Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, University of Hawaii John A. Burns School of Medicine, Honolulu, HI 96813, USA.
Department of Quantitative Health Sciences, University of Hawaii John A. Burns School of Medicine, Honolulu, HI 96813, USA.
Mol Hum Reprod. 2021 Mar 24;27(4). doi: 10.1093/molehr/gaab015.
Early embryos are vulnerable to environmental insults, such as medications taken by the mother. Due to increasing prevalence of hypercholesterolemia, more women of childbearing potential are taking cholesterol-lowering medications called statins. Previously, we showed that inhibition of the mevalonate pathway by statins impaired mouse preimplantation development, by modulating HIPPO signaling, a key regulator for trophectoderm (TE) lineage specification. Here, we further evaluated molecular events that are altered by mevalonate pathway inhibition during the timeframe of morphogenesis and cell lineage specification. Whole transcriptome analysis revealed that statin treatment dysregulated gene expression underlying multiple processes, including cholesterol biosynthesis, HIPPO signaling, cell lineage specification and endoplasmic reticulum (ER) stress response. We explored mechanisms that link the mevalonate pathway to ER stress, because of its potential impact on embryonic health and development. Upregulation of ER stress-responsive genes was inhibited when statin-treated embryos were supplemented with the mevalonate pathway product, geranylgeranyl pyrophosphate (GGPP). Inhibition of geranylgeranylation was sufficient to upregulate ER stress-responsive genes. However, ER stress-responsive genes were not upregulated by inhibition of ras homolog family member A (RHOA), a geranylgeranylation target, although it interfered with TE specification and blastocyst cavity formation. In contrast, inhibition of Rac family small GTPase 1 (RAC1), another geranylgeranylation target, upregulated ER stress-responsive genes, while it did not impair TE specification or cavity formation. Thus, our study suggests that the mevalonate pathway regulates cellular homeostasis (ER stress repression) and differentiation (TE lineage specification) in preimplantation embryos through GGPP-dependent activation of two distinct small GTPases, RAC1 and RHOA, respectively. Translation of the findings to human embryos and clinical settings requires further investigations.
早期胚胎易受环境因素的影响，如母亲服用的药物。由于高胆固醇血症的患病率不断上升，越来越多有生育能力的女性正在服用降胆固醇药物，即他汀类药物。此前，我们研究表明，他汀类药物通过调节 Hippo 信号通路，干扰胆固醇生物合成，从而抑制甲羟戊酸通路，损害了小鼠的胚胎植入前发育。Hippo 信号通路是滋养外胚层（TE）谱系特化的关键调节因子。在这里，我们进一步评估了在形态发生和细胞谱系特化的时间框架内，甲羟戊酸通路抑制所改变的分子事件。全转录组分析显示，他汀类药物处理后，多个过程的基因表达发生了紊乱，包括胆固醇生物合成、Hippo 信号通路、细胞谱系特化和内质网（ER）应激反应。我们探索了甲羟戊酸通路与 ER 应激之间的联系机制，因为这可能对胚胎的健康和发育产生影响。当用甲羟戊酸通路产物香叶基香叶基焦磷酸（GGPP）补充他汀类药物处理的胚胎时，上调的 ER 应激反应基因受到抑制。然而，尽管抑制了 geranylgeranylation 的靶点 ras 同源家族成员 A（RHOA），但 ER 应激反应基因并未被上调，尽管它干扰了滋养外胚层的特化和囊胚腔的形成。相比之下，另一个 geranylgeranylation 靶点 Rac 家族小 GTPase1（RAC1）的抑制上调了 ER 应激反应基因，而不会损害滋养外胚层的特化或囊胚腔的形成。因此，我们的研究表明，甲羟戊酸通路通过 GGPP 依赖性激活两种不同的小 GTPases RAC1 和 RHOA，分别调节胚胎植入前胚胎的细胞内稳态（ER 应激抑制）和分化（滋养外胚层谱系特化）。将这些发现转化为人类胚胎和临床环境需要进一步研究。
