We seek to elucidate the impact of hypoxic stress on placental differentiation and function, and consequently fetal growth. An adequate supply of proteins, carbohydrates and fat is obligatory for fetal development. Transfer of these nutrients is regulated by a set of well-orchestrated signals, programmed by genetic and environmental cues. Whereas our understanding of placental import of proteins and carbohydrates has markedly advanced in recent years, the mechanisms that govern uptake, accumulation and trafficking of fatty acids in placental trophoblasts are largely unknown and insufficiently investigated. Recent data implicate the nuclear receptor PPARy, a master regulator of adipogenesis, bioenergetics and inflammation, in regulation of placental fatty acid uptake and transport. PPARY-null mouse embryos exhibit intrauterine growth restriction and subsequently fetal death, associated with diminished fat accumulation within the labyrinthine placenta. We have recently determined that PPARy enhances trophoblast differentiation, and stimulates trophoblast uptake of fatty acids as well as the expression of proteins that govern accumulation and trafficking of fatty acids in the placenta. Importantly, environmental insults, such as exposure to hypoxia, adversely impact placental function and are associated with intrauterine death or substandard fetal growth. The mechanisms underlying these injuries are unknown. Our basic and translational research approaches are designed to understand cellular and molecular underpinnings of trophoblast fat transport and metabolism, their regulation by PPARy and the impact of hypoxic stress on these processes. We utilize novel in vivo and in vitro approaches to interrogate previously unknown gene- environment interactions that determine synthesis, utilization and efflux of fatty acids in trophoblasts, and the molecular pathways that regulate the expression and function of pertinent fatty acid transporters. We pursue feedback circuits that are instigated by free fatty acid and influence triglyceride synthesis in human trophoblasts. Together, our research will unveil previously unrecognized links between placental lipid trafficking and hypoxic injury. Consequently, our studies are likely to pave the way to better understanding of placental dysfunction that culminates in fetal growth restriction and its life-long sequelae.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Heindel, Jerrold
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Magee-Women's Research Institute and Foundation
United States
Zip Code
Bildirici, Ibrahim; Schaiff, W Timothy; Chen, Baosheng et al. (2018) PLIN2 Is Essential for Trophoblastic Lipid Droplet Accumulation and Cell Survival During Hypoxia. Endocrinology 159:3937-3949
Larkin, J C; Sears, S B; Sadovsky, Y (2014) The influence of ligand-activated LXR on primary human trophoblasts. Placenta 35:919-24
Mohammadyani, Dariush; Tyurin, Vladimir A; O'Brien, Matthew et al. (2014) Molecular speciation and dynamics of oxidized triacylglycerols in lipid droplets: Mass spectrometry and coarse-grained simulations. Free Radic Biol Med 76:53-60
Makkar, A; Mishima, T; Chang, G et al. (2014) Fatty acid binding protein-4 is expressed in the mouse placental labyrinth, yet is dispensable for placental triglyceride accumulation and fetal growth. Placenta 35:802-7
Larkin, Jacob; Chen, Baosheng; Shi, Xiao-Hua et al. (2014) NDRG1 deficiency attenuates fetal growth and the intrauterine response to hypoxic injury. Endocrinology 155:1099-106
Kanter, D J; O'Brien, M B; Shi, X-H et al. (2014) The impact of ionizing radiation on placental trophoblasts. Placenta 35:85-91
Shi, Xiao-Hua; Larkin, Jacob C; Chen, Baosheng et al. (2013) The expression and localization of N-myc downstream-regulated gene 1 in human trophoblasts. PLoS One 8:e75473
Shalom-Barak, Tali; Zhang, Xiaowen; Chu, Tianjiao et al. (2012) Placental PPARýý regulates spatiotemporally diverse genes and a unique metabolic network. Dev Biol 372:143-55
Oh, S-Y; Chu, T; Sadovsky, Y (2011) The timing and duration of hypoxia determine gene expression patterns in cultured human trophoblasts. Placenta 32:1004-9
Mishima, Takuya; Miner, Jeffrey H; Morizane, Mayumi et al. (2011) The expression and function of fatty acid transport protein-2 and -4 in the murine placenta. PLoS One 6:e25865

Showing the most recent 10 out of 31 publications