AOP Report: Decreased ALDH1A (RALDH) activity leading to decreased fertility via disrupted meiotic initiation of fetal oogonia

This report describes a novel adverse outcome pathway (AOP) highlighting how the inhibition of aldehyde dehydrogenase 1A (ALDH1A) enzymatic activity can lead to female infertility in mammals through disrupted meiotic entry of fetal germ cells (AOP-Wiki 398). In mammals, all-trans retinoic acid (atRA) can induce germ cell meiosis; during fetal life in females, germ cells enter meiosis prophase I. Reduced levels or absence of atRA disrupts this process, impairing germ cell development and leading to a reduced ovarian reserve in postnatal ovaries. The synthesis of atRA from vitamin A precursors involves an intermediate catalytic conversion of retinal by ALDH1A. Evidence for this AOP, particularly the upstream events, is primarily derived from mouse studies (both genetic models and exposure studies, including explanted ovaries). Human evidence, especially for downstream events, corroborates that the ovarian reserve directly impacts fertility. In reproductive toxicity studies (both animal studies and human epidemiology), fertility is a critical endpoint for chemical safety assessments. Although infertility has multiple causes, this AOP specifically captures events of perturbed meiosis due to reduced atRA signaling during development, thus supporting the use of in silico and in vitro data on nuclear receptor activity of the retinoic acid and retinoid X receptors (RAR/RXR) and atRA synthesis/expression to predict potential in vivo effects.