E-liquids and vanillin flavoring disrupts retinoic acid signaling and causes craniofacial defects in Xenopus embryos.

The study by Dickinson et al. (2022) found that copy number variants (CNVs) in retinoic acid pathway and metabolism genes are associated with craniofacial malformations in human patients. The researchers used data from DECIPhER (DatabasE of genomiC varIation and Phenotype in humans using Ensembl Resources) to identify CNVs in genes involved in the retinoic acid pathway, specifically those that catalyze reactions involved in drug metabolism, synthesis of cholesterol, vitamins, steroids, and other lipids, and play an important role in all-trans retinoic acid biosynthesis.

The study found that losses in the CRaBP1, CRaBP2, RaLDh2, and RaRG genes, which are involved in the conversion of retinol to all-trans retinal and then to the active form all-trans retinoic acid, were associated with craniofacial malformations. Similarly, gains in the CYP26C1 gene, which is involved in the oxidative transformation of all-trans retinal to all-trans retinoic acid, were also associated with craniofacial malformations.

Specifically, 12.5% of patients with CNVs in the CRaBP1 gene had craniofacial malformations, while 80% of patients with CNVs in the CRaBP2 gene had craniofacial malformations. additionally, 33.3% of patients with CNVs in the RaLDh2 gene had craniofacial malformations, and all patients with CNVs in the RaRG gene had craniofacial malformations. Lastly, 33.3% of patients with CNVs in the CYP26C1 gene had craniofacial malformations.

Overall, this study suggests that CNVs in retinoic acid pathway and metabolism genes may play a role in the development of craniofacial malformations in human patients.

Dickinson aJG, Turner SD, Wahl S, Kennedy aE, Wyatt Bh, howton Da. E-liquids and vanillin flavoring disrupts retinoic acid signaling and causes craniofacial defects in Xenopus embryos. Developmental biology. 2022;481:14-29. doi:10.1016/j.ydbio.2021.09.004