title: Zinc deficiency affects the STAT1/3 signaling pathways in part through redox-mediated mechanisms.
abstract: Zinc deficiency affects the development of the central nervous system (CNS) through mechanisms only partially understood. We previously showed that zinc deficiency causes CNS oxidative stress, damaging microtubules and impairing protein nuclear shuttling. STAT1 and STAT3 transcription factors, which require nuclear import for their functions, play major roles in CNS development. Thus, we investigated whether zinc deficiency disrupts STAT1 and STAT3 signaling pathways in the developing fetal CNS, characterizing the involvement of oxidative stress and the cytoskeleton in the adverse effects. Maternal (gestation day 0-19) marginal zinc deficiency (MZD) reduced STAT1 and STAT3 tyrosine phosphorylation and their nuclear translocation in the embryonic day 19 (E19) rat brain. Similar effects were observed in zinc depleted IMR-32 neuroblastoma cells, with an associated decrease in STAT1- and STAT3-dependent gene transactivation. Zinc deficiency caused oxidative stress (increased 4-hydroxynonenal-protein adducts) in E19 brain and IMR-32 cells, which was prevented in cells by supplementation with 0.5mM α-lipoic acid (LA). In zinc depleted IMR-32 cells, the low tyrosine phosphorylation of STAT1, but not that of STAT3, recovered upon incubation with LA. STAT1 and STAT3 nuclear transports were also restored by LA. Accordingly, chemical disruption of the cytoskeleton partially reduced STAT1 and STAT3 nuclear levels. In summary, the redox-dependent tyrosine phosphorylation, and oxidant-mediated disruption of the cytoskeleton are involved in the deleterious effects of zinc deficit on STAT1 and STAT3 activation and nuclear translocation. Therefore, disruption of the STAT1 and STAT3 signaling pathways may in part explain the deleterious effects of maternal MZD on fetal brain development.
authors.affiliation: Department of Nutrition, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA; Department of Environmental Toxicology, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: S
authors.initials: S
authors.lastname: Supasai
authors.affiliation: Department of Nutrition, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA; Department of Environmental Toxicology, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: L
authors.initials: L
authors.lastname: Aimo
authors.affiliation: Department of Biological Chemistry and IQUIFIB (UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: A M
authors.initials: AM
authors.lastname: Adamo
authors.affiliation: Department of Nutrition, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: G G
authors.initials: GG
authors.lastname: Mackenzie
authors.affiliation: Department of Nutrition, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA; Department of Environmental Toxicology, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA. Electronic address: poteiza@ucdavis.edu.
authors.forename: P I
authors.initials: PI
authors.lastname: Oteiza
mesh_terms: D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D008063:Thioctic Acid / Q000008:administration & dosage; D015533:Transcriptional Activation / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism; D015032:Zinc / Q000172:deficiency / Q000378:metabolism*
chemical_list: D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494081:Stat1 protein, rat; D014443:Tyrosine; D008063:Thioctic Acid; D015032:Zinc