Hyperhomocysteinemia is detrimental to pregnancy in mice and is associated with preterm birth

Abstract

Elevated levels of homocysteine produce detrimental effects in humans but its role in preterm birth is not known. Here we used a mouse model of hyperhomocysteinemia to examine the relevance of homocysteine to preterm birth. The mouse carries a heterozygous deletion of cystathionine β-synthase (Cbs(+/-)). Gestational period was monitored in wild type and Cbs(+/-) female mice. Mouse uterine and placental tissues, human primary trophoblast cells, and human myometrial and placental cell lines were used to determine the influence of homocysteine on expression of specific genes in vitro. The activity of BKCa channel in the myometrial cell line was monitored using the patch-clamp technique. We found that hyperhomocysteinemia had detrimental effects on pregnancy and induced preterm birth in mice. Homocysteine increased the expression of oxytocin receptor and Cox-2 as well as PGE2 production in uterus and placenta, and initiated premature uterine contraction. A Cox-2 inhibitor reversed these effects. Gpr109a, a receptor for niacin, induced Cox-2 in uterus. Homocysteine upregulated GPR109A and suppressed BKCa channel activity in human myometrial cells. Deletion of Gpr109a in Cbs(+/-) mice reversed premature birth. We conclude that hyperhomocysteinemia causes preterm birth in mice through upregulation of the Gpr109a/Cox-2/PGE2 axis and that pharmacological blockade of Gpr109a may have potential in prevention of preterm birth.

Association between SNPs in genes involved in folate metabolism and preterm birth risk

“…Additionally, hyperhomocysteinemia was found to be associated with preterm birth in mice (Sonne et al, 2013). Growing evidence suggests that genes related to the folate metabolism pathway are involved in PTB and that their possible roles in PTB are likely complicated by interactions with dietary habits.…”

Mouse models of preterm birth: suggested assessment and reporting guidelines†

“…CBS −/− pregnant mice had increased blood levels of homocysteine, developed preterm uterine contractions, and delivered significantly early (16.6 dpc vs. 20.2 dpc). Further analysis of this model demonstrated that the contractions were caused by preterm expression of the oxytocin receptor and increased PGE2 synthesis by the enzyme prostaglandin endoperoxide synthase 2 [102].…”

Hydrogen sulfide pathway and skeletal muscle: an introductory review

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