Tert-Butyl Hydroperoxide Stimulates Parturition-Associated Pathways in a Human Placental Cell Line.

Tert-butyl Hydroperoxide Stimulates Parturition-associated Pathways in a Human Placental Cell Line;Obstetrics and Gynecology;Public Health;Health Sciences;Toxicology

Korte, Cassandra S.Mancuso, Peter ;

University of Michigan

关键词: Tert-butyl Hydroperoxide Stimulates Parturition-associated Pathways in a Human Placental Cell Line;    Obstetrics and Gynecology;    Public Health;    Health Sciences;    Toxicology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/102346/kortecas_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Preterm birth is a leading cause of infant mortality and morbidity. Increased understanding of the etiology of preterm birth is needed to accelerate medical and public health interventions. Parturition is associated with markers of the damaging effects of reactive oxygen species (ROS). Whereas roles for prostaglandins, cytokines, and apoptosis in parturition have been described, the effect of ROS on these parturition pathways is unclear. Using the human placental trophoblast cell line HTR-8/SVneo, we investigated the effect of the lipophilic ROS-producing chemical tert-butyl hydroperoxide (TBHP) on trophoblast apoptosis, prostaglandin production, and cytokine release.Exposure to TBHP stimulated significant, though modest, increases in redox- related responses including production of ROS, glutathione redox potential (Eh), reporter activity at the antioxidant response element (ARE), and expression of the antioxidant genes thioredoxin reductase 1 and glutaredoxin 2. Under our treatment conditions, TBHP significantly increased caspase 3/7 activity and decreased cell viability, indicative of apoptosis. Apoptotic responses were inhibited by the iron-chelating antioxidant, deferoxamine. Likewise, TBHP stimulated release of prostaglandin E2 (PGE2) and mRNA expression of prostaglandin-endoperoxide synthase 2 (PTGS2), an enzyme in the prostaglandin synthetic pathway. In addition, TBHP increased release of the cytokine interleukin-6 (IL-6) and reporter activity of the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB). Cotreatment with the PTGS inhibitor indomethacin or the antioxidants butylated hydroxyanisole (BHA) and diphenyl phenylenediamine (DPPD) blocked the TBHP-stimulated PGE2 response. Similarly, TBHP-stimulated IL-6 release was blocked by the antioxidants BHA, DPPD, and deferoxamine.We next examined the redox-sensitive mitogen activated protein kinases (MAPKs) as an upstream pathway for the TBHP-stimulated responses. Treatment with TBHP increased phosphorylation of p38 MAPK, indicative of activation, and pretreatment with the p38 MAPK inhibitor PD169316 blocked the TBHP-stimulated increases in IL-6 as well as PGE2 and PTGS2, suggesting dependence of these responses on p38 MAPK activity.In summary, these results suggest that exposure to an ROS-producing chemical stimulates responses in human placental cells linked to parturition. Because exposure to some environmental pollutants causes cellular ROS formation, these findings suggest a plausible mechanism that may underlie associations between pollutant exposures and increased risk for preterm birth.