Genetically programmed retinoic acid deficiency during gastrulation phenocopies most known developmental defects due to acute prenatal alcohol exposure in FASD

B Petrelli; A Oztürk; M Pind; H Ayele; A Fainsod; G G Hicks

doi:10.3389/fcell.2023.1208279

Genetically programmed retinoic acid deficiency during gastrulation phenocopies most known developmental defects due to acute prenatal alcohol exposure in FASD

Front Cell Dev Biol. 2023 Jun 16:11:1208279. doi: 10.3389/fcell.2023.1208279. eCollection 2023.

Authors

B Petrelli¹, A Oztürk¹, M Pind¹, H Ayele¹, A Fainsod², G G Hicks¹

Affiliations

¹ Department of Biochemistry and Medical Genetics, Regenerative Medicine Program, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada.
² Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.

Abstract

Fetal Alcohol Spectrum Disorder (FASD) arises from maternal consumption of alcohol during pregnancy affecting 2%-5% of the Western population. In Xenopus laevis studies, we showed that alcohol exposure during early gastrulation reduces retinoic acid (RA) levels at this critical embryonic stage inducing craniofacial malformations associated with Fetal Alcohol Syndrome. A genetic mouse model that induces a transient RA deficiency in the node during gastrulation is described. These mice recapitulate the phenotypes characteristic of prenatal alcohol exposure (PAE) suggesting a molecular etiology for the craniofacial malformations seen in children with FASD. Gsc ^+/Cyp26A1 mouse embryos have a reduced RA domain and expression in the developing frontonasal prominence region and delayed HoxA1 and HoxB1 expression at E8.5. These embryos also show aberrant neurofilament expression during cranial nerve formation at E10.5 and have significant FASD sentinel-like craniofacial phenotypes at E18.5. Gsc ^+/Cyp26A1 mice develop severe maxillary malocclusions in adulthood. Phenocopying the PAE-induced developmental malformations with a genetic model inducing RA deficiency during early gastrulation strongly supports the alcohol/vitamin A competition model as a major molecular etiology for the neurodevelopmental defects and craniofacial malformations seen in children with FASD.

Keywords: craniofacial malformations; fetal alcohol spectrum disorder (FASD); gastrulation; malocclusion; prenatal alcohol exposure (PAE); retinoic acid; vitamin A deficiency.

Grants and funding

This research was supported by grants from Manitoba Liquor and Lotteries to GH and AF, Children’s Hospital Foundation of Manitoba to GH, Canadian Institutes of Health Research to GH and AF, the Wolfson Family Chair in Genetics to AF, and Research Manitoba/Children’s Hospital Research Institute of Manitoba PhD Studentship to BP. All animal studies were performed under approved animal research protocol AC11509 from the University of Manitoba.