ZINC DEPRIVATION AND TERATOGENESIS

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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.