Rhon-Calderon Eric A, Hemphill Cassidy N, Savage Alexandra J, Riesche Laren, Schultz Richard M, Bartolomei Marisa S
Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
JCI Insight. 2025 Mar 4;10(8). doi: 10.1172/jci.insight.188931. eCollection 2025 Apr 22.
In vitro fertilization (IVF) is a noncoital method of conception used to treat human infertility. Although IVF is viewed as largely safe, it is associated with adverse outcomes in the fetus, placenta, and adult offspring. Because studies focusing on the effect of IVF on the male reproductive system are limited, we used a mouse model to assess the morphological and molecular effects of IVF on male offspring. We evaluated 3 developmental stages: 18.5-day fetuses and 12- and 39-week-old adults. Regardless of age, we observed changes in testicular-to-body weight ratios, serum testosterone levels, testicular morphology, gene expression, and DNA methylation. Also, sperm showed changes in morphology and DNA methylation. To assess multigenerational phenotypes, we mated IVF-conceived and naturally conceived males with wild-type females. Offspring from IVF males exhibited decreased fetal-to-placental weight ratios and changes in placenta gene expression and morphology regardless of sex. At 12 weeks of age, offspring showed higher body weights and differences in glucose, triglyceride, insulin, total cholesterol, HDL-C, and LDL/VLDL-C levels. Both sexes showed changes in gene expression in liver, testes, and ovaries and decreased global DNA methylation. Collectively, our findings demonstrate that male IVF offspring exhibit abnormal testicular and sperm morphology and molecular alterations with a multigenerational impact.
体外受精（IVF）是一种用于治疗人类不孕症的非性交受孕方法。尽管体外受精在很大程度上被视为安全的，但它与胎儿、胎盘和成年后代的不良后果有关。由于聚焦于体外受精对雄性生殖系统影响的研究有限，我们使用小鼠模型来评估体外受精对雄性后代的形态学和分子影响。我们评估了3个发育阶段：18.5天的胎儿以及12周龄和39周龄的成年小鼠。无论年龄如何，我们均观察到睾丸与体重之比、血清睾酮水平、睾丸形态、基因表达和DNA甲基化的变化。此外，精子在形态和DNA甲基化方面也出现了变化。为了评估多代表型，我们将体外受精受孕和自然受孕的雄性小鼠与野生型雌性小鼠交配。体外受精雄性小鼠的后代无论性别，均表现出胎儿与胎盘重量之比降低以及胎盘基因表达和形态的变化。在12周龄时，后代体重更高，且在葡萄糖、甘油三酯、胰岛素、总胆固醇、高密度脂蛋白胆固醇（HDL-C）和低密度脂蛋白/极低密度脂蛋白胆固醇（LDL/VLDL-C）水平方面存在差异。两性在肝脏、睾丸和卵巢中的基因表达均出现变化，且整体DNA甲基化水平降低。总的来说，我们的研究结果表明，体外受精雄性后代表现出睾丸和精子形态异常以及分子改变，并具有多代影响。
