A California panel known as the “Developmental and Reproductive Toxicant Identification Committee” has recently declared tetrahydrocannabinol (THC), a primary psychoactive constituent of marijuana, as well as marijuana smoke itself to be detrimental to the health of pregnant women and their developing fetuses. A vote was cast to require a warning label directed toward this demographic to be placed on any product containing THC available throughout California’s many legal dispensaries. Members of the committee reached their decision after thoroughly evaluating scientific literature about this topic. This article will focus on an example of such literature, a recent study published in the leading scientific journal Nature (“Paternal Activation of CB2 Cannabinoid Receptor Impairs Placental and Embryonic Growth via an Epigenetic Mechanism”).
Upon entering the body, THC activates cannabinoid receptors CB1 and CB2 via a binding interaction. Cannabinoid receptors, along with their associated components as well as those components which act upon them, all make up the “endocannabinoid system.” This system is highly involved in the process of sexual reproduction. CB1 and CB2 are present in the testis where they have differing, yet equally important roles within the process of reproduction.
CB1 is expressed in Leydig cells and mature sperm (i.e. “spermatozoa”). CB2 is found in Sertoli cells and spermatogonia (sperm present in the early or immature stages of sperm genesis, i.e., “spermatogenesis.”). Leydig cells produce testosterone and are responsible for a number of the secondary sexual characteristics (i.e., increased body hair growth, muscle mass, height, development of Adam’s apple, etc.) classically seen developing during puberty. The testosterone produced by the Leydig cells is essential for developing spermatozoa. Sertoli Cells provide nourishment to the developing spermatogonia and are not needed in forming spermatozoa.
Both CB1 and CB2 are essential in the development of sperm suitable for reproduction. Like many processes within the body, the endocannabinoid system contains components that not only work together to achieve an ultimately higher objective but to regulate one another throughout the pursuit of whatever higher objective this may be.
In this instance, CB1 serves an inhibitory function by negatively affecting sperm through the inhibition of sperm motility, capacitation, and acrosome reaction. “Motility” refers to the sperm’s ability to move in this context within the female reproductive system to achieve fertilization. “Capacitation” refers to the process by which spermatozoa can develop (i.e., sperm can fully mature). A marker of sperm maturity is motility. The “acrosome” is the cap that covers the head of the sperm. “Acrosome reaction” refers to the final stages of achieving fertility in which a female egg is fertilized by male sperm. Acrosome reaction occurs when the acrosome cap essentially recedes, allowing the sperm to bind to and penetrate the female egg. This allows fertilization to occur.
CB2 activation is responsible for the progression of spermatogenesis. Increased CB2 activation will cause an increase in spermatogenesis. Therefore, an inhibition of CB2 activation will have the opposite effect and hinder this process.
Conversely, in the absence of CB1 receptor activation, which normally plays a regulatory role, sperm will become motile much earlier than expected, which can ultimately lead to infertility.
This study used male mice to understand further the relationship between CB2 activation within spermatogonia and the affect this may have on fertility as well as the outcome of the following newborn pregnancy. Researchers used a pharmacological compound named “JWH-133” on the mice to study this relationship. JWH-133 is an agent that potentiates the effects of CB2 activation.
The purpose of this study was to provide insight into an area of medicine that has been relatively uncharted until now. This insight would be used to determine if outside influences on genetics, i.e., “epigenetics,” such as exposure to JWH-133, could affect subsequent generations of sperm from the offspring of exposed mice. This determination would point towards either a potential risk, or lack thereof, of cannabis consumption about the development of the placenta during pregnancy, growth of the offspring, and sperm count.
After observing the effects of exposure to JWH-133 in male laboratory rats, researchers arrived at several conclusions concerning the various points of interest that they had set out to study.
They first concluded that the exposure of male mice to JWH-133 negatively affected the growth of their offspring.
Findings showed that the offspring of mice exposed to JWH-133 were of lower birth weight and size than those in the control group who were not exposed. However, it is of interest to note that the pregnancy rate of females who were selected to mate with JWH-133 exposed males did not change as compared to the control group. Individual organ weights of JWH-133 exposed offspring were recorded and were found to all be of reduced weight compared to the control. This finding isn’t necessarily indicative of anything peculiar, as logic would dictate that smaller mice would have smaller organs. However, it is of particular interest to note that the ratio between total body weight and organ weight did not change as calculated per each organ. This finding suggested that fathers exposed to JWH-133 impacted the overall development of their offspring, as opposed to one or a few specific organs.
The second conclusion found that exposure of male mice to JWH-133 caused defects in the embryo and placenta of female rats that they were mated with.
This finding holds particular significance when concerning both the ability of a fetus to develop into a healthy child and the impact of that development on the rest of the child’s life up until adulthood. The embryo is what eventually develops into a fetus, and is nourished by the placenta throughout its development. As you can imagine, if any part of this relationship is compromised due to genetic defects, then this can affect not only the viability of the fetus to develop into a healthy newborn, but for that newborn to then develop into a healthy child and adult. In this instance, it is suggested that the administration of JWH-133 to paternal mice had caused an alteration of genetic material present in their sperm. This “defective” genetic material then caused defects within the reproductive system of female mice.
Researchers also found that consistent exposure to JWH-133 resulted in reduced sperm count.
Sperm count is an important factor in the ability of sperm to create viable fertilization of the female egg. When assessing for the cause of infertility in those who are unable to conceive, infertility clinics will often time assess male sperm count as one of the first orders of action. A decrease in sperm count increases the risk of infertility.
Additionally, the sperm of mice that had been exposed to JWH-133 was found to have altered DNA “methylation.”
DNA methylation is a natural process that occurs regularly in all animals, including humans. Methylation of DNA is essential for regulating how our genes are expressed, and so, therefore, serves a very important role within our body. The alteration of normal DNA methylation can lead to unnatural expressions of genetic information that can lead to problems with normal human development and disease.
Lastly, the researchers found that consistent exposure to JWH-133 negatively affected the immune system.
CB2 receptors are primarily found within our immune system. Because JWH-133 is an agent that selectively propagates the action of CB2, this constant over-activation of the receptor will result in the eventual downgrading of the immune system. Researchers found a significantly decreased number of white blood cells, key components of the immune system, in mice treated with JWH-133.
Limitations & Significance
Although the objective of this study was to explore the implication of JWH-133 administration on fertility patterns in mice, the underlying motive for studying such an implication, as outlined by the authors, was to evaluate the potential risks of cannabis use about fertility, health, and development of offspring. Cannabis contains over a hundred cannabinoids apart from just THC, and we still are essentially unaware of how they act upon the body. THC itself acts on both CB1 and CB2 receptors, and it does so with partial selectivity at each receptor. JWH-133 acts almost completely on CB2 receptors with very little action on CB1. With this information, it could be argued that drawing a comparison between these results and then using them to speculate upon the effects of cannabis usage in humans may be somewhat problematic.
This study alone would most likely not suffice as the “smoking gun” in regards to the decision to enact recent legislation change in California. However, it may certainly have served as the final nail in the coffin to sway the decision to do so in one direction, as this is one of many studies that have linked cannabis use, or aspects of cannabis use, to infertility and fertility problems in humans.
By all accounts, this is a very intriguing, highly valid, meticulously designed, and executed study that gives us further insight on the subject of infertility and cannabis use. As legislation nationwide begins to welcome the use of legal cannabis, so to must we begin to examine the potential hazards of that use.