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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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Western blot analysis of cytochrome P450 aromatase (P450Arom), 17β-hydroxysteroid dehydrogenase 7 (17β-HSD7) and 20α-HSD in wild-type (WT) and Cnr1−/− ovaries during late gestation.
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pone-0003320-g004: Western blot analysis of cytochrome P450 aromatase (P450Arom), 17β-hydroxysteroid dehydrogenase 7 (17β-HSD7) and 20α-HSD in wild-type (WT) and Cnr1−/− ovaries during late gestation.

Mentions: Western blotting analysis of key steroid biosynthetic and metabolic enzymes demonstrated that while levels of cytochrome P450 cholesterol side-chain cleavage enzyme and 3β-hydroxysteroid dehydrogenase (3β-HSD) were comparable in wild-type and Cnr1 ovaries (data not shown), levels of cytochrome P450 aromatase (P450Arom) and 17β-HSD7, which primarily contribute to ovarian E2 biosynthesis during gestation in mice [38], were upregulated in Cnr1−/− ovaries (Figure 4). Moreover, levels of 20α-HSD, which metabolizes P4 into biologically inactive 20α-dihydroprogesterone, were substantially increased in Cnr1−/− ovaries on day 19 of pregnancy as opposed to that occurs in WT ovaries on day 20 (Figure 4). These temporal changes in P4 metabolic and estrogen biosynthetic enzymes in ovaries correlate well with our finding of early fall in P4 with rising E2 levels preceding early onset of parturition. As shown in Figure S2A & B, our observation of restoration of normal parturition in Cnr1−/− mice by a subcutaneous injection of P4 (1 mg/mouse) on day 18 further supports that a decreased P4/E2 ratio is a cause of preterm labor in females. With respect to contribution of gonadotropins and prolactin on this altered ovarian P4 and E2 secretion pattern in the absence of CB1, similar circulating levels of luteinizing hormone were observed in WT and Cnr1−/− mice on days 14–18 of pregnancy. However, basal levels of follicle stimulating hormone substantially increased in Cnr1−/− mice (data not shown). Placenta-derived prolactin-like hormones, but not pituitary prolactin, primarily act to maintain luteal P4 secretion during late gestation in mice [38], [39]. Nonetheless, it would be interesting to see in future studies whether CB1 deficiency alters prolactin secretion at various stages of pregnancy.


Loss of cannabinoid receptor CB1 induces preterm birth.

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

Western blot analysis of cytochrome P450 aromatase (P450Arom), 17β-hydroxysteroid dehydrogenase 7 (17β-HSD7) and 20α-HSD in wild-type (WT) and Cnr1−/− ovaries during late gestation.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003320-g004: Western blot analysis of cytochrome P450 aromatase (P450Arom), 17β-hydroxysteroid dehydrogenase 7 (17β-HSD7) and 20α-HSD in wild-type (WT) and Cnr1−/− ovaries during late gestation.
Mentions: Western blotting analysis of key steroid biosynthetic and metabolic enzymes demonstrated that while levels of cytochrome P450 cholesterol side-chain cleavage enzyme and 3β-hydroxysteroid dehydrogenase (3β-HSD) were comparable in wild-type and Cnr1 ovaries (data not shown), levels of cytochrome P450 aromatase (P450Arom) and 17β-HSD7, which primarily contribute to ovarian E2 biosynthesis during gestation in mice [38], were upregulated in Cnr1−/− ovaries (Figure 4). Moreover, levels of 20α-HSD, which metabolizes P4 into biologically inactive 20α-dihydroprogesterone, were substantially increased in Cnr1−/− ovaries on day 19 of pregnancy as opposed to that occurs in WT ovaries on day 20 (Figure 4). These temporal changes in P4 metabolic and estrogen biosynthetic enzymes in ovaries correlate well with our finding of early fall in P4 with rising E2 levels preceding early onset of parturition. As shown in Figure S2A & B, our observation of restoration of normal parturition in Cnr1−/− mice by a subcutaneous injection of P4 (1 mg/mouse) on day 18 further supports that a decreased P4/E2 ratio is a cause of preterm labor in females. With respect to contribution of gonadotropins and prolactin on this altered ovarian P4 and E2 secretion pattern in the absence of CB1, similar circulating levels of luteinizing hormone were observed in WT and Cnr1−/− mice on days 14–18 of pregnancy. However, basal levels of follicle stimulating hormone substantially increased in Cnr1−/− mice (data not shown). Placenta-derived prolactin-like hormones, but not pituitary prolactin, primarily act to maintain luteal P4 secretion during late gestation in mice [38], [39]. Nonetheless, it would be interesting to see in future studies whether CB1 deficiency alters prolactin secretion at various stages of pregnancy.

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