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Published: 03 February 2022

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Epidemiological association of cannabinoid- and drug- exposures &  sociodemographic factors with limb Reduction Defects

Limblessness: Cannabinoids Inhibit Key Embryonic Morphogens both Directly and Epigenomically

Dear Editor

The predominant questions to emerge from the striking findings that 45 of 62 (72.5%) congenital anomalies tracked longitudinally in USA [1] and 89 of 95 (93.7%) of congenital anomalies in Europe [2] could be related to various indices of cannabinoid exposure must surely be mechanistic: “How” and “Why?”. And in particular “Are cannabinoids inhibiting fundamental cellular processes to account for this significant multisystem panorganismal teratogenic effect?”

It is important to appreciate that most body tissues are formed by a complex interaction of declining key morphogen gradients that control and specify developmental cell type with great precision across the embryo. Hence the neuraxis (brain and spinal cord) is controlled in its anterior-posterior cell specification by sonic hedgehog coming form the ventral notocord (embryonic organizer) and bone morphogenetic proteins (BMP’s) and Wnt’s coming from the overlying epidermis dorsally. Similar gradients control proximal-distal, left-right and outside-inside cell growth, connection and specification.

The developing limb bud is controlled by gradients of retinoic acid (RA) and sonic hedgehog (shh) proximally vs fibroblast growth factors (FGF’s) and Wnt’s from the anterior epidermal ridge distally. Limb length is controlled by Meis and hox genes. Fingers grow under the influence of FGF8. Regression of tissue in the web spaces between fingers is controlled by BMP’s 2, 4 and 7 and RA amongst others. Shh signals to its receptor patched, and to gremlin and Hand2 [3].

Strong as the signal is for limb reduction anomalies in USA datasets (P=0.0134) it is much stronger in the European dataset making Europe the leading continent on which to study these severe deformities (P=8.20x10-65) [1, 2].

Research has recently discovered that both Δ9THC and cannabidiol, along with various synthetic cannabinoids inhibit shh signalling by blocking smoothened which acts downstream of the patched shh receptor. Moreover cannabinoids have also been shown to inhibit FGF, BMP, RA, notch, Wnt and hippo gradients [4].

Clearly broad spectrum disruption of the major morphogenic gradients of embryonic development can only be expected to have manifold severe embryotoxic outcomes.

A deeply insightful epigenomic study recently demonstrated in its 359-page Supplementary material that cannabinoid exposure can disrupt human sperm DNA methylation patterns at five key genes critically involved in limb morphogenesis [5]. Of these GLI3 (Gli family zinc finger 3), MEGF8 (multiple EGF-like domains 8), TMEM107 (transmembrane protein 107) and BMP4 are directly involved in mediating, interacting with or antagonising shh signalling.

Such vitally salient results indicate not only that cannabinoids can interfere with limb development directly but that they do so epigenomically. This critically important finding raises the stakes on cannabinoid-induced embryopathy enormously from merely the exposed infants potentially to multigenerational inheritable teratogenic effects.

Professor Albert S. Reece, 31 January 2022 (https://www.bmj.com/content/376/bmj.n3114/rapid-responses )

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