Self-reinforcing ROS-aneuploidy feedback loop shapes preimplantation development

Abstract

Aneuploidy and oxidative stress have each been implicated in impaired embryonic development, yet their relationship remains unclear. Here we discover a self-reinforcing ROS-aneuploidy feedback loop with hysteretic properties in preimplantation development. In human blastocysts, oxidative stress associates with aneuploidy at the population level. Paradoxically, euploid and aneuploid embryos can show overlapping oxidative states, and oxidative stress is uncoupled from morphological, temporal, and maternal age-associated indicators of developmental competence. To test whether oxidative stress and aneuploidy merely co-occur or actively influence one another, we used IVF-derived mouse embryos. Induced chromosome missegregation elevates oxidative damage, while oxidative perturbations promote aneuploidy. Crucially, restoring ROS to baseline levels fails to rescue chromosome integrity or developmental potential, revealing hysteresis whereby outcomes depend more on prior chromosomal history than on instantaneous redox state. Together, these reveal that transient redox perturbations can induce persistent chromosomal alterations that shape developmental outcomes even after redox balance is restored, thereby challenging proposals of ROS as a biomarker of embryonic competence.