title: Genetic loss of Faah compromises male fertility in mice.
abstract: Marijuana is the most commonly used illicit drug. Although there is some indication that reproductive functions in males are impaired in chronic marijuana users, the genetic evidence and underlying causes remain largely unknown. Herein we show that genetic loss of Faah, which encodes fatty acid amide hydrolase (FAAH), results in elevated levels of anandamide, an endocannabinoid, in the male reproductive system, leading to compromised fertilizing capacity of sperm. This defect is rescued by superimposing deletion of cannabinoid receptor 1 (Cnr1). Retention of Faah(-/-) sperm on the egg zona pellucida provides evidence that the capacity of sperm to penetrate the zona barrier is hampered by elevated anandamide levels. Collectively, the results show that aberrant endocannabinoid signaling via CNR1 impairs normal sperm function. Besides unveiling a new regulatory mechanism of sperm function, this study has clinical significance in male fertility.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Sun
authors.forename: Haibin
authors.initials: H
authors.lastname: Wang
authors.forename: Masaru
authors.initials: M
authors.lastname: Okabe
authors.forename: Kenneth
authors.initials: K
authors.lastname: Mackie
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kingsley
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Sudhansu K
authors.initials: SK
authors.lastname: Dey
mesh_terms: D000581:Amidohydrolases / Q000235:genetics* / Q000502:physiology; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D063388:Endocannabinoids; D017353:Gene Deletion; D005816:Genetic Complementation Test; D007248:Infertility, Male / Q000235:genetics* / Q000503:physiopathology / Q000662:veterinary; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013081:Sperm Motility / Q000235:genetics; D013094:Spermatozoa / Q000378:metabolism / Q000502:physiology; D014566:Urogenital System / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide