Retinaldehyde Dehydrogenase Inhibition-Related Adverse Outcome Pathway: Potential Risk of Retinoic Acid Synthesis Inhibition during Embryogenesis

Abstract

Retinoic acid (RA) is one of the factors crucial for cell growth, differentiation, and embryogenesis; it interacts with the retinoic acid receptor and retinoic acid X receptor to eventually regulate target gene expression in chordates. RA is transformed from retinaldehyde via oxidization by retinaldehyde dehydrogenase (RALDH), which belongs to the family of oxidoreductases. Several chemicals, including disulphiram, diethylaminobenzaldehyde, and SB-210661, can effectively inhibit RALDH activity, potentially causing reproductive and developmental toxicity. The modes of action can be sequentially explained based on the molecular initiating event toward key events, and finally the adverse outcomes. Adverse outcome pathway (AOP) is a conceptual and theoretical framework that describes the sequential chain of casually liked events at different biological levels from molecular events to adverse effects. In the present review, we discussed a recently registered AOP (AOP297; inhibition of retinaldehyde dehydrogenase leads to population decline) to explain and support the weight of evidence for RALDH inhibition-related developmental toxicity using the existing knowledge.

Retinoic Acid is Required for Normal Morphogenetic Movements During Gastrulation

“…Mutation of each of these genes in vertebrate embryos results in post-gastrula delays and loss of viability ( Niederreither et al, 1999 ; Begemann et al, 2001 ; Sandell et al, 2007 ). Therefore, we propose that the pharmacological inhibitors of RA biosynthesis used in these and the present study (DEAB, citral, ethanol) likely target more than one ALDH enzyme during early embryogenesis ( Morgan et al, 2015 ; Cho et al, 2021 ). The specificity of the RA reduction by these reagents is supported by the similar results obtained by overexpressing Cyp26a1, an RA catabolic enzyme ( Yelin et al, 2005 ; this work).…”

Thallium - poisoner’s poison: An overview and review of current knowledge on the toxicological effects and mechanisms

“…Aldehyde dehydrogenase catalyzes the production of retinoic acid from retinol (vitamin A), and endogenous retinoic acid is essential for embryonic development and adult physiological processes ( Wang et al, 2023 ). Retinoic acid also plays an important role in the development of the BBB in humans and mice ( Mizee et al, 2013 ), and its signaling is a critical process for neurodevelopment ( Cho et al, 2021 , Menegola et al, 2021 ). The inhibition of aldehyde dehydrogenase by Tl + exposure may prevent the development of the BBB as well as neurodevelopment by decreasing retinoic acid levels.…”

Pet Wellness and Vitamin A: A Narrative Overview

“…In mammals, including felines and canines, this oxidation reaction is mediated by enzymes called alcohol dehydrogenases (ADHs), particularly class I ADH and class IV ADH, which convert retinol to retinaldehyde [79][80][81][82][83][84][85]. Retinaldehyde can further metabolize to produce ATRA through the enzymatic activity of retinaldehyde dehydrogenases (RALDHs) [86][87][88]. The primary isoform responsible for this conversion, as evidenced by studies in dogs, is RALDH1A2 [89].…”