Interactive endogenous small molecule (gaseous) signaling: implications for teratogenesis

Dioxygen (O2) is an exogenously supplied gas with a number of properties that make it valuable as a biological source of energy and as a result much of life has become dependent on this molecule. Nitric oxide (NO), carbon dioxide (CO) and hydrogen sulfide (H2S) are small molecules that are sometimes in a gaseous state and that can be either exogenously or endogenously supplied. The chemistry of these four molecules allows them to share some common biological targets and signal transduction pathways as well as providing for unique aspects to the biochemistry of each one. Dioxygen can be teratogenic either in excess (hyperoxia) or in deficiency (hypoxia). Although there is a great deal known about the chemistry and physiology of dioxygen, the mechanisms by which it induces toxic endpoints, such as teratogenesis, are unknown. This review examines some fundamental concepts of these four signaling molecules and considers some of the molecular targets and pathways by which they interact. The information regarding the teratogenicity of either excess or deficiency of the four gases is summarized. Interaction information is generally unavailable for teratogenicity endpoints with the four gases and also a mechanistic understanding of the toxicodynamics of the compounds is lacking. Although it could be theoretically predicted that certain interactions would be additive, for example carbon monoxide and hypoxia, based on the physiological role of these molecules, the data is unavailable. Consequently, these small (gaseous) signaling molecules have been demonstrated to interact with respect to signaling pathways, but whether this indicates a similar result for teratogenesis remains unevaluated.