Limits...
Loss of cannabinoid receptor CB1 induces preterm birth.

Wang H, Xie H, Dey SK - PLoS ONE (2008)

Bottom Line: Radioimmunoassay analysis of circulating levels of ovarian steroid hormones revealed that premature birth resulting from CB1 inactivation is correlated with altered progesterone/estrogen ratios prior to parturition.In addition, loss of CB1 resulted in aberrant secretions of corticotrophin-releasing hormone and corticosterone during late gestation.Moreover, CB1 inactivation resulted in aberrant corticotrophin-releasing hormone and corticosterone activities prior to parturition, suggesting that CB1 regulates labor by interacting with the corticotrophin-releasing hormone-driven endocrine axis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

ABSTRACT

Background: Preterm birth accounting approximate 10% of pregnancies in women is a tremendous social, clinical and economic burden. However, its underlying causes remain largely unknown. Emerging evidence suggests that endocannabinoid signaling via cannabinoid receptor CB1 play critical roles in multiple early pregnancy events in both animals and humans. Since our previous studies demonstrated that loss of CB1 defers the normal implantation window in mice, we surmised that CB1 deficiency would influence parturition events.

Methods and findings: Exploiting mouse models with targeted deletion of Cnr1, Cnr2 and Ptgs1 encoding CB1, CB2 and cyclooxygenase-1, respectively, we examined consequences of CB1 or CB2 silencing on the onset of parturition. We observed that genetic or pharmacological inactivation of CB1, but not CB2, induced preterm labor in mice. Radioimmunoassay analysis of circulating levels of ovarian steroid hormones revealed that premature birth resulting from CB1 inactivation is correlated with altered progesterone/estrogen ratios prior to parturition. More strikingly, the phenotypic defects of prolonged pregnancy length and parturition failure in mice missing Ptgs1 were corrected by introducing CB1 deficiency into Ptgs1 mice. In addition, loss of CB1 resulted in aberrant secretions of corticotrophin-releasing hormone and corticosterone during late gestation. The pathophysiological significance of this altered corticotrophin-releasing hormone-driven endocrine activity in the absence of CB1 was evident from our subsequent findings that a selective corticotrophin-releasing hormone antagonist was able to restore the normal parturition timing in Cnr1 deficient mice. In contrast, wild-type females receiving excessive levels of corticosterone induced preterm birth.

Conclusions: CB1 deficiency altering normal progesterone and estrogen levels induces preterm birth in mice. This defect is independent of prostaglandins produced by cyclooxygenase-1. Moreover, CB1 inactivation resulted in aberrant corticotrophin-releasing hormone and corticosterone activities prior to parturition, suggesting that CB1 regulates labor by interacting with the corticotrophin-releasing hormone-driven endocrine axis.

Show MeSH

Related in: MedlinePlus

Pharmacological silencing of CRH activities by Antalarmin hydrochloride (AH) on days 15–17 restores normal labor in Cnr1−/− mice with little effects on fetal birth weights (A & B), while enhanced corticosterone (CTS) activity on days 14–18 induces preterm birth with impaired fetal growth in wild-type (WT) mice (C & D).Numbers within bars indicate the number of mice examined in panels A and C. The average fetal weights (mg) are shown in panels B and D. The bars with different letters are significantly different (P<0.01).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2553193&req=5

pone-0003320-g007: Pharmacological silencing of CRH activities by Antalarmin hydrochloride (AH) on days 15–17 restores normal labor in Cnr1−/− mice with little effects on fetal birth weights (A & B), while enhanced corticosterone (CTS) activity on days 14–18 induces preterm birth with impaired fetal growth in wild-type (WT) mice (C & D).Numbers within bars indicate the number of mice examined in panels A and C. The average fetal weights (mg) are shown in panels B and D. The bars with different letters are significantly different (P<0.01).

Mentions: Moreover, as seen for CB1 (Figure 2B), immunostaining showed the presence of CRH and its type I receptor (CRH-RI) in WT day 18 corpora lutea (Figure S3), suggesting potential interactions of CB1 and CRH signaling within the ovary prior to parturition. In fact, we noted an early induction of ovarian CRH expression in Cnr1−/− mice with preterm labor (Figure 6C), further supporting that an altered CRH activity is one cause of preterm birth in mice missing CB1. Since there is evidence that CRH interferes with hypothalamic-pituitary-gonadal axis function by acting directly at the ovarian level [50], [51], we speculate that CB1 deficiency-induced aberrant CRH signaling is a potential cause of abnormal P4 and E2 secretion in Cnr1−/− ovary. However, it is to be noted that while the ovary as the primary site of P4 synthesis in pregnant mice contributes to CRH secretion, CRH like P4 is mainly produced by the placenta during late gestation in humans [47]. Regardless of the site of origin of CRH in various species, the physiological relevance of CRH-CTS axis in the onset of normal labor in mice is further supported by our observations that Antalarmin hydrochloride (AH), a CRH-RI selective antagonist, restored normal parturition in Cnr1−/− mice with little effects on fetal birth weights when females were treated on days 15–17 of pregnancy (Figure 7A & B). In contrast, elevated levels of CTS imposed by exogenous administration induced preterm birth with reduced fetal weights in WT females (Figure 7C & D), similar to labor defects in Cnr1−/− mice.


Loss of cannabinoid receptor CB1 induces preterm birth.

Wang H, Xie H, Dey SK - PLoS ONE (2008)

Pharmacological silencing of CRH activities by Antalarmin hydrochloride (AH) on days 15–17 restores normal labor in Cnr1−/− mice with little effects on fetal birth weights (A & B), while enhanced corticosterone (CTS) activity on days 14–18 induces preterm birth with impaired fetal growth in wild-type (WT) mice (C & D).Numbers within bars indicate the number of mice examined in panels A and C. The average fetal weights (mg) are shown in panels B and D. The bars with different letters are significantly different (P<0.01).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2553193&req=5

pone-0003320-g007: Pharmacological silencing of CRH activities by Antalarmin hydrochloride (AH) on days 15–17 restores normal labor in Cnr1−/− mice with little effects on fetal birth weights (A & B), while enhanced corticosterone (CTS) activity on days 14–18 induces preterm birth with impaired fetal growth in wild-type (WT) mice (C & D).Numbers within bars indicate the number of mice examined in panels A and C. The average fetal weights (mg) are shown in panels B and D. The bars with different letters are significantly different (P<0.01).
Mentions: Moreover, as seen for CB1 (Figure 2B), immunostaining showed the presence of CRH and its type I receptor (CRH-RI) in WT day 18 corpora lutea (Figure S3), suggesting potential interactions of CB1 and CRH signaling within the ovary prior to parturition. In fact, we noted an early induction of ovarian CRH expression in Cnr1−/− mice with preterm labor (Figure 6C), further supporting that an altered CRH activity is one cause of preterm birth in mice missing CB1. Since there is evidence that CRH interferes with hypothalamic-pituitary-gonadal axis function by acting directly at the ovarian level [50], [51], we speculate that CB1 deficiency-induced aberrant CRH signaling is a potential cause of abnormal P4 and E2 secretion in Cnr1−/− ovary. However, it is to be noted that while the ovary as the primary site of P4 synthesis in pregnant mice contributes to CRH secretion, CRH like P4 is mainly produced by the placenta during late gestation in humans [47]. Regardless of the site of origin of CRH in various species, the physiological relevance of CRH-CTS axis in the onset of normal labor in mice is further supported by our observations that Antalarmin hydrochloride (AH), a CRH-RI selective antagonist, restored normal parturition in Cnr1−/− mice with little effects on fetal birth weights when females were treated on days 15–17 of pregnancy (Figure 7A & B). In contrast, elevated levels of CTS imposed by exogenous administration induced preterm birth with reduced fetal weights in WT females (Figure 7C & D), similar to labor defects in Cnr1−/− mice.

Bottom Line: Radioimmunoassay analysis of circulating levels of ovarian steroid hormones revealed that premature birth resulting from CB1 inactivation is correlated with altered progesterone/estrogen ratios prior to parturition.In addition, loss of CB1 resulted in aberrant secretions of corticotrophin-releasing hormone and corticosterone during late gestation.Moreover, CB1 inactivation resulted in aberrant corticotrophin-releasing hormone and corticosterone activities prior to parturition, suggesting that CB1 regulates labor by interacting with the corticotrophin-releasing hormone-driven endocrine axis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

ABSTRACT

Background: Preterm birth accounting approximate 10% of pregnancies in women is a tremendous social, clinical and economic burden. However, its underlying causes remain largely unknown. Emerging evidence suggests that endocannabinoid signaling via cannabinoid receptor CB1 play critical roles in multiple early pregnancy events in both animals and humans. Since our previous studies demonstrated that loss of CB1 defers the normal implantation window in mice, we surmised that CB1 deficiency would influence parturition events.

Methods and findings: Exploiting mouse models with targeted deletion of Cnr1, Cnr2 and Ptgs1 encoding CB1, CB2 and cyclooxygenase-1, respectively, we examined consequences of CB1 or CB2 silencing on the onset of parturition. We observed that genetic or pharmacological inactivation of CB1, but not CB2, induced preterm labor in mice. Radioimmunoassay analysis of circulating levels of ovarian steroid hormones revealed that premature birth resulting from CB1 inactivation is correlated with altered progesterone/estrogen ratios prior to parturition. More strikingly, the phenotypic defects of prolonged pregnancy length and parturition failure in mice missing Ptgs1 were corrected by introducing CB1 deficiency into Ptgs1 mice. In addition, loss of CB1 resulted in aberrant secretions of corticotrophin-releasing hormone and corticosterone during late gestation. The pathophysiological significance of this altered corticotrophin-releasing hormone-driven endocrine activity in the absence of CB1 was evident from our subsequent findings that a selective corticotrophin-releasing hormone antagonist was able to restore the normal parturition timing in Cnr1 deficient mice. In contrast, wild-type females receiving excessive levels of corticosterone induced preterm birth.

Conclusions: CB1 deficiency altering normal progesterone and estrogen levels induces preterm birth in mice. This defect is independent of prostaglandins produced by cyclooxygenase-1. Moreover, CB1 inactivation resulted in aberrant corticotrophin-releasing hormone and corticosterone activities prior to parturition, suggesting that CB1 regulates labor by interacting with the corticotrophin-releasing hormone-driven endocrine axis.

Show MeSH
Related in: MedlinePlus