Interactive Endogenous Small Molecule (Gaseous) Signaling: Implications for Teratogenesis

Abstract

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.

Reactive Nitrogen Species and Hydrogen Sulfide as Regulators of Protein Tyrosine Phosphatase Activity

“…Although H 2 S has only recently been considered an important signal transduction molecule, its physiological levels may reach high values, approximately 50-160 lM in the mammalian brain, and 10-100 lM in the peripheral blood (34,94). At least four independent pathways of H 2 S synthesis have been identified, acting at different anatomical sites.…”

“…All the pathways of H 2 S synthesis cited earlier use cysteine as a precursor. Cysteine can be formed from N-acetyl-cysteine, which is commonly administered as a clinical antioxidant that is considered as serving as a glutathione precursor (34,99).…”

“…Subjects with trisomy 21 manifesting as Down syndrome produce high H 2 S levels, because the CBS gene is located at 21q22.3, and the H 2 S over-production is hypothesized to be responsible for the progressive mental retardation manifesting within the first year of life of Down syndrome subjects (13,48). Acute H 2 S intoxication leads to the loss of central respiratory drive, cytochrome c oxidase inhibition, glutathione depletion, reduction of ferric to ferrous ions, and reduction of O 2 to ROS (34).…”

“…Concentrations of HS -can, thus, reach 38-112 lM in the brain and 7-75 lM in the peripheral blood, which is equivalent to the levels of glutathione considering that the pK a of glutathione is 8.5 and its intracellular concentration is 1-5 mM. H 2 S is, thus, hypothesized to serve as a major intracellular reductant, with particular importance for cysteines that are inaccessible to larger physiological reductants such as GS -, thioredoxin, or glutaredoxin (34). Knowledge on direct molecular targets of H 2 S is far from being complete.…”

Carbon Monoxide Signaling in Human Red Blood Cells: Evidence for Pentose Phosphate Pathway Activation and Protein Deglutathionylation

“…In fact, CO is largely a redox-inert molecule, unreactive with most biological species, while NO is an effector of redox-regulated pathways. Both NO and CO bind to hemoproteins and are known to mutually regulate each other's production (12,35,37). However, while the mechanisms of NO-dependent signaling have been thoroughly studied, there is still a lack of consensus on the specific cellular target(s) of CO, with the exception of hemoglobin (Hb).…”