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Mono-2-ethylhexyl Phthalate Stimulates Parturition-Related Responses in Human Gestational Tissues and Cells.

dc.contributor.authorTetz, Lauren M.en_US
dc.date.accessioned2012-10-12T15:33:24Z
dc.date.available2012-10-12T15:33:24Z
dc.date.issued2012en_US
dc.date.submitted2012en_US
dc.identifier.urihttps://hdl.handle.net/2027.42/94101
dc.description.abstractDiethyhexyl phthalate (DEHP) is an environmental pollutant used universally as a plasticizer in polyvinyl consumer products. Exposure to DEHP increases risk of adverse pregnancy outcomes in humans, including decreased gestation length, preterm birth, low birth weight, and early pregnancy loss. Moreover, monoethylhexyl phthalate (MEHP), the active metabolite of DEHP increases oxidative stress and inflammatory responses in vitro. Because oxidative stress and inflammatory responses are linked to the pathogenesis of preterm birth, we investigated MEHP stimulated oxidative stress and inflammatory responses in human gestational cells and tissues as mechanisms by which MEHP exposure may contribute to preterm birth. To identify whether MEHP exposure induces oxidative stress responses in the gestational compartment, we treated human placental cells (HTR-8/SVneo) with MEHP and measured reactive oxygen species (ROS) generation using the dichlorofluorescein (DCF) assay, oxidized thymine (oT) with mass-spectrometry, redox-sensitive gene expression with RT-PCR, and activation of caspase 3/7 using a luminescence assay. We found that MEHP increased ROS generation, oxidative DNA damage, and apoptosis, and modified redox-sensitive gene expression. Notably, MEHP significantly induced mRNA expression of prostaglandin-endoperoxide synthase 2 (PTGS2), the gene for COX-2, an enzyme important for prostaglandin synthesis. To assess whether MEHP may stimulate inflammatory responses in the gestational compartment, we treated human primary placental macrophages, primary decidual macrophages, gestational membrane explants, and HTR-8 cells with MEHP and measured prostaglandin and cytokine release using enzyme-linked immunosorbent assays (ELISA) and PTGS2 mRNA expression using RT-PCR. Our results demonstrate that MEHP treatment significantly increased total prostaglandin, PGF2α, and PGE2 release in human primary placental macrophage Hofbauer cells, and induced PTGS2 mRNA expression in the HTR-8 human trophoblast cell line. MEHP treatment showed no effect on pro-inflammatory cytokine release. The results from the present study are consistent with the hypothesis that MEHP stimulates oxidative stress and prostaglandin synthesis in gestational tissues and cells. The findings from the current study warrant future epidemiological studies of oxidative stress and prostaglandin synthesis as mechanisms by which MEHP may contribute to preterm birth and other adverse pregnancy outcomes.en_US
dc.language.isoen_USen_US
dc.subjectMono-2-Ethylhexyl Phthalate Stimulates Parturition-Related Responses in Human Gestational Tissues and Cellsen_US
dc.titleMono-2-ethylhexyl Phthalate Stimulates Parturition-Related Responses in Human Gestational Tissues and Cells.en_US
dc.typeThesisen_US
dc.description.thesisdegreenamePhDen_US
dc.description.thesisdegreedisciplineToxicologyen_US
dc.description.thesisdegreegrantorUniversity of Michigan, Horace H. Rackham School of Graduate Studiesen_US
dc.contributor.committeememberLoch-Caruso, Ritaen_US
dc.contributor.committeememberOsawa, Yoichien_US
dc.contributor.committeememberHarris, Craigen_US
dc.contributor.committeememberMancuso, Peteren_US
dc.contributor.committeememberMeeker, John D.en_US
dc.subject.hlbsecondlevelPublic Healthen_US
dc.subject.hlbtoplevelHealth Sciencesen_US
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/94101/1/ltetz_1.pdf
dc.owningcollnameDissertations and Theses (Ph.D. and Master's)


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