Clinical Epigenomic Explanation of the Epidemiology of Cannabinoid Genotoxicity Manifesting as Transgenerational Teratogenesis, Cancerogenesis and Aging Acceleration

Abstract

As global interest in the therapeutic potential of cannabis and its’ derivatives for the management of selected diseases increases, it is increasingly imperative that the toxic profile of cannabinoids be thoroughly understood in order to correctly assess the balance between the therapeutic risks and benefits. Modern studies across a number of jurisdictions, including Canada, Australia, the US and Europe have confirmed that some of the most worrying and severe historical reports of both congenital anomalies and cancer induction following cannabis exposure actually underestimate the multisystem thousand megabase-scale transgenerational genetic damage. These findings from teratogenic and carcinogenic literature are supported by recent data showing the accelerated patterns of chronic disease and the advanced DNA methylation epigenomic clock age in cannabis exposed patients. Together, the increased multisystem carcinogenesis, teratogenesis and accelerated aging point strongly to cannabinoid-related genotoxicity being much more clinically significant than it is widely supposed and, thus, of very considerable public health and multigenerational impact. Recently reported longitudinal epigenome-wide association studies elegantly explain many of these observed effects with considerable methodological sophistication, including multiple pathways for the inhibition of the normal chromosomal segregation and DNA repair, the inhibition of the basic epigenetic machinery for DNA methylation and the demethylation and telomerase acceleration of the epigenomic promoter hypermethylation characterizing aging. For cancer, 810 hits were also noted. The types of malignancy which were observed have all been documented epidemiologically. Detailed epigenomic explications of the brain, heart, face, uronephrological, gastrointestinal and limb development were provided, which amply explained the observed teratological patterns, including the inhibition of the key morphogenic gradients. Hence, these major epigenomic insights constituted a powerful new series of arguments which advanced both our understanding of the downstream sequalae of multisystem multigenerational cannabinoid genotoxicity and also, since mechanisms are key to the causal argument, inveighed strongly in favor of the causal nature of the relationship. In this introductory conceptual overview, we present the various aspects of this novel synthetic paradigmatic framework. Such concepts suggest and, indeed, indicate numerous fields for further investigation and basic science research to advance the exploration of many important issues in biology, clinical medicine and population health. Given this, it is imperative we correctly appraise the risk–benefit ratio for each potential cannabis application, considering the potency, severity of disease, stage of human development and duration of use.

Perturbation of 3D nuclear architecture, epigenomic aging and dysregulation, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 2—Metabolome, immunome, synaptome

“…These features also mechanistically underpin several recent large epidemiological studies linking cannabis to the incidence of several cancers ( 2 – 12 ) and numerous congenital anomalies in both USA and Europe ( 13 – 19 ) and with aging syndromes of various types ( 12 , 20 ), which were detailed further in Part 1.…”

Sociodemographically Stratified Exploration of Pancreatic Cancer Incidence in Younger US Patients: Implication of Cannabis Exposure as a Risk Factor

“…However, in the light of now-robust epidemiological evidence implicating cannabis in yet another significant cancer renaissance nationwide across the USA [10,[83][84][85][86][87][88][89][90], it becomes essential and imperative that communities take cannabinoid carcinogenesis seriously and restrict access of their populations to cannabinoid genotoxicity just as it is for many other significantly genotoxic compounds. This is not only for cancer prevention and public health concerns in regard to extant populations, but also to protect the generations to come from the implicit and now well-defined multigenerational cannabinoid epigenotoxicity with which carcinogenicity is so often intricately and intimately involved [77][78][79]117,[189][190][191][192][193].…”

“…Cannabis has been found to have a large epigenomic footprint and changes the methylation status of up to 9% of the whole genome [15]. This has far-reaching implications on virtually every cellular system including the epigenomic machinery for DNA methylation and demethylation, for histone methylation and acetylation and their reversal and for the active repositioning of the nucleosomes to allow new gene transcription to occur [17,[77][78][79]117]. Cannabis causes DNA breaks [24][25][26][27][28][29][30] which ages the genome [21].…”

Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 1–aging and epigenomics

“…Fifteen hallmarks of aging have been described in cannabis dependence, including (1) increased acute and chronic physical and mental illness ( 138 ), (2) acceleration of cardiovascular and organismal age ( 15 ), (3) endocrine disruption, particularly of the hypothalamo-pituitary-gonadal axis ( 139 , 140 ), (4) mitochondrial inhibition ( 141 – 144 ), (5) DNA hypomethylation and advanced epigenetic age ( 14 , 145 – 147 ), (6) neuroinflammation accompanying cannabis-associated mental illnesses ( 148 – 173 ), (7) cirrhosis ( 174 – 176 ), (8) degeneration of oocytes and sperm ( 177 , 178 ), (9) increased carcinogenesis ( 28 , 179 – 190 ), (10) heightened rates of many congenital anomalies and teratologic syndromes ( 27 – 29 , 191 – 207 ), (11) telomerase inhibition ( 11 , 208 ), (12) chromosomal damage ( 2 , 4 , 8 , 178 ), (13) reduction in histones ( 5 , 21 , 26 , 209 – 211 ), (14) immunostimulation ( 93 , 94 , 99 – 101 , 212 – 217 ), and (15) elevated mortality rates in long-term users ( 218 – 229 ). These are elaborated in detail elsewhere ( 31 , 185 , 230 ).…”