A cellular-signaling system that responds to THC, the active substance in marijuana, as well as to anandamide, a cannabinoid-like molecule normally produced in the body, may regulate sperm functions required for fertilization in humans, a study headed by UB scientists has found.

In addition, the findings suggest that men and women who abuse marijuana could overload this natural cannabinoid-signaling system that regulates sperm structure, vigor and fertility.

Herbert Schuel, professor of anatomy and cell biology and lead author, will present results of the research on Tuesday at the annual meeting of the American Society for Cell Biology in San Francisco.

Collaborating on the research were Lani Burkman and Jack Lippes of UB and colleagues from the University of Connecticut, Eastern Virginia Medical School and University of California at Irvine.

The study presents the first evidence that anandamide exists in human seminal plasma, mid-cycle oviductal fluid and follicular fluid, and can regulate directly the human sperm's ability to fertilize an egg.

"These findings suggest that defects in the cannabinoid receptor-signaling system could account for certain types of infertility," Schuel said. "A better understanding of these mechanisms might lead to the development of drugs useful in reproductive medicine. For heavy marijuana users, the results raise the possibility they are jeopardizing fertility by overloading this system."

A receptor for cannabinoids was found in the human brain in the late 1980s. This finding suggested that the body must produce its own chemical version of THC to activate these receptors, and a substance called anandamide was found to be that chemical. Schuel and collaborators were the first to report cannabinoid receptors in sperm, using sea urchins as a model, and that anandamide also activated those receptors.

The regulatory mechanisms that prepare sperm to fertilize eggs remain, for the most part, a scientific mystery. Human sperm are bathed in male reproductive-tract secretions when they are ejaculated into the female's vagina, and are not immediately capable of fertilizing eggs. However, once exposed for several hours to secretions within the female reproductive tract, sperm become "capacitated" and can fertilize eggs.

Capacitated sperm exhibit a pattern of vigorous swimming called hyperactivated motility. When they bind to a specific protein in the egg's surface coat, sperm can be stimulated to secrete enzymes that enable them to penetrate the egg coat during fertilization, a secretory process called the acrosome reaction.

"We know that sperm capacitation and fertilizing potential are tightly regulated within the female reproductive tract," Schuel said. "We also know that the cannabinoid receptor found in the human brain is expressed in the human testis, and that anandamide is produced in the testis and uterus of mammals. Within the uterus, anandamide regulates early development of the fertilized egg, and determines where the embryo will implant to initiate pregnancy. Cannabinoids also affect this process," he noted.

Now, Schuel and collaborators have the first evidence that anandamide can regulate directly human sperm's ability to fertilize an egg. Using a synthetic equivalent of natural anandamide called AM-356 and THC, the substance responsible for the "high" produced by marijuana smoke, the researchers showed that both chemicals regulate in vitro capacitation and fertilizing potential of human sperm in three ways:

- AM-356 produces opposite effects on hyperactivated sperm swimming, depending on the amount. Too much inhibits swimming while a lower dose stimulates swimming.

- Both AM-356 and THC inhibit structural changes over the acrosome. The structural integrity of the acrosome during capacitation is known to be a critical factor in the sperm's ability to fertilize eggs.

- AM-356 significantly inhibits sperm binding to the egg coat.