Hypoxia, the major cause of ischemia, leads to debilitating disease in infants via birth asphyxia and cerebral palsy, whereas in adults via heart attack and stroke. A widespread, natural protective phenomenon termed 'Hypoxic Preconditioning' occurs when prior exposures to hypoxia eventually results in robust hypoxia resistance. Accordingly, we have developed a novel model of sex-specific hypoxic preconditioning in adult zebrafish to mimic the tolerance of mini stroke(s) in human, which appears to protect against the severe damage inflicted by a major stroke event. Remarkable difference in the progression pattern of neuroprotection between preconditioning hypoxia followed by acute hypoxia (PH) group, and acute hypoxia (AH) group were observed with noticeable sex difference. Since gender difference has been reported in stroke, it was pertinent to investigate whether any such sex difference also exists in PH's protective mechanism against acute ischemic stroke. In order to elucidate the neural molecular mechanisms behind sex difference in neuroprotection induced by PH, a high throughput proteomics approach utilizing iTRAQ was performed, followed by protein enrichment analysis
The role of Y chromosome in sex determination and male fertility is well established. It is also known that infertile men are prone to psychological disturbances. Earlier studies in the laboratory identified genes expressed in testes that are putatively regulated by Y chromosome in man and mouse. With the availability of a Y-deleted mouse model, that is subfertile, we studied the effect of a partial deletion of Y-chromosomal heterochromatin on mouse behavior when compared to its wild type. The partial Y-deleted mice exhibited anxiety like phenotype under stress when different anxiety (open field test and elevated plus maze, EPM test) and depression related tests (tail suspension and force swim) were performed. The mutant mice also showed reduction in hippocampal neurogenesis and altered expression of neurogenesis markers such as Nestin, Sox2, Gfap, NeuroD1 and Dcx using quantitative real time PCR (qPCR) analysis. The genes with altered expression contained short stretches of homology to Y-derived transcripts only in their Untranslated Regions (UTRs). Our study suggests putative regulation of these genes by the Y chromosome in mouse brain altering stress related behavior.
Understanding the molecular basis of sex differences in neural response to acute hypoxic insult has profound implications for the effective prevention and treatment of ischemic stroke. Global hypoxic-ischemic induced neural damage has been studied recently under the well-controlled, non-invasive, reproducible conditions using zebrafish model. Our earlier report on sex difference in global acute hypoxia induced neural damage and recovery in zebrafish prompted us for comprehensive study on the mechanisms underlying the recovery. An omics approach for studying quantitative changes in brain proteome upon hypoxia insult following recovery was undertaken using iTRAQ-based LC-MS/MS approach. The results shed light on altered expression of many regulatory proteins in zebrafish brain upon acute hypoxia following recovery. The sex difference in differentially expressed proteins along with the proteins expressed in uniform direction in both the sexes was studied. Core expression analysis by Ingenuity Pathway analysis (IPA) showed a distinct sex difference in the disease function heatmap. Most of the upstream regulators obtained through IPA were validated at the transcriptional level. Translational upregulation of H3K9me3 in male led us to elucidate the mechanism of recovery by confirming transcriptional targets through ChIP-qPCR. The upregulation of H3K9me3 level in male at 4 hr post-hypoxia appears to affect the early neurogenic markers nestin, klf4 and sox2, which might explain the late recovery in male, compared to female. Acute hypoxia-induced sex-specific comparison of brain proteome led us to 2 reveal many differentially expressed proteins, which can be further studied for the development of novel targets for better therapeutic strategy.
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