Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.
Obstetrics and Gynecology Department, Songjiang Maternal and Child Health-Care Hospital, Shanghai, China.
Ecotoxicol Environ Saf. 2022 Mar 15;233:113307. doi: 10.1016/j.ecoenv.2022.113307. Epub 2022 Feb 16.
Several epidemiological studies have reported significant associations between prenatal polybrominated diphenyl ethers (PBDEs) exposure and adverse birth outcomes. Placental injury is thought to mediate these associations. However, few study has investigated the adverse effects of PBDEs exposure on placental growth and development. We examined the impacts of gestational exposure to BDE-209, the most abundant PBDE conger detected in human samples, on placental structure and function, and its model of action in vivo and in vitro. Pregnant mice were exposed to 0, 2, 20, 200 mg/kg/day of BDE-209 by gavages from gestational day (GD) 0 to GD18. Results showed that gestational BDE-209 exposure significantly reduced placental weight, impaired placental vascular development and induced placental cell apoptosis. In addition, gestational BDE-209 exposure impaired placental transport and endocrine function as demonstrated by markedly downregulated expression of Glut1, Znt1, Pgf and Igf2 in BDE-209-treated placentas. Mechanistically, gestational exposure to BDE-209 upregulated the expression of GRP78, and 3 downstream proteins (p-eIF2α, ATF4 and CHOP) of the PERK signaling, suggesting the activation of endoplasmic reticulum (ER) stress and PERK signaling pathway in mouse placentas. Further in vitro study showed that PERK siRNA pretreatment markedly reversed BDE-209-induced cell apoptosis in human JEG-3 cells. Collectively, our results suggest that the activation of the ER stress-mediated PERK/ATF4/CHOP signaling pathway played a role in BDE-209-induced placental injury. Our findings provide new insight into the mechanisms of BDE-209 induced reproductive and developmental toxicity.
几项流行病学研究报告称，产前多溴联苯醚（PBDEs）暴露与不良出生结局之间存在显著关联。胎盘损伤被认为介导了这些关联。然而，很少有研究调查 PBDEs 暴露对胎盘生长和发育的不良影响。我们研究了母体妊娠期暴露于 BDE-209（在人体样本中检测到的最丰富的 PBDE 同系物）对胎盘结构和功能的影响，以及其在体内和体外的作用模式。怀孕的小鼠通过灌胃从妊娠第 0 天（GD）至第 18 天每天接受 0、2、20、200mg/kg 的 BDE-209 暴露。结果表明，母体妊娠期 BDE-209 暴露显著降低了胎盘重量，损害了胎盘血管发育并诱导了胎盘细胞凋亡。此外，母体妊娠期 BDE-209 暴露损害了胎盘的转运和内分泌功能，表现为 BDE-209 处理的胎盘中 Glut1、Znt1、Pgf 和 Igf2 的表达明显下调。从机制上讲，母体妊娠期暴露于 BDE-209 上调了 PERK 信号的 GRP78 和 3 个下游蛋白（p-eIF2α、ATF4 和 CHOP）的表达，提示内质网（ER）应激和 PERK 信号通路在小鼠胎盘中被激活。进一步的体外研究表明，PERK siRNA 预处理可显著逆转 BDE-209 诱导的人 JEG-3 细胞凋亡。总之，我们的研究结果表明，ER 应激介导的 PERK/ATF4/CHOP 信号通路的激活在 BDE-209 诱导的胎盘损伤中起作用。我们的研究结果为 BDE-209 诱导的生殖和发育毒性的机制提供了新的见解。
