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

TL;DR

This paper describes how reduced ALDH1A activity disrupts retinoid signaling, leading to infertility in mammals through impaired meiosis in fetal germ cells.

Contribution

The paper introduces a novel AOP linking ALDH1A inhibition to fertility disruption via meiotic failure.

Findings

ALDH1A inhibition reduces atRA levels, impairing germ cell meiosis and ovarian reserve.

Mouse and human evidence supports the role of atRA in fertility and ovarian reserve.

In silico and in vitro data can predict in vivo effects of retinoid signaling disruption.

Abstract

•Description of a novel AOP relevant for disrupted retinoid signaling.•ALDH1A inhibition is linked to decreased fertility via disrupted germ cell meiosis.•The AOP supports the use of in silico and in vitro data to predict in vivo effects.

Description of a novel AOP relevant for disrupted retinoid signaling.

ALDH1A inhibition is linked to decreased fertility via disrupted germ cell meiosis.

The AOP supports the use of in silico and in vitro data to predict in vivo effects.

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.

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