Vitamin A and clefting: putative biological mechanisms

Abstract

Nutritional factors such as vitamin intake contribute to the etiology of cleft palate. Vitamin A is a regulator of embryonic development. Excess vitamin A can cause congenital malformations such as spina bifida and cleft palate. Therefore, preventive nutritional strategies are required. This review identifies putative biological mechanisms underlying the association between maternal vitamin A intake and cleft palate. Excessive vitamin A may disturb all three stages of palatogenesis: 1) during shelf outgrowth, it may decrease cell proliferation and thus prevent tissue development; 2) it may prevent shelf elevation by affecting extracellular matrix composition and hydration; and 3) during shelf fusion, it may affect epithelial differentiation and apoptosis, which precludes the formation of a continuous palate. In general, high doses of vitamin A affect palatogenesis through interference with cell proliferation and growth factors such as transforming growth factor β and platelet-derived growth factor. The effects of lower doses of vitamin A need to be investigated in greater depth in order to improve public health recommendations.

Retinoic acid inhibits histone methyltransferase Whsc1 during palatogenesis

“…There are many reports regarding the pathogenesis of cleft palate by environmental factors [1,4]. Recent findings also demonstrate that metabolic diseases and cancer caused by environmental factors are associated with epigenetic changes in a target gene(s) [21,22].…”

“…Maternal smoking; some specific teratogens, for example valproic acid; nutritional factors, such as folate deficiency; and exposure to maternal alcohol consumption have all been suggested as risk factors for cleft palate [1]. Retinoic acid (RA) is the one of the environmental factors for which both deficiency and overdose cause CL/P in mice and humans [4].…”

Micronutrients and Oral Clefts

“…High-dose vitamin A (greater than 10,000 IU per day) is linked to an increased risk of malformations and cranialneural-crest defects in some but not all studies (Rothman et al, 1995;Khoury et al, 1996;Shaw et al, 1996;Mitchell et al, 2003). It is posited that vitamin A is teratogenic at low or high levels, although specific thresholds are unknown (Ackermans et al, 2011). Our finding of an increased risk with vitamin A supplement use, though statistically imprecise, was opposite of our finding for liver consumption, perhaps because vitamin A from supplements increases plasma concentrations of teratogenic metabolites of vitamin A whereas liver does not (Buss et al, 1994).…”

Metabolic Characterization of All-Trans-Retinoic Acid (ATRA)–Induced Craniofacial Development of Murine Embryos Using In Vivo Proton Magnetic Resonance Spectroscopy

“…All-trans retinoic acid (RA), an endogenous metabolite of vitamin A, is required for normal pattern formation during embryogenesis [10]. Conversely, abnormally high concentrations in both experimental animals and humans result in fetal malformations, including cleft palate [10], [11].…”