Gestational exposure to environmental stress induces fetal growth restriction (FGR), and thereby increasing the risk of infant death and chronic noncommunicable diseases in adults. However, the mechanism by which environmental stress induces FGR remains unclear. Based on case-control study, we found that the reduced level of melatonin (MT), a major secretory product from the pineal gland, was observed in placentae of FGR. This work was to investigate the protective effect of MT on environmental stress-caused FGR and its mechanisms. We used cadmium (Cd) as an environmental stressor to stimulate pregnant mice and thereby establishing a FGR model. The data showed that maternal Cd exposure lowered the P4 concentration in maternal sera, placentae and amniotic fluid, and caused FGR. Correspondingly, the expression of CYP11A1, a critical P4 synthase, was markedly downregulated in Cd-treated placentae. Simultaneously, Cd triggered BNIP3-dependent mitophagy in placental trophoblasts, as determined by the degradation of mitochondrial proteins, including HSP60 and COX IV, and the accumulation of puncta representing co-localization of TOM20 with LC3B or BNIP3 with LC3B. Based on our case-control study, we also found that activated BNIP3-dependent mitophagy and P4 synthesis inhibition occurred in SGA placentae. Most importantly, BNIP3 siRNA reversed Cd-induced P4 synthesis suppression in human placental trophoblasts. It is noteworthy that MT alleviated Cd-caused P4 synthesis suppression and FGR via antagonizing BNIP3-dependent mitophagy in placental trophoblasts. Further results confirmed that MT attenuated Cd-triggered BNIP3-dependent mitophagy via blocking GCN2/ATF4 signaling. Amusingly, Cd triggered oxidative stress and then activating GCN2/ATF4 signaling in placental trophoblasts. As expected, MT obviously suppressed Cd-caused reactive oxygen species (ROS) release. In the present study, we propose a neoteric mechanism by which MT protects against environmental stress-impaired P4 synthesis and fetal growth via suppressing ROS-mediated GCN2/ATF4/BNIP3-dependent mitophagy in placental trophoblasts. As above, MT is a potential therapeutic agent antagonizing environmental stress-induced developmental toxicity.

妊娠暴露于环境压力下会导致胎儿生长受限（FGR），从而增加成人婴儿死亡和慢性非传染性疾病的风险。但是，环境压力诱导FGR的机制仍不清楚。根据病例对照研究，我们发现在FGR的胎盘中发现了褪黑激素（MT）含量降低，这是松果体的主要分泌产物。这项工作是调查MT对环境压力引起的FGR的保护作用及其机理。我们使用镉（Cd）作为环境应激源刺激怀孕的小鼠，从而建立了FGR模型。数据显示，母体镉暴露降低了母体血清，胎盘和羊水中的P4浓度，并导致了FGR。相应地，关键的P4合酶CYP11A1的表达 镉处理过的胎盘中的蛋白明显下调。同时，Cd在胎盘滋养细胞中触发了依赖BNIP3的线粒体化，这是由线粒体蛋白（包括HSP60和COX IV）的降解以及点状积累（代表TOM20与LC3B或BNIP3与LC3B共同定位）确定的。根据我们的病例对照研究，我们还发现SGA胎盘中发生了活化的BNIP3依赖性线粒体吞噬和P4合成抑制。最重要的是，我们还发现在SGA胎盘中发生了活化的BNIP3依赖性线粒体和P4合成抑制作用。最重要的是，我们还发现在SGA胎盘中发生了活化的BNIP3依赖性线粒体和P4合成抑制作用。最重要的是，BNIP3siRNA逆转了人胎盘滋养细胞中Cd诱导的P4合成抑制。值得注意的是，MT通过拮抗胎盘滋养细胞中BNIP3依赖性线粒体减轻了Cd引起的P4合成抑制和FGR。进一步的结果证实，MT通过阻断GCN2 / ATF4信号传导减弱了Cd触发的BNIP3依赖性线粒体。有趣的是，Cd触发了氧化应激，然后激活了胎盘滋养细胞中的GCN2 / ATF4信号传导。不出所料，MT明显抑制了Cd引起的活性氧（ROS）释放。在本研究中，我们提出了一种新的机制，MT通过抑制胎盘滋养细胞中ROS介导的GCN2 / ATF4 / BNIP3依赖的细胞吞噬作用来防止环境应激损害的P4合成和胎儿生长。如上，