The overall objective of this research is to understand the contribution of the MAPK and NFkB pathways in the etiology of inflammation of extra-placental gestational membranes. Understanding the etiology of inflammation in gestational membranes is important because of the strong link between inflammation-associated release of cytokines and prostaglandins in preterm birth and other adverse birth outcomes. The critical knowledge gaps addressed in this research are: 1) initiation of inflammation in gestational membranes by noninfectious stimuli such as environmental pollutants, 2) activation of the MAPK pathway by infectious and noninfectious stimuli, and 3) cross-talk and amplification of cytokine and prostaglandin production by positive feedback on the MAPK and NFkB pathways. The overarching hypothesis is that infectious and noninfectious agents stimulate increased release of pro- inflammatory cytokines and prostaglandins through activation and positive feedback of the MAPK and NFkB signal transduction pathways. This hypothesis will be tested using human gestational membrane cell and tissue explant cultures exposed to the bacterial toxin lipopolysaccharide (LPS) as a model infectious stimulus and the environmental pollutants polybrominated diphenyl ethers (PBDEs) and p,p'-DDE as model noninfectious stimuli.
The Specific Aims are to: 1) identify the cell targets in human gestational membranes for PBDE-stimulated release of proinflammatory cytokines and prostaglandins;2) determine whether PBDEs stimulate release of pro- inflammatory cytokines from gestational tissues at relevant concentrations;3) delineate the roles of the NF-:B and MAPK pathways in cytokine and prostaglandin synthesis in human gestational membranes following stimulation with infectious and noninfectious agents;and 4) determine whether prostaglandins and cytokines interact in a positive feedback manner through the NF-:B and MAPK pathways to amplify production of prostaglandins in gestational membranes in response to infectious and noninfectious pro-inflammatory stimuli. Results from this research will increase our understanding of the causes of inflammation in gestational membranes and, as such, may contribute to improved pregnancy outcomes through enhanced strategies for prediction and prevention of risks for preterm birth and other associated adverse birth outcomes. Reducing preterm births is a Health People 2010 objective.

Public Health Relevance

Knowledge of pollutant contributions to preterm birth is scarce, yet epidemiologic study of pollutant risks to pregnancy is difficult, expensive and time-consuming. Given the thousands of chemicals to which pregnant women may be exposed, a strategy is required for selection of exposures for epidemiologic analysis. By using PBDEs and DDE as model toxicants to investigate biologic plausibility, the proposed experiments may provide a rational approach for selection of pollutants for further study. Moreover, the results from this research may increase understanding of the causes of inflammation in gestational membranes and, as such, may contribute to improved pregnancy outcomes through enhanced strategies for prediction and prevention of risks for preterm birth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES014860-05
Application #
8272635
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Heindel, Jerrold
Project Start
2008-09-09
Project End
2013-12-31
Budget Start
2012-06-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$373,164
Indirect Cost
$116,627
Name
University of Michigan Ann Arbor
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Boldenow, Erica; Hogan, Kelly A; Chames, Mark C et al. (2015) Role of cytokine signaling in group B Streptococcus-stimulated expression of human beta defensin-2 in human extraplacental membranes. Am J Reprod Immunol 73:263-72
Park, Hae-Ryung; Kamau, Patricia W; Korte, Cassandra et al. (2014) Tetrabromobisphenol A activates inflammatory pathways in human first trimester extravillous trophoblasts in vitro. Reprod Toxicol 50:154-62
Park, Hae-Ryung; Loch-Caruso, Rita (2014) Protective effect of nuclear factor E2-related factor 2 on inflammatory cytokine response to brominated diphenyl ether-47 in the HTR-8/SVneo human first trimester extravillous trophoblast cell line. Toxicol Appl Pharmacol 281:67-77
Park, Hae-Ryung; Kamau, Patricia W; Loch-Caruso, Rita (2014) Involvement of reactive oxygen species in brominated diphenyl ether-47-induced inflammatory cytokine release from human extravillous trophoblasts in vitro. Toxicol Appl Pharmacol 274:283-92
Tetz, Lauren M; Kamau, Patricia W; Cheng, Adrienne A et al. (2013) Troubleshooting the dichlorofluorescein assay to avoid artifacts in measurement of toxicant-stimulated cellular production of reactive oxidant species. J Pharmacol Toxicol Methods 67:56-60
Boldenow, E; Jones, S; Lieberman, R W et al. (2013) Antimicrobial peptide response to group B Streptococcus in human extraplacental membranes in culture. Placenta 34:480-5
Miller, Mark F; Chernyak, Sergei M; Domino, Steven E et al. (2012) Concentrations and speciation of polybrominated diphenyl ethers in human amniotic fluid. Sci Total Environ 417-418:294-8
Thiex, Natalie W; Chames, Mark C; Loch-Caruso, Rita K (2010) Tissue-specific induction of COX-2 and prostaglandins in lipopolysaccharide-stimulated extraplacental human gestational membranes in a 2-chamber transwell culture system. Reprod Sci 17:1120-9
Miller, Mark F; Loch-Caruso, Rita (2010) Comparison of LPS-stimulated release of cytokines in punch versus transwell tissue culture systems of human gestational membranes. Reprod Biol Endocrinol 8:121
Miller, Mark F; Chernyak, Sergei M; Batterman, Stuart et al. (2009) Polybrominated diphenyl ethers in human gestational membranes from women in southeast Michigan. Environ Sci Technol 43:3042-6

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