This proposal examines potential mechanisms by which maternal and embryonic Zn deficiency arise, and how this deficiency results in abnormal development and growth. We will use pre-, peri-, and post-implantation embryo and cell culture techniques to confirm and extend results we obtain at the whole animal level. Embryo culture systems will allow us to study the influence of varying Zn concentration on the embryo during discrete periods of development. In addition, we will investigate the hypothesis that one mechanism by which an embryonic Zn deficiency can arise is due to a reduction in Zn transfer to the conceptus in cases where the mother has been subjected to a stressor which induces an acute phase response. According to this hypothesis, as part of the acute phase response there is an increase in the metallothionein concentration in maternal liver which results in a sequestration of Zn in the liver and concomitant hypozincemia. The hypozincemia results in a reduction in Zn transfer to the conceptus which presents a developmental risk. The above hypothesis will be tested using MT-knockout mice which we predict will show a reduced sensitivity to select teratogens. We suggest that embryonic Zn deficiency can lead to a compromised oxidant defense system, an increase in the concentration of reactive oxygen species (ROS), and resultant shifts in the redox state of cells. We suggest that Zn deficiency-associated cellular oxidative damage to lipid, protein and/or DNA contributes to the teratogenicity of Zn deficiency. We hypothesize that the altered redox states also results in the inactivation of oxidatively sensitive transcription factors such as NF-kappaB, and AP-1 and inactivation of Zn finger transcription factors GATA-4 and p53. It is predicted that an additional consequence of increased ROS in the embryo can be inappropriate and excessive apoptosis. Another mechanism for Zn deficiency-induced apoptosis is direct activation of caspase 3 protease that initiates the nucleolytic cascade of apoptosis. The down-regulation of growth factors and/or the functional blocking of growth factor signal transduction has also been demonstrates to result in apoptosis. Given that Zn deficiency can result in altered IGF metabolism, we hypothesize that a cell's ability to be rescued from apoptosis is reduced in Zn deficient embryos.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD001743-32A1
Application #
2695228
Study Section
Special Emphasis Panel (ZRG2-REB (02))
Project Start
1977-09-01
Project End
2002-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
32
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California Davis
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Yang, Hsunhui; Keen, Carl L; Lanoue, Louise (2015) Influence of intracellular zinc on cultures of rat cardiac neural crest cells. Birth Defects Res B Dev Reprod Toxicol 104:11-22
Omata, Yo; Salvador, Gabriela A; Supasai, Suangsuda et al. (2013) Decreased zinc availability affects glutathione metabolism in neuronal cells and in the developing brain. Toxicol Sci 133:90-100
Nuttall, J R; Oteiza, P I (2012) Zinc and the ERK kinases in the developing brain. Neurotox Res 21:128-41
Oteiza, Patricia I (2012) Zinc and the modulation of redox homeostasis. Free Radic Biol Med 53:1748-59
Mackenzie, Gerardo G; Salvador, Gabriela A; Romero, Carolina et al. (2011) A deficit in zinc availability can cause alterations in tubulin thiol redox status in cultured neurons and in the developing fetal rat brain. Free Radic Biol Med 51:480-9
Adamo, Ana M; Zago, Maria P; Mackenzie, Gerardo G et al. (2010) The role of zinc in the modulation of neuronal proliferation and apoptosis. Neurotox Res 17:1-14
Aimo, Lucila; Mackenzie, Gerardo G; Keenan, Alison H et al. (2010) Gestational zinc deficiency affects the regulation of transcription factors AP-1, NF-*B and NFAT in fetal brain. J Nutr Biochem 21:1069-75
Aimo, Lucila; Cherr, Gary N; Oteiza, Patricia I (2010) Low extracellular zinc increases neuronal oxidant production through nadph oxidase and nitric oxide synthase activation. Free Radic Biol Med 48:1577-87
Hanna, Lynn A; Clegg, Michael S; Ellis-Hutchings, Robert G et al. (2010) The influence of gestational zinc deficiency on the fetal insulin-like growth factor axis in the rat. Exp Biol Med (Maywood) 235:206-14
Adamo, Ana M; Oteiza, Patricia I (2010) Zinc deficiency and neurodevelopment: the case of neurons. Biofactors 36:117-24

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