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Relationship: 2401
Title
Decreased, ALDH1A activity leads to Decreased, atRA concentration
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
|---|---|---|---|---|---|---|
| Decreased ALDH1A (RALDH) activity leading to decreased fertility via disrupted meiotic initiation of fetal oogonia | adjacent | High | Moderate | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | Under Development |
| Inhibition of RALDH2 causes reduced all-trans retinoic acid levels, leading to transposition of the great arteries | adjacent | High | Moderate | Gina Mennen (send email) | Open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Male | High |
| Female | High |
Life Stage Applicability
| Term | Evidence |
|---|---|
| All life stages |
Key Event Relationship Description
All-trans retinoic acid (atRA) is the active metabolite of vitamin A in developing mammals and its physiological levels is tightly regulated by enzymatic pathways. This KER is particularly relevant for mammalian embryogenesis/fetal development stages.
atRA is synthesized from dietary vitamin A (retinol) by a two-step oxidation pathway (Chatzi et al, 2013; Kedishvili, 2016): 1) retinol dehydrogenase (RDH10) metabolizes retinol to retinaldehyde (reversible step), 2) retinaldehyde dehydrogenase ALDH1A (ALDH1A1, ALDH1A2, ALDH1A3) metabolizes retinaldehyde to RA (irreversible step). All three isoenzymes can carry out the second (irreversible step) to produce atRA, but ALDH1A2 is the most active form during development (Kedishvili, 2016). Thus, inhibition of ALDH1A2 during development will decrease atRA concentrations.
Evidence Collection Strategy
This KER is considered canonical knowledge and supporting literature was sourced from e.g. key review articles from open literature. I.e. evidence was not sourced by systematic literature search strategies.
Evidence Supporting this KER
Evidence showing that retinaldehyde dehydrogenases is responsible for the irreversible oxidation of retinal to retinoic acid was provided by several studies in the 1960s, using calf and rat livers (Dmitrovskii, 1961; Dunagin Jr et al, 1964; Elder & Topper, 1962; Futterman, 1962; Lakshmanan et al, 1964; Mahadevan et al, 1962), as reviewed by (Kedishvili, 2016). The identification of the three isoenzymes ALDH1A1 (RALDH1), ALDH1A2 (RALDH2), ALDH1A3 (RALDH3) followed during 1980-1990 (Kedishvili, 2016). It is now considered canonical knowledge that the three retinaldehyde dehydrogenases are responsible for the in vivo biosynthesis of retinoic acid from retinal (Marchitti et al, 2008; Napoli, 2012).
Biological Plausibility
Embryogenesis/fetal development in mammals
Of the three isoenzymes, ALDH1A2 is the most active form during early development in mammals. This is evidenced in mice ablated for Aldh1a2 (Raldh2-/-), which are incapable of producing atRA and present with severe developmental defects (Niederreither et al, 1999). Conversely, mice lacking Aldh1a1 or Aldh1a3 survive fetal development, with phenotypes presenting postnatally (Dupé et al, 2003; Fan et al, 2003; Molotkov & Duester, 2003). Thus, the biological plausibility that inhibition of ALDH1A2 will lead to decreased atRA in cells and tissues during development is strong.
Empirical Evidence
The empirical evidence for linkage is strong and widely accepted. The enzymatic activity of ALDH1A2 and capacity to oxidize retinal has been proven in vitro (see KE 1880). In vivo, the strongest evidence comes from the Aldh1a2-deficient mice that fail to synthesize retinoic acid during embryogenesis (Niederreither et al, 1999). Additionally, ovary culture with the potent ALDH1A2 inhibitor WIN18,446 results in failure to upregulate the atRA-regulated gene Stra8 in oocytes, resulting in germ cell loss (Rosario et al, 2020). Additional evidence for this relationship using WIN18,466 also comes from in vivo studies looking at spermatogenesis; inhibition of ALDH1A2 via WIN18,466 results in loss of atRA expression and halted spermatogenesis in diverse species such as mice, rabbits and zebrafish (Amory et al, 2011; Paik et al, 2014; Pradhan & Olsson, 2015).
Uncertainties and Inconsistencies
There are redundant pathways for atRA synthesis (e.g. ALDH isoforms) which may buffer a decrease in atRA concentrations caused by reduced ALDH1A activity, complicating the prediction of changes to atRA concentration. There is also tissue-specific expression of various components of the atRA synthesis pathways, which introduces additional variability in atRA concentration outcomes depending on biological context.
Known modulating factors
Quantitative Understanding of the Linkage
The distribution of retinoic acid in cells and tissues are highly variable, as has been shown across species including chicken (Maden et al, 1998), frogs (Chen et al, 1994), mice (Kane et al, 2005; Obrochta et al, 2014) and rats (Bhat, 1997), as well as serum/plasma from humans (Kane et al, 2008; Miyagi et al, 2001; Napoli et al, 1985).
The exact relationship between ALDH1A2 inhibition and resulting atRA concentrations in mammalian ovaries is unclear. The ALDH1A2 inhibitor WIN18,446 inhibits enzyme activity in vitro with an IC(50) of 0.3 μM (Amory et al, 2011), and a dose of only 0.01 µM is sufficient to significantly reduce expression of Stra8 in cultured mouse fetal ovaries and with actual loss of oocytes from 2 µM (Rosario et al, 2020).
Response-response Relationship
Time-scale
Since atRA must be enzymatically synthesized by ALDH1A enzymes (in this case ALDH1A2), the temporal and linear relationship between the two KEs are essential.
Known Feedforward/Feedback loops influencing this KER
Retinoic acid status is regulated by complex feedback loops. For instance, atRA induces expression of retinoid enzymes to promote synthesis of retinyl esters, but simultaneously atRA induces expression of its own catabolizing CYP26 enzymes (Kedishvili, 2013; Kedishvili, 2016; Teletin et al, 2017).