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Expression of the Endocannabinoid System in Human First Trimester Placenta and Its Role in Trophoblast Proliferation

Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE2 7LX, United Kingdom

Address all correspondence and requests for reprints to: Professor Justin Konje, Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE2 7LX, United Kingdom. E-mail: jck4{at}le.ac.uk.

The endocannabinoid, anandamide, which binds to two major receptor proteins, the cannabinoid receptors (CBs) 1 and 2 (CB₁ and CB₂), has been shown to play a role in first trimester miscarriage possibly through impairment of the developing trophoblast. Although the precise molecular mechanisms underlying this are unknown, plasma anandamide levels are known to be regulated by the progesterone-induced enzyme, fatty acid amide hydrolase (FAAH). Here, we tested the hypothesis that temporal-spatial expression of FAAH, CB₁, and CB₂ is regulated during early pregnancy and that anandamide detrimentally alters trophoblast proliferation. Transcripts for CB₁, CB₂, and FAAH were demonstrated in first trimester trophoblast extracts with only the CB₁ transcript being significantly regulated. The significant 4.7-fold increase in expression at wk 10 gestation was reduced to 8.9% of the peak value by wk 12. Transcripts for CB₂ showed a similar pattern of expression but were not significantly induced. By contrast, FAAH transcript levels appeared to increase toward the end of the first trimester, but again did not reach significance. These observations were supported by immunohistochemical studies that demonstrated a similar pattern of expression at the protein level, with cellular localization for all three proteins concentrated within the syncytiotrophoblast layer. Anandamide also prevented BeWo trophoblast cell proliferation in a dose-dependent manner, with a 50–60% significant inhibition of cell proliferation with concentrations in excess of 3 µM. This effect was mediated through CB₂. Together, these data provide insights into how elevated plasma anandamide levels increase the risk of first trimester miscarriage.