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. 2008;3(12):e3969.
doi: 10.1371/journal.pone.0003969. Epub 2008 Dec 18.

CB1 expression is attenuated in Fallopian tube and decidua of women with ectopic pregnancy

Andrew W Horne  1 , John A Phillips 3rd, Nicole Kane, Paula C Lourenco, Sarah E McDonald, Alistair R W Williams, Carlos Simon, Sudhansu K Dey, Hilary O D Critchley
Affiliations

CB1 expression is attenuated in Fallopian tube and decidua of women with ectopic pregnancy

Andrew W Horne et al. PLoS One. 2008.

Abstract

Background: Embryo retention in the Fallopian tube (FT) is thought to lead to ectopic pregnancy (EP), a considerable cause of morbidity. In mice, genetic/pharmacological silencing of cannabinoid receptor Cnr1, encoding CB1, causes retention of embryos in the oviduct. The role of the endocannabinoids in tubal implantation in humans is not known.

Methods and findings: Timed FT biopsies (n = 18) were collected from women undergoing gynecological procedures for benign conditions. Endometrial biopsies and whole blood were collected from women undergoing surgery for EP (n = 11); management of miscarriage (n = 6), and termination of pregnancy (n = 8). Using RT-PCR and immunohistochemistry, CB1 mRNA and protein expression levels/patterns were examined in FT and endometrial biopsies. The distribution of two polymorphisms of CNR1 was examined by TaqMan analysis of genomic DNA from the whole blood samples. In normal FT, CB1 mRNA was higher in luteal compared to follicular-phase (p<0.05). CB1 protein was located in smooth muscle of the wall and of endothelial vessels, and luminal epithelium of FT. In FT from women with EP, CB1 mRNA expression was low. CB1 mRNA expression was also significantly lower (p<0.05) in endometrium of women with EP compared to intrauterine pregnancies (IUP). Although of 1359G/A (rs1049353) polymorphisms of CNR1 gene suggests differential distribution of genotypes between the small, available cohorts of women with EP and those with IUP, results were not statistically significant.

Conclusions: CB1 mRNA shows temporal variation in expression in human FT, likely regulated by progesterone. CB1 mRNA is expressed in low levels in both the FT and endometrium of women with EP. We propose that aberrant endocannabinoid-signaling in human FT leads to EP. Furthermore, our finding of reduced mRNA expression along with a possible association between polymorphism genotypes of the CNR1 gene and EP, suggests a possible genetic predisposition to EP that warrants replication in a larger sample pool.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Genomic organization of CNR1 gene and SNPs.
The CNR1 gene is a single exon gene located on chromosome 6q14–15 that is represented by a rectangle box (the orientation of the transcription of the gene is indicated by the arrow). The SNPs genotyped are represented by the vertical lines and their position in base pairs according to their chromosomal location. The names of the CNR1 SNPs according to the NCBI database are indicated by the prefix ‘rs’.
Figure 2
Figure 2. CB1 expression in the Fallopian tube.
CB1 mRNA expression was lower in the follicular compared to the luteal phase. In Fallopian tube from women with ectopic pregnancy, CB1 mRNA expression was also low (p<0.05).
Figure 3
Figure 3. CB1 mRNA expression in the decidualized endometrium of women with ongoing pregnancies, miscarriage and ectopic pregnancies.
In decidualized endometrium from women with ectopic pregnancy, CB1 mRNA expression was lower than in women with intra-uterine pregnancies (p<0.05).
Figure 4
Figure 4. Immunohistochemistry for CB1 protein expression in Fallopian tube.
CB1 protein was expressed in the smooth muscle of the wall (A and B), the smooth muscle of the endothelial vessels (A and C) and in the cytoplasm of the luminal epithelium of the Fallopian tube (A, B and D). There was no evidence of nuclear or stromal expression. EPI = epithelium, STR = stroma, SM = smooth muscle, BV = blood vessel. Scale bar = 50 microns.
Figure 5
Figure 5. Allelic frequencies of rs1049353 (1359G/A) and rs806368 (3′UTR) single nucleotide polymorphisms (SNPs) of the CNR1 gene in women with ectopic and intra-uterine (surgical termination of pregnancies and miscarriage groups combined) pregnancies.
While rs1049353 GG homozygotes constituted 55 versus 29% of ectopic and intra-uterine cohorts, respectively, differences in genotype distributions were not statistically significant (Likelihood Ratio and Pearson analyses had p = 0.18 and 0.15, respectively). The rs806368 SNP was not informative as all ectopic and 13/14 intra-uterine subject DNAs were TT homozygotes.
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