Genetic loss of Faah compromises male fertility in mice.
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.
Sun
Xiaofei
X
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Wang
Haibin
H
Okabe
Masaru
M
Mackie
Kenneth
K
Kingsley
Philip J
PJ
Marnett
Lawrence J
LJ
Cravatt
Benjamin F
BF
Dey
Sudhansu K
SK
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
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