Viewing teratogens through the lens of nicotinamide adenine dinucleotide (NAD+)

Abstract

Background Nicotinamide adenine dinucleotide (NAD+) depletion is associated with numerous diseases in humans. Recently it was revealed that genetic blockage of the NAD+ synthesis pathway in humans causes birth defects in multiple organ systems and miscarriage. Additionally, mice with NAD+ deficiency created through dietary restriction of tryptophan and vitamin B3 were shown to have congenital anomalies affecting virtually every organ system along with miscarriage. Perturbations in NAD+/NADH affect mechanisms of teratogenesis presented by Wilson and others, including genetic alterations, altered energy sources, and lack of precursors and substrates needed for biosynthesis. Methods Medical literature was evaluated to demonstrate how perturbations in NAD+/NADH affect mechanisms of teratogenesis. In addition, literature describing several different teratogens of various types (infectious, physical, maternal health factors, drugs) was reviewed showing the impact of these teratogens on NAD+ and NAD+/NADH ratios. Result Many teratogens affect NAD+ by altering its metabolism, decreasing its intracellular availability, or decreasing its production, which in turn is a plausible mechanism for the creation of birth defects. Conclusion Looking at teratogens through the lens of their impact on NAD+ could provide valuable insight into the mechanism by which some teratogens cause birth defects and miscarriage.

Ear anomalies and hearing loss in patients with VACTERL association and the effect of maternal diabetes

“…We hypothesize that diabetes may act as an environmental factor influencing the phenotypic expression in patients with the VACTERL association spectrum. A possible explanation of this association is the known relationship between diabetes and dysregulation of NAD metabolism (Allegri et al, 2003; Fan et al, 2020; Mark & Dunwoodie, 2022). Diabetes may also increase the risk of vascular disruption which has been proposed as a mechanism in VACTERL (Stevenson & Hunter, 2013).…”

Differential responses to maternal diabetes in embryo and visceral yolk sac

“…NAD levels in pregnancy are dependent on intake of Niacin, and diets low in Niacin were linked to a higher prevalence of birth defects ( Palawaththa et al, 2022 ). Mice with mutations that reduce NAD availability exhibit developmental defects ( Cuny et al, 2020 ; Cuny et al, 2023 ) and suggest that low NAD levels could be involved in teratogenesis upon exposure to various agents ( Mark et al, 2022 ). Our finding of predicted increased activity of NAD metabolism in diabetes-exposed embryos could be indicative of a compensatory response.…”

Supplementation with NAD+ and its precursors: A rescue of female reproductive diseases

“…Restriction of maternal intake of NAD + precursors leads to embryonic loss and multiple congenital malformations in wild-type mice. Therefore, there is an elevated risk of NAD + deficiency during pregnancy, when an adequate supply of NAD + is required to ensure normal embryonic development [ 71 ]. Birth defects resulting from insufficient NAD + synthesis during embryogenesis are called congenital NAD + deficiency and most commonly affect the heart, kidneys, vertebrae and limbs [ 72 ].…”