arise as a consequence of acute phase reactions which disrupt maternal zinc homeostasis. We propose that acute phase reactions, such as that mediated by administration of recombinant TNFalpha, will lead to the so-called "maternal toxicity syndrome" and will include a sequestering of zinc in maternal liver due to enhanced production of the acute phase protein metallothionein coupled with an enhanced uptake of zinc into liver due to an increase in plasma alpha2 macroglobulin. The consequence of these events will be reduced zinc transfer to the embryo/fetus. The abnormalities that occur are due to a number of factors including zinc deficiency induced alterations in the rate and extent of cellular lipid, nucleic acid and protein oxidation and altered methylation of DNA. Support for these hypotheses would have major health implications, both for zinc supplementation during maternal toxicity/acute phase reactions as well as for providing a unifying hypothesis for understanding the potential interactions between multiple exogenous insults, zinc deficiency and developmental abnormalities.