Marijuana Exposure May Affect Pregnancy Outcomes.

Abstract

Legalization of marijuana has become more prevalent in the United States, but a definitive conclusion on the safety of its use has yet to be reached. In a recent paper, Sun et al. [1] report on the interplay between marijuana exposure and reproduction. Sun and his team studied the effects of cannabinoid signaling on pregnancy using a mouse model lacking the membrane-bound fatty acid amide hydrolase (FAAH) as a proxy. FAAH hydrolyzes N-arachidonoylethanolamide (anandamide), which can activate CB1 and CB2—two cannabinoid receptors. In Faah mutants with sustained excessive cannabinoid levels, CB receptors activated as if exposed to delta-9tetrahydrocannabinol, a major psychoactive component in marijuana and synthetic cannabinoids. Upon subjecting the mice to an inflammatory insult, lipopolysaccharide (LPS), investigators found Faah females to be more vulnerable to preterm birth and increased incidence of stillborn pups than wild-type mice. Investigators tested a variety of possible causes for this uptick in preterm birth, and ruled out a drop in progesterone levels associated with lipopolysaccharide treatment and the influence of prostaglandins on myometrial contractions. Next, investigators explored premature decidual senescence using senescence-associated beta-galactosidase staining as a marker of decidual aging. Faah decidual cells showed increased staining compared to cells in wild-type mice, establishing that preterm birth in this model could be linked back to premature decidual senescence. Notably, Sun et al. ruled out increased mammalian target of rapamycin complex 1 (mTORC1) signaling—a known marker of decidual senescence [2]—as a trigger for preterm birth. Instead, they determined that increased levels of mitogen-activated protein kinase (MAPK) p38, activated by cannabinoid receptors, were the cause. The findings that CB1 receptor neutralization downregulated p38 activation, and that Faah mice treated with the CB1 antagonist and LPS had a much lower preterm birth rate, lends credence to their conclusion. These effects did not manifest solely over the long term. Mice with acute exposure to anandamide revealed similar results to Faah mutants: p38 levels increased in decidual cells, with those females more prone to preterm birth following LPS challenge. By elucidating the relationship between endocannabinoids, CB1, and p38 activation, Sun et al. exposed a signaling pathway that contributes to premature decidual senescence, which may lead to preterm birth if the mother is exposed to an inflammatory stimulus. This study has relevance for patient counseling and for developing targeted therapies to reduce pregnancy risks associated with immoderate marijuana exposure.