ZINC DEPRIVATION AND TERATOGENESIS

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Our laboratory has been focusing on factors that influence pregnancy outcome. Two potential risk factors are adolescence and micronutrient deficiencies. Specifically, we have been studying adolescence and zinc (ZN) deficiency as potential risk factors for pregnancy outcome in the rhesus macaque. Our data have demonstrated a significant adverse impact of ZN deprivation on pregnancy outcome, as well as parameters of immune function, growth and brain development. In this study, we will continue to define the mechanisms that lead to progressive linear growth retardation, the observed delay in maturation of brain function and the immune defects that occur in zn compromised adolescence. We will address these issues by detailed characterization of insulin-like growth factors and their receptors in both control and zn deficient adolescents. We will also take advantage of newer techniques of magnetic resonance imaging that correlate our biochemical findings with in vivo changes. In addition, we hypothesize that embryonic ZN deficiency can arise as a consequence of cytokine-induced acute phase responses which disrupt maternal ZN homeostasis. The most common cause of embryo IC ZN deficiency is low maternal plasma ZN that occurs secondary to either inadequate dietary intake, genetic metabolic disturbances and/or disease and drug-induced changes in ZN homeostasis. Our hypothesis extends these findings and suggests that during an acute phase reaction there is a sequestering of ZN in maternal liver due to increased production of the acute phase protein metallothionein (MT), coupled with an enhanced uptake of ZN into liver due to an increase in plasma a2-macroglobulin (a2m). The consequence will be a reduction in maternal plasma ZN and a concurrent reduction of ZN transfer to the embryo/fetus. The impact of ZN depletion on embryonic development may be mediated by increased rates of DNA, protein and lipid oxidative damage, and/or altered production of growth factors. We have pilot data in both the mouse and the rhesus macaques which support this hypothesis; following administration of TNF-alpha we provide evidence for poor pregnancy outcome and the development of an acute phase reaction, including changes in MT and a2m metabolism. Our thesis has major implications for reducing adverse developmental and pregnancy outcomes. Understanding the relationships between cytokine-induced acute phase responses and ZN nutriture would be an important consideration for ZN supplementation during adolescence as well as during a maternal acute phase reaction.