Jamshed Laiba, Perono Genevieve A, Yacoub Lina R, Gutgesell Robert M, Frank Richard A, Hewitt L Mark, Thomas Philippe J, Holloway Alison C
Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON L8S 4K1, Canada.
Water Science, and Technology Directorate, Environment and Climate Change Canada, Burlington, ON, Canada.
Toxicol Appl Pharmacol. 2022 Apr 15;441:115970. doi: 10.1016/j.taap.2022.115970. Epub 2022 Mar 5.
Exposure to compounds present in petroleum and wastewaters from oil and gas extraction sites in the Alberta Oil Sands Region can impair reproductive health. It has been established that acid extractable organics found in oil sands process-affected water (OSPW) such as naphthenic acids (NA-fraction components; NAFC) can adversely affect reproductive outcomes. We have shown that NAFC exposure results in a significant upregulation of GDF15 in placental trophoblasts, a cellular stress marker known to be involved in human embryonic development and necessary for the maintenance of pregnancy. However, little is known regarding the mechanism(s) underlying NAFC-induced increases in GDF15 production during early placentation. The goal of this study was to examine the effects of NAFC exposure on the regulation of critical transcription factors of GDF15 in extravillous trophoblast cells. Of these transcription factors, inflammatory mediators including prostaglandins have been reported to inhibit proliferation and migration of trophoblast cells in vitro. Hence, the secondary goal of this study was to determine whether inflammation mediated through prostaglandin production is critical to GDF15 secretion. HTR-8/SVneo cells were exposed to an NAFC for 6 and 24 h to assess the expression of key transcriptional regulators, GDF15 secretion, and prostaglandin (PGE) output. Treatment with NAFC (125 mg/L only) significantly increased GDF15 expression and secretion in association with upregulation of the transcription factors KLF4, EGR1, ATF3 and TP53. Similarly, PTGS2 (i.e. COX2) expression and PGE output were significantly increased at the same concentration. However, co-treatment with a COX2 selective antagonist (SC236) only partially blocked the NAFC-induced increase in PGE output and did not block GDF15 expression or secretion. These findings suggest that while NAFC may affect GDF15 production, it is not exclusively a result of prostaglandin-mediated inflammation. This study provides new insights into the mechanisms by which NAFC may adversely affect placental trophoblast cell function in mammals.
接触艾伯塔油砂地区石油和天然气开采场地的石油及废水中存在的化合物会损害生殖健康。已证实，在油砂加工影响水（OSPW）中发现的酸可提取有机物，如环烷酸（NA-组分；NAFC），会对生殖结果产生不利影响。我们已经表明，NAFC暴露会导致胎盘滋养层细胞中GDF15显著上调，GDF15是一种细胞应激标志物，已知参与人类胚胎发育且对维持妊娠至关重要。然而，关于早期胎盘形成过程中NAFC诱导GDF15产生增加的潜在机制知之甚少。本研究的目的是研究NAFC暴露对绒毛外滋养层细胞中GDF15关键转录因子调控的影响。在这些转录因子中，包括前列腺素在内的炎症介质已被报道在体外可抑制滋养层细胞的增殖和迁移。因此，本研究的次要目的是确定通过前列腺素产生介导的炎症是否对GDF15分泌至关重要。将HTR-8/SVneo细胞暴露于NAFC 6小时和24小时，以评估关键转录调节因子的表达、GDF15分泌和前列腺素（PGE）产量。用NAFC（仅125mg/L）处理显著增加了GDF15的表达和分泌，并伴随着转录因子KLF4、EGR1、ATF3和TP53的上调。同样，在相同浓度下，PTGS2（即COX2）的表达和PGE产量也显著增加。然而，与COX2选择性拮抗剂（SC236）共同处理仅部分阻断了NAFC诱导的PGE产量增加，并未阻断GDF15的表达或分泌。这些发现表明，虽然NAFC可能影响GDF15的产生，但这并非完全是前列腺素介导的炎症所致。本研究为NAFC可能对哺乳动物胎盘滋养层细胞功能产生不利影响的机制提供了新的见解。
