Loss of tumor protein 53 protects against alcohol‐induced facial malformations in mice and zebrafish. (28th September 2021)

• Record Type: Journal Article
• Authors: Fish, Eric W.; Tucker, Scott K.; Peterson, Rachel L.; Eberhart, Johann K.; Parnell, Scott E.
• Is Part Of: Alcoholism. Volume 45:Number 10(2021)
• Page Start: 1965
• Page End: 1979
• Publication Date: 2021-09-28
• Subjects: apoptosis -- birth defects -- craniofacial -- fetal alcohol syndrome -- ocular; Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.14688
• Languages: English
• ISSNs: 0145-6008

Abstract

Abstract: Background: Alcohol exposure during the gastrulation stage of development causes the craniofacial and brain malformations that define fetal alcohol syndrome. These malformations, such as a deficient philtrum, are exemplified by a loss of midline tissue and correspond, at least in part, to regionally selective cell death in the embryo. The tumor suppressor protein Tp53 is an important mechanism for cell death, but the role of Tp53 in the consequences of alcohol exposure during the gastrulation stage has yet to be examined. The current studies used mice and zebrafish to test whether genetic loss of Tp53 is a conserved mechanism to protect against the effects of early developmental stage alcohol exposure. Methods: Female mice, heterozygous for a mutation in the Tp53 gene, were mated with Tp53 heterozygous males, and the resulting embryos were exposed during gastrulation on gestational day 7 (GD 7) to alcohol (two maternal injections of 2.9 g/kg, i.p., 4 h apart) or a vehicle control. Zebrafish mutants or heterozygotes for the tp53 zdf1 M214K mutation and their wild‐type controls were exposed to alcohol (1.5% or 2%) beginning 6 h postfertilization (hpf), the onset of gastrulation. Results: Examination of GD 17 mice revealed that eye defects were the most common phenotype among alcohol‐exposed fetuses, occurring in nearly 75% of the alcohol‐exposed wild‐type fetuses. Tp53 gene deletion reduced the incidence of eye defects in both the heterozygous and mutant fetuses (to about 35% and 20% of fetuses, respectively) and completely protected against alcohol‐induced facial malformations. Zebrafish (4 days postfertilization) also demonstrated alcohol‐induced reductions of eye size and trabeculae length that were less common and less severe in tp53 mutants, indicating a protective effect of tp53 deletion. Conclusions: These results identify an evolutionarily conserved role of Tp53 as a pathogenic mechanism for alcohol‐induced teratogenesis. Abstract : Early gestational alcohol exposure causes excessive cell death in the embryonic tissues that become the eyes, face, and brain. Modeling the craniofacial features of fetal alcohol syndrome (FAS), we report that the Tumor Protein 53 (Tp53), which regulates apoptotic cell death, is an important mediator of alcohol‐induced teratogenesis. Partial or full deletion of Tp53 protected mice and zebrafish from developing several FAS‐like dysmorphologies, ranging from microphthalmia to palatal and neurocranial defects.