Energetic Metabolism and Human Sperm Motility: Impact of CB1 Receptor Activation

Abstract

It has been reported that the endocannabinoid anandamide (AEA) exerts an adverse effect on human sperm motility, which has been ascribed to inhibition of mitochondrial activity. This seems to be at variance with evidence suggesting a major role of glycolysis in supplying ATP for sperm motility; furthermore, the role of AEA-binding receptors in mediating mitochondrial inhibition has not yet been explored. In this study, human sperm exposure to Met-AEA (methanandamide, nonhydrolyzable analog of AEA) in the micromolar range significantly decreased mitochondrial transmembrane potential (ΔΨm), similarly to rotenone, mitochondrial complex I inhibitor. The effect of Met-AEA (1 μm) was prevented by SR141716, CB(1) cannabinoid receptor antagonist, but not by SR144528, CB(2) antagonist, nor by iodoresiniferatoxin, vanilloid receptor antagonist. The effect of Met-AEA did not involve activation of caspase-9 or caspase-3 and was reverted by washing. In the presence of glucose, sperm exposure either to Met-AEA up to 1 μm or to rotenone for up to 18 h did not affect sperm motility. At higher doses Met-AEA produced a CB(1)-independent poisoning of spermatozoa, reducing their viability. Under glycolysis blockage, 1 μm Met-AEA, similarly to rotenone, dramatically abolished sperm motility, an effect that was prevented by SR1 and reverted by washing. In conclusion, CB(1) activation induced a nonapoptotic decrease of ΔΨm, the detrimental reflection on sperm motility of which could be revealed only under glycolysis blockage, unless very high doses of Met-AEA, producing CB(1)-independent sperm toxicity, were used. The effects of CB(1) activation reported here contribute to elucidate the relationship between energetic metabolism and human sperm motility.

Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility

“…Met AEA (stable form of AEA) was shown to decrease human sperm motility and viability via its action through CB1 [69]. Several other in vitro studies on human spermatozoa are in agreement with these findings [46,47,64,107]. Whan et al [108] exposed human spermatozoa to both therapeutic and recreational levels of THC and showed clearly that it reduced the percentage of motile and progressively motile spermatozoa, while the kinematic parameters such as straight line velocity and average path velocity were also decreased.…”

Involvement of cannabinoid receptor‐1 activation in mitochondrial depolarizing effect of lipopolysaccharide in human spermatozoa

“…Human spermatozoa exhibit the complete biochemical machinery needed to synthesize (N‐acylphosphatidylthanolamine‐hydrolyzing phospholipase D, NAPE‐PLD) and degrade (fatty acid amide hydrolase, FAAH) AEA (Francavilla et al ., ), to synthesize (phospholipase C and diacylglycerol lipase) and degrade (monoacylglycerol lipase) 2‐AG (Lewis et al ., ) and express receptors for (endo)cannabinoids: CB1 (Rossato et al ., ; Francavilla et al ., ), a non‐functional CB2 (Francavilla et al ., ; Agirregoitia et al ., ) and the transient receptor potential vanilloid 1 (TRPV1) receptor (Francavilla et al ., ). We have previously demonstrated that the CB1 activation by methanandamide (Met‐AEA), non‐hydrolyzable analogue of AEA, inhibited sperm mitochondrial membrane potential (ΔΨm) (Barbonetti et al ., ).…”

Soluble Products of Escherichia coli Induce Mitochondrial Dysfunction-Related Sperm Membrane Lipid Peroxidation Which Is Prevented by Lactobacilli

“…Evidence has been produced that both in mouse [14] and human spermatozoa [15,16] glycolysis compensates for any lack of ATP production by mitochondria in maintaining sperm motility. However, independently from the impaired mitochondrial ATP generation, a mitochondrial dysfunction could affect sperm motility, when it is accompanied by increased intrinsic mitochondrial generation of ROS.…”