Zhou Yiran, Neyt Christine, Batchelor Nicola J, Kelley Rebecca L, Jaafar Amsak Karmilla, Anderson Greg M, Oorschot Dorothy E, Jasoni Christine L, Girling Jane E, Pankhurst Michael W
Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
School of Biosciences, University of Melbourne, Melbourne, Australia.
J Endocrinol. 2022 Mar 5;253(2):53-62. doi: 10.1530/JOE-21-0430.
Female anti-Müllerian hormone (AMH) overexpressing (Thy1.2-AMHTg/0) mice experience fetal resorption (miscarriage) by mid-gestation. This study examined whether the ovary, uterine implantation sites and hypothalamus are potential sites of AMH action, as AMH type-2 receptor (AMHR2) expression is reported in each tissue. Pregnancy in Thy1.2-AMHTg/0 mice was compared to wild-type (WT) mice via histological examination of implantation sites, hormone assays, embryo culture and embryo transfer. Uterine AMH and AMHR2 expression was examined by RT-qPCR and immunohistochemistry. The first signs of fetal resorption in the Thy1.2-AMHTg/0 dams occurred at embryonic day 9.5 (E9.5) with 100% of fetuses resorbing by E13.5. Cultured embryos from Thy1.2-AMHTg/0 dams had largely normal developmental rates but a small proportion experienced a minor developmental delay relative to embryos from WT dams. However, embryos transferred from WT donor females always failed to survive to term when transferred into Thy1.2-AMHTg/0 dams. Amh and Amhr2 mRNA was detected in the gravid uterus but at very low levels relative to expression in the ovaries. Progesterone and estradiol levels were not significantly different between WT and Thy1.2-AMHTg/0 dams during pregnancy but luteinizing hormone (LH) levels were significantly elevated in Thy1.2-AMHTg/0 dams at E9.5 and E13.5 relative to WT dams. Collectively, these experiments suggest that AMH overexpression does not cause fetal resorption through an effect on oocytes or preimplantation embryo development. The Thy1.2-AMHTg/0 fetal resorption phenotype is nearly identical to that of transgenic LH overexpression models, suggesting that neuroendocrine mechanisms may be involved in the cause of the miscarriage.
雌性抗苗勒管激素（AMH）过表达（Thy1.2-AMHTg/0）小鼠在妊娠中期会出现胚胎吸收（流产）。本研究探讨卵巢、子宫着床部位和下丘脑是否为AMH的潜在作用部位，因为据报道每个组织中都有AMH 2型受体（AMHR2）表达。通过对着床部位进行组织学检查、激素测定、胚胎培养和胚胎移植，将Thy1.2-AMHTg/0小鼠的妊娠情况与野生型（WT）小鼠进行比较。通过RT-qPCR和免疫组织化学检测子宫中AMH和AMHR2的表达。Thy1.2-AMHTg/0母鼠胚胎吸收的最初迹象出现在胚胎第9.5天（E9.5），到E13.5时100%的胎儿被吸收。来自Thy1.2-AMHTg/0母鼠的培养胚胎发育速度基本正常，但相对于来自WT母鼠的胚胎，一小部分经历了轻微的发育延迟。然而，从WT供体雌性转移来的胚胎在转移到Thy1.2-AMHTg/0母鼠体内后总是无法存活至足月。在妊娠子宫中检测到Amh和Amhr2 mRNA，但相对于卵巢中的表达水平非常低。WT和Thy1.2-AMHTg/0母鼠在妊娠期间孕酮和雌二醇水平无显著差异，但在E9.5和E13.5时，Thy1.2-AMHTg/0母鼠的促黄体生成素（LH）水平相对于WT母鼠显著升高。总体而言，这些实验表明，AMH过表达不会通过影响卵母细胞或着床前胚胎发育导致胚胎吸收。Thy1.2-AMHTg/0胚胎吸收表型与转基因LH过表达模型的表型几乎相同，表明神经内分泌机制可能与流产原因有关。
