CS Mott Center for Human Growth and Development, Department of Ob/Gyn, Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, Detroit, Michigan, USA.
Reproductive Stress 3M Inc, Grosse Pointe Farms, Michigan, USA.
Birth Defects Res. 2022 Oct 1;114(16):1014-1036. doi: 10.1002/bdr2.2079. Epub 2022 Aug 18.
A problem in developmental toxicology is the massive loss of life from fertilization through gastrulation, and the surprising lack of knowledge of causes of miscarriage. Half to two-thirds of embryos are lost, and environmental and genetic causes are nearly equal. Simply put, it can be inferred that this is a difficult period for normal embryos, but that environmental stresses may cause homeostatic responses that move from adaptive to maladaptive with increasing exposures. At the lower 50% estimate, miscarriage causes greater loss-of-life than all cancers combined or of all cardio- and cerebral-vascular accidents combined. Surprisingly, we do not know if miscarriage rates are increasing or decreasing. Overshadowed by the magnitude of miscarriages, are insufficient data on teratogenic or epigenetic imbalances in surviving embryos and their stem cells. Superimposed on the difficult normal trajectory for peri-gastrulation embryos are added malnutrition, hormonal, and environmental stresses. An overarching hypothesis is that high throughput screens (HTS) using cultured viable reporter embryonic and placental stem cells (e.g., embryonic stem cells [ESC] and trophoblast stem cells [TSC] that report status using fluorescent reporters in living cells) from the pre-gastrulation embryo will most rapidly test a range of hormonal, environmental, nutritional, drug, and diet supplement stresses that decrease stem cell proliferation and imbalance stemness/differentiation. A second hypothesis is that TSC respond with greater sensitivity in magnitude to stress that would cause miscarriage, but ESC are stress-resistant to irreversible stemness loss and are best used to predict long-term health defects. DevTox testing needs more ESC and TSC HTS to model environmental stresses leading to miscarriage or teratogenesis and more research on epidemiology of stress and miscarriage. This endeavor also requires a shift in emphasis on pre- and early gastrulation events during the difficult period of maximum loss by miscarriage.
发育毒理学的一个问题是，从受精到原肠胚形成阶段大量胚胎死亡，而导致流产的原因却令人惊讶地知之甚少。有一半到三分之二的胚胎会丢失，环境和遗传原因几乎各占一半。简单地说，可以推断出这是正常胚胎的一个困难时期，但环境压力可能会引起内稳态反应，随着暴露的增加，从适应性反应转变为适应性反应。在较低的 50%估计中，流产导致的死亡人数超过所有癌症的总和或所有心脑血管意外的总和。令人惊讶的是，我们不知道流产率是在增加还是在减少。流产的数量如此之大，以至于幸存胚胎及其干细胞中致畸或表观遗传失衡的数据不足。在原肠胚形成期胚胎的正常轨迹之外，还存在营养不良、激素和环境压力等问题。一个总体假设是，使用培养的有活力的报告胚胎和胎盘干细胞（例如，使用荧光报告基因在活细胞中报告状态的胚胎干细胞[ESC]和滋养层干细胞[TSC]）进行高通量筛选（HTS），可以最快地测试一系列激素、环境、营养、药物和饮食补充压力，这些压力会降低干细胞增殖并使干细胞特性/分化失衡。另一个假设是，TSC 对导致流产的应激的反应幅度更大，但 ESC 对不可逆的干细胞特性丧失有抵抗力，最适合用于预测长期健康缺陷。DevTox 测试需要更多的 ESC 和 TSC HTS 来模拟导致流产或致畸的环境压力，以及更多关于应激和流产的流行病学研究。这一努力还需要将重点转移到受孕和早期原肠胚形成期间，这是流产风险最大的困难时期。
