Epidemiological studies revealed that prenatal caffeine exposure (PCE) is associated with adverse gestational outcomes and susceptibility to chronic diseases in offspring, yet the effects of PCE on glomerulosclerosis susceptibility in adult female offspring and its intergenerational transmission remain to be further investigated. Here, we found that PCE caused fetal kidney dysplasia and glomerulosclerosis of the female offspring. Besides, the kidney of F1 offspring in PCE group exhibited the “low expressional programming of AT2R” and “GC-IGF1 programming” alteration. Intergenerational genetic studies revealed that the renal defect and GC-IGF1 programming alteration was inherited to F2 adult female offspring derived from the female germ line, but Low expression of AT2R did not extend to the F2 female offspring. Taken together, PCE caused renal dysplasia and adult glomerulosclerosis in the F1 female offspring, which might be mediated by renal AT2R low expressional programming and GC-IGF1 axis alteration. Furthermore, PCE induced transgenerational toxicity on kidney, and GC-IGF1 programming alteration might be the potential molecular mechanism. This study provided experimental evidence for the mechanism study of the intergenerational inheritance of kidney developmental toxicity caused by PCE.

流行病学研究表明，产前咖啡因暴露（PCE）与不良妊娠结局和后代慢性病易感性有关，但 PCE 对成年女性后代肾小球硬化易感性及其代际传播的影响仍有待进一步研究。在这里，我们发现 PCE 会导致女性后代的胎儿肾发育不良和肾小球硬化。此外，PCE组F1后代的肾脏表现出“AT2R低表达编程”和“GC-IGF1编程”改变。代际遗传研究表明，肾缺陷和 GC-IGF1 编程改变遗传给来自雌性生殖系的 F2 成年雌性后代，但 AT2R 的低表达并未延伸到 F2 雌性后代。综合起来，PCE导致F1雌性后代肾发育不良和成年肾小球硬化，这可能是由肾AT2R低表达编程和GC-IGF1轴改变介导的。此外，PCE 对肾脏具有跨代毒性，GC-IGF1 编程改变可能是潜在的分子机制。本研究为PCE致肾脏发育毒性的代际遗传机制研究提供了实验依据。