Deficiency of hydrogen sulfide production and pregnancy rate in an experimental model: Association with preterm delivery

Abstract

ProblemPro‐inflammatory phenomena drive preterm delivery (PTD). Hydrogen sulfide is a gasotransmitter with anti‐inflammatory properties produced through the activity of the enzyme cystathionine‐γ‐lyase (CSE), and its impact was studied in models of normal delivery and PTD in mice.Method of studyFemale CSE+/+ and CSE−/− mice were mated with male CSE+/+ mice; mating was done with drinking water unsupplemented and supplemented with cysteine. The pregnancy rate was monitored. PTD was induced by the intraperitoneal injection of bacterial lipopolysaccharide (LPS) on day 14.5 of pregnancy. Mice were sacrificed for tissue collection and splenocyte isolation after 6 and 12 h. Isolated splenocytes were stimulated for the production of tumor necrosis factor‐alpha (TNFα), interleukin (IL)‐10 and interferon‐gamma (IFNγ); TNFα and vascular endothelial growth factor (VEGF) were measured in the fetuses and the placenta.ResultsThe successful pregnancy rate was lower in CSE−/− mice and it was restored with cysteine supplementation. CSE deficiency was associated with higher tissue concentrations of TNFα in the fetuses, attenuated IL‐10 responses and higher IFNγ production from splenocytes. CSE deficiency was not associated with PTD. Following PTD induction, CSE−/− mice did not show attenuated IL‐10 responses but the production of TNFα and IFNγ was lowered over‐time; placental VEGF was also increased over‐time.ConclusionsCSE deficiency has an unfavorable impact on pregnancy. H2S deficiency through CSE does not drive PTD but mediates pro‐inflammatory phenomena in fetuses.

Hydrogen sulfide and its role in female reproduction

“…Recent research focused on the fertility of CSE-KO mice showed that CSE-KO leads to a reduced number of successful pregnancies and a higher pro-inflammatory status of fetuses. This suggests that CBS is not the sole key enzyme in H 2 S production in the context of female reproduction ( 70 ).…”

“…Besides its tocolytic effects, H 2 S may also impact uterine immune response and placental vessel remodeling through the modulation of the uterine natural killer (uNK) cells ( 121–123 ). H 2 S signaling is also essential for maintaining early pregnancy, and its deficiency can lead to reduced litter size due to early embryo loss or placental inflammation ( 70 , 124 ). H2S may further facilitate the physiological implantation of the embryo by regulating ion transport activity in the endometrial epithelium and supporting DNA synthesis ( 125–127 ).…”