A new study by scientists at the Icahn School of Medicine at Mount Sinai has shown that Δ9-tetrahydrocannabinol (THC)—the psychoactive component in cannabis—can cause birth defects in genetically predisposed mice. The researchers investigated whether THC could exacerbate the effects of a mutation that affects Hedgehog (HH) signaling, a mechanism that cells use to communicate with each other. They found that when administered to pregnant mice, THC acts as a “conditional teratogen,” causing a brain and facial defect called holoprosencephaly (HPE), but only in pups that carried a specific mutation in a HH pathway-related gene. Holoprosencephaly is a birth defect seen in 1 in 250 human conceptions, which includes failure of the forebrain to divide into two distinct segments.

And while THC alone wasn’t sufficient to disrupt Hedgehog signaling and cause defects in pups with normal HH genes, in animals where Hedgehog signaling was already weakened through genetic mutation, THC had significant effects.

“THC directly inhibits Hedgehog signaling in mice, but it is not a very powerful inhibitor; this is presumably why a genetic predisposition is required for it to cause holoprosencephaly in mice,” explained Robert Krauss, PhD, professor of cell, developmental and regenerative biology at the Icahn School of Medicine at Mount Sinai. Krauss is lead author of the team’s published paper in Development, in a paper titled, “Δ9-tetrahydrocannabinol inhibits Hedgehog-dependent patterning during development,” in which the team concluded, “Cannabis consumption during pregnancy may contribute to a combination of risk factors underlying specific developmental disorders. These findings, therefore, have significant public health relevance.”

Cannabis is used by hundreds of millions of people worldwide. Although restricted in most countries, increasing legalization of cannabis for recreational and medicinal consumption means that use of the substance is on the rise. Cannabis is also the most common illicit drug used by pregnant women, but its effects on embryonic development are not well understood, and it is also important to understand the effects the drug might have on genetically predisposed individuals who carry genetic mutations that increase the risk of environmental conditions triggering a defect or disease.

Congenital malformations affect approximately eight million newborns worldwide each year and are a leading cause of death for infants and children of all ages, the authors noted. While mutations in single genes or exposure to individual teratogens is sufficient to cause a developmental disorder in most or all affected individuals, for many of the most common structural birth effects, a single causative factor can’t be identified. “Many developmental disorders are thought to arise from an interaction between genetic and environmental risk factors,” the scientists stated.

The Hedgehog signaling pathway regulates a myriad of developmental processes. “The HH signaling pathway plays a fundamental role during development and is involved in growth and morphogenesis of a wide variety of body structures, including limbs, brain, heart, and craniofacial structures,” the investigators further commented. It’s thus possible that environmental agents that perturb HH signaling at specific times during embryogenesis could represent risk factors for developmental disorders, perhaps acting alongside predisposing genetic variants.

THC is a compound that has previously been found to impact HH signaling. “Several years ago, it was reported that THC could inhibit Hedgehog signaling in cells grown in a dish,” said Krauss. And it’s also known that HPE is associated with heterozygous mutations in the HH pathway. But while cannabinoids are HH pathway inhibitors, little is known about their effects on HH-dependent processes in mammalian embryos, and the mechanism of cannabinoid action is also unclear. “Cannabinoids are HH pathway inhibitors but they have not been linked to human HPE, the most common outcome of genetic deficiency in HH signaling.” Krauss continued, “We reasoned that THC might be an environmental risk factor for birth defects, but that it would require additional risk factors, such as specific mutations in the genes required for Hedgehog signaling, to induce these defects in mice.”

To address their hypothesis, Krauss and colleagues administered a single dose of THC, equivalent to exposures achieved when humans smoke cannabis, to pregnant mice, about a week after conception. They then studied the embryonic development of their pups, some of which carried a mutation that meant Hedgehog signaling was not functioning at full efficiency. The scientists found that pups without the HH pathway mutation developed normally, even when exposed to THC, as did pups that carried the mutation but were not exposed to the drug. In contrast, pups that were exposed to THC and also carried the mutation developed HPE.

A developing mouse neural tube. Hedgehog signaling is required to produce different types of neuronal progenitor cells, indicated by the different colors. THC inhibits Hedgehog signaling in genetically susceptible mice, leading to developmental defects, including in the neural tube. [Lo, H.-F., Hong, M., Szutorisz, H., Hurd, Y.L., Krauss, R.S. (2021). Δ9-Tetrahydrocannabinol inhibits Hedgehog-dependent patterning during development. Development, 148, dev199585. doi:10.1242/dev.199585]
The researchers showed that the defect occurs because THC can interfere with Hedgehog signaling in the embryo, leading to defects, but only in animals where Hedgehog signaling was already weakened. “THC dose-dependently induced HH loss-of-function phenotypes, including HPE, in these mice but not in wild-type mice,” the scientists noted. “THC, therefore, acted as a ‘conditional teratogen,’ dependent on a complementary but insufficient genetic insult.”

These first studies in mice have important implications for human health, highlighting the need for more research into the effects of cannabis use during pregnancy in humans. “Cannabis consumption during pregnancy may therefore result in partial inhibition of a major morphogenetic pathway in embryos, thereby contributing to the complex combination of genetic and environmental risk factors that are thought to underlie many common developmental disorders,” the authors concluded. “… these results raise the possibility that human cannabis consumption during early pregnancy may expose embryos to HH inhibition, presenting an environmental risk factor for birth defects.”

“The THC concentration in cannabis is now very high, so it is important to perform epidemiology studies looking at whether cannabis consumption is associated with developmental defects,” Krauss pointed out. “Women are already advised not to consume cannabis while pregnant, but our results show that embryos are sensitive at a very early period, before many women know they are pregnant. Cannabis consumption may therefore be inadvisable even when women are trying to get pregnant.” The team further noted, “… recent findings that correlate increased cannabis usage with specific structural birth defects, combined with our identification of THC as a conditional teratogen, indicates that further research into this question is important and of significant public health relevance.”

Although this study focussed on one chemical in cannabis and one genetic mutation, further research could reveal other combinations that cause similar effects. “Many of the mutations found in human holoprosencephaly patients could conceivably synergize with THC,” said Krauss. “We would also like to test the related chemical CBD in genetically predisposed mice. Like THC, CBD inhibits Hedgehog signaling in cells grown in a dish, but CBD appears to work differently. As CBD is widely available and often viewed as beneficial—or at least innocuous—it would be worth investigating this as well,” he added.

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