Inhibition of peroxisome proliferator gamma (PPARɣ) : a potential link between chronic maternal hypoxia and impaired fetal growth

Abstract

Background and Objective: Chronic maternal hypoxia impairs fetal growth and increases the incidence of intrauterine growth restriction (IUGR). To identify the mechanisms underlying these hypoxia-related effects, we evaluated whether exposure to chronic hypoxia during pregnancy alters maternal gene-expression patterns relative to normoxic pregnancy and, if so, to define the dominant genes and pathways involved. Methods: Gene expression profiles were generated using NimbleGen Human Gene Expression microarrays for 79 peripheral blood mononuclear cell samples collected from 43 women residing at high (n = 25, 3600–4300m) or low (n = 18, 300m) altitude in the nonpregnant state or during pregnancy (20 or 36 weeks). Transcriptional differences between altitudes were detected using Limma, Lme4, and Car packages in R; the relationship of such differences to biological processes and pathways was assessed in IPA. Results: Gene expression differed at high versus low altitude in the non-pregnant state(43 genes), at 20 weeks of pregnancy (59 genes) and at 36 weeks of pregnancy (985 genes). Several genes of known pathologic significance for IUGR varied between altitudes during pregnancy but not in the non-pregnant state. Among the pathways enriched by these genes was the peroxisome proliferator-activated receptor gamma (PPARc) signaling pathway. Transcriptional changes were consistent with the negative regulation of PPARc at high versus low altitude during pregnancy, but not in the non-pregnant state. Conclusions: Pregnancy magnifies the influence of environmental hypoxia on gene expression in ways that may be related to fetal growth. Given its involvement in the regulation of inflammation, vascular function, and glucose metabolism, we consider PPARc to be an important candidate for future study.