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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.

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Aberrant levels of CRH and corticosterone from CB1 deficiency contribute to preterm birth in mice.(A & B) Circulating levels of CRH and corticosterone in pregnant WT and Cnr1−/− mice during late gestation (n = 4–5, *P<0.05). (C) Western blot analysis of CRH in WT and Cnr1−/− ovaries during late gestation, showing an early induction of ovarian CRH expression in mutant females.
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pone-0003320-g006: Aberrant levels of CRH and corticosterone from CB1 deficiency contribute to preterm birth in mice.(A & B) Circulating levels of CRH and corticosterone in pregnant WT and Cnr1−/− mice during late gestation (n = 4–5, *P<0.05). (C) Western blot analysis of CRH in WT and Cnr1−/− ovaries during late gestation, showing an early induction of ovarian CRH expression in mutant females.

Mentions: Increasing evidence suggests that the endocannabinoid system influences the secretion of CRH [47], [48], which serves as a clock regulating the length of human pregnancy [25], [26]. To further reveal underlying causes of preterm birth in Cnr1−/− mice, we examined the status of CRH levels during late pregnancy. As illustrated in Figure 6A, while circulating CRH levels peaked on day 19 of pregnancy proceeding the day of labor onset in WT females, an aberrant CRH secretion pattern was noted in mutant females; the levels showed an early rise on day 14 and thereafter remained steady through day 20 in Cnr1−/− females. This early rise in CRH levels in peripheral circulation could be due to dysregulation of the hypothalamus-adrenal axis with an enhanced circadian drive on this stress-related axis in Cnr1−/− mice as previously demonstrated [49]. In fact, we observed significant increases in circulating corticosterone (CTS) levels on days 14–16 of pregnancy in mutant females compared with WT females (Figure 6B). These observations collectively point toward the concept that CB1 signaling is crucial for maintaining normal CRH-CTS activities prior to the onset of parturition in mice.


Loss of cannabinoid receptor CB1 induces preterm birth.

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

Aberrant levels of CRH and corticosterone from CB1 deficiency contribute to preterm birth in mice.(A & B) Circulating levels of CRH and corticosterone in pregnant WT and Cnr1−/− mice during late gestation (n = 4–5, *P<0.05). (C) Western blot analysis of CRH in WT and Cnr1−/− ovaries during late gestation, showing an early induction of ovarian CRH expression in mutant females.
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Related In: Results  -  Collection

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

pone-0003320-g006: Aberrant levels of CRH and corticosterone from CB1 deficiency contribute to preterm birth in mice.(A & B) Circulating levels of CRH and corticosterone in pregnant WT and Cnr1−/− mice during late gestation (n = 4–5, *P<0.05). (C) Western blot analysis of CRH in WT and Cnr1−/− ovaries during late gestation, showing an early induction of ovarian CRH expression in mutant females.
Mentions: Increasing evidence suggests that the endocannabinoid system influences the secretion of CRH [47], [48], which serves as a clock regulating the length of human pregnancy [25], [26]. To further reveal underlying causes of preterm birth in Cnr1−/− mice, we examined the status of CRH levels during late pregnancy. As illustrated in Figure 6A, while circulating CRH levels peaked on day 19 of pregnancy proceeding the day of labor onset in WT females, an aberrant CRH secretion pattern was noted in mutant females; the levels showed an early rise on day 14 and thereafter remained steady through day 20 in Cnr1−/− females. This early rise in CRH levels in peripheral circulation could be due to dysregulation of the hypothalamus-adrenal axis with an enhanced circadian drive on this stress-related axis in Cnr1−/− mice as previously demonstrated [49]. In fact, we observed significant increases in circulating corticosterone (CTS) levels on days 14–16 of pregnancy in mutant females compared with WT females (Figure 6B). These observations collectively point toward the concept that CB1 signaling is crucial for maintaining normal CRH-CTS activities prior to the onset of parturition in 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