Potential roles of imprinted genes in the teratogenic effects of alcohol on the placenta, somatic growth, and the developing brain

Gutherz, Olivia R.; Deyssenroth, Maya A.; Li, Qian; Hao, Ke; Jacobson, Joseph L.; Chen, Jia; Carter, R. Colin

doi:10.1016/j.expneurol.2021.113919

Cited by 11 publications

(6 citation statements)

References 171 publications

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“…This foundational centrality of epigenotoxicity to the understanding of cannabinoid toxicity is highly reminiscent of the central understanding which the fundamentally epigenomic nature of fetal alcohol syndrome has been shown to display [ 309 , 310 , 311 , 312 , 313 , 314 , 315 , 316 , 317 , 318 , 319 , 320 ]. Indeed, fetal alcohol syndrome has been shown to be primarily mediated epigenomically via cannabinoid type 1 receptors (CB1Rs) [ 321 , 322 , 323 , 324 , 325 , 326 , 327 , 328 , 329 , 330 , 331 ].…”

Section: Resultsmentioning

confidence: 99%

Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis

Reece

Hulse

2022

IJERPH

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Background: Twelve separate streams of empirical data make a strong case for cannabis-induced accelerated aging including hormonal, mitochondriopathic, cardiovascular, hepatotoxic, immunological, genotoxic, epigenotoxic, disruption of chromosomal physiology, congenital anomalies, cancers including inheritable tumorigenesis, telomerase inhibition and elevated mortality. Methods: Results from a recently published longitudinal epigenomic screen were analyzed with regard to the results of recent large epidemiological studies of the causal impacts of cannabis. We also integrate theoretical syntheses with prior studies into these combined epigenomic and epidemiological results. Results: Cannabis dependence not only recapitulates many of the key features of aging, but is characterized by both age-defining and age-generating illnesses including immunomodulation, hepatic inflammation, many psychiatric syndromes with a neuroinflammatory basis, genotoxicity and epigenotoxicity. DNA breaks, chromosomal breakage-fusion-bridge morphologies and likely cycles, and altered intergenerational DNA methylation and disruption of both the histone and tubulin codes in the context of increased clinical congenital anomalies, cancers and heritable tumors imply widespread disruption of the genome and epigenome. Modern epigenomic clocks indicate that, in cannabis-dependent patients, cannabis advances cellular DNA methylation age by 25–30% at age 30 years. Data have implications not only for somatic but also stem cell and germ line tissues including post-fertilization zygotes. This effect is likely increases with the square of chronological age. Conclusion: Recent epigenomic studies of cannabis exposure provide many explanations for the broad spectrum of cannabis-related teratogenicity and carcinogenicity and appear to account for many epidemiologically observed findings. Further research is indicated on the role of cannabinoids in the aging process both developmentally and longitudinally, from stem cell to germ cell to blastocystoids to embryoid bodies and beyond.

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Section: Resultsmentioning

confidence: 99%

Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis

Reece

Hulse

2022

IJERPH

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“…Some syndromes were chosen because they are known to have pathophysiological overlap with cannabinoid effects, such as foetal alcohol syndrome, which has been shown to signal to the epigenome through the cannabinoid type 1 receptor (CB1R) [ 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 ]. Moreover, cannabis is often co-abused with alcohol and each has been described as being a gateway drug for the other [ 38 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

Patterns of Cannabis- and Substance-Related Congenital General Anomalies in Europe: A Geospatiotemporal and Causal Inferential Study

Reece

Hulse

2023

Pediatric Reports

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Introduction: Recent series of congenital anomaly (CA) rates (CARs) have showed the close and epidemiologically causal relationship of cannabis exposure to many CARs. We investigated these trends in Europe where similar trends have occurred. Methods: CARs from EUROCAT. Drug use from European Monitoring Centre for Drugs and Drug Addiction. Income data from World Bank. Results: CARs were higher in countries with increasing daily use overall (p = 9.99 × 10−14, minimum E-value (mEV) = 2.09) and especially for maternal infections, situs inversus, teratogenic syndromes and VACTERL syndrome (p = 1.49 × 10−15, mEV = 3.04). In inverse probability weighted panel regression models the series of anomalies: all anomalies, VACTERL, foetal alcohol syndrome, situs inversus (SI), lateralization (L), and teratogenic syndromes (TS; AAVFASSILTS) had cannabis metric p-values from: p < 2.2 × 10−16, 1.52 × 10−12, 1.44 × 10−13, 1.88 × 10−7, 7.39 × 10−6 and <2.2 × 10−16. In a series of spatiotemporal models this anomaly series had cannabis metric p-values from: 8.96 × 10−6, 6.56 × 10−6, 0.0004, 0.0019, 0.0006, 5.65 × 10−5. Considering E-values, the cannabis effect size order was VACTERL > situs inversus > teratogenic syndromes > FAS > lateralization syndromes > all anomalies. 50/64 (78.1%) E-value estimates and 42/64 (65.6%) mEVs > 9. Daily cannabis use was the strongest predictor for all anomalies. Conclusion: Data confirmed laboratory, preclinical and recent epidemiological studies from Canada, Australia, Hawaii, Colorado and USA for teratological links between cannabis exposure and AAVFASSILTS anomalies, fulfilled epidemiological criteria for causality and underscored importance of cannabis teratogenicity. VACTERL data are consistent with causation via cannabis-induced Sonic Hedgehog inhibition. TS data suggest cannabinoid contribution. SI&L data are consistent with results for cardiovascular CAs. Overall, these data show that cannabis is linked across space and time and in a manner which fulfills epidemiological criteria for causality not only with many CAs, but with several multiorgan teratologic syndromes. The major clinical implication of these results is that access to cannabinoids should be tightly restricted in the interests of safeguarding the community’s genetic heritage to protect and preserve coming generations, as is done for all other major genotoxins.

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“…Epigenetic changes and disrupted development. Epigenetic changes are chemical modifications (methylation or acetylation) to DNA and surrounding histones that influence gene expression and often occur in response to environmental exposures 118,119 . Normal development depends on numerous epigenetic changes in embryonic stem cells that facilitate their transition to fully differentiated and functional cell lineages such as neurons, muscle and fat cells 120 .…”

Section: Mechanisms Of Alcohol Teratogenesismentioning

confidence: 99%

“…Alcohol can disrupt development by inducing DNA methylation and histone acetylation in gene clusters and altering gene expression 121 . Epigenetic alterations resulting from PAE have been observed in animal models and humans, and these changes may be lifelong and inherited by future generations 118,[122][123][124] . A pattern of DNA methylation in buccal epithelial cells was reasonably accurate (positive predictive value 90%; negative predictive value 78.6%) in discriminating children with FASD from typically developing controls or children with autism spectrum disorders 125 .…”

Section: Mechanisms Of Alcohol Teratogenesismentioning

confidence: 99%

Fetal alcohol spectrum disorders

Popova

Charness

Burd

et al. 2023

Nat Rev Dis Primers

116

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Alcohol readily crosses the placenta and may disrupt fetal development. Harm from prenatal alcohol exposure (PAE) is determined by the dose, pattern, timing and duration of exposure, fetal and maternal genetics, maternal nutrition, concurrent substance use, and epigenetic responses. A safe dose of alcohol use during pregnancy has not been established. PAE can cause fetal alcohol spectrum disorders (FASD), which are characterized by neurodevelopmental impairment with or without facial dysmorphology, congenital anomalies and poor growth. FASD are a leading preventable cause of birth defects and developmental disability. The prevalence of FASD in 76 countries is >1% and is high in individuals living in out-of-home care or engaged in justice and mental health systems. The social and economic effects of FASD are profound, but the diagnosis is often missed or delayed and receives little public recognition. Future research should be informed Nature Reviews Disease Primers | (2023) 9:11 2 0123456789();: PrimerFASD occur in all socioeconomic and ethnic groups 15 and are complex, chronic conditions that affect health and family functioning 16 . Individuals with FASD usually require lifelong health care as well as social and vocational support. Some require remedial education and others interact with the justice system. Early diagnosis and a strength-based management approach will optimize health outcomes.FASD are the most common of the potentially preventable conditions associated with birth anomalies and neurodevelopmental problems 13 , and their global effects, including huge social and economic costs, are substantial 17 . For example, in Canada, the annual cost associated with FASD is an estimated ~CAD$ 1.8 billion (CAD$ 1.3 billion to CAD$ 2.3 billion) 17 , which is attributable in part to productivity loss (41%), correction services (29%) and health care (10%). In North America, the lifetime cost of supporting an individual with FASD is estimated at >CAD$ 1 million 18 . Addressing and preventing alcohol use in pregnancy is a public-health imperative.This Primer presents the epidemiology of FASD and the latest understanding of its pathophysiology as well as approaches to diagnosis, screening and prevention. The Primer also describes outcomes across the lifespan, management and quality of life (QOL) of people living with FASD, and highlights important areas for future research and clinical practice. Epidemiology Alcohol use during pregnancyNo safe level of PAE has been established 19 , and international guidelines advise against any amount or type of alcohol use during pregnancy [20][21][22][23] . Nevertheless, ~10% of pregnant women worldwide consume alcohol 24,25 . The highest prevalence of alcohol use during pregnancy is in the WHO European Region (25.2% 24 ; Fig. 1), consistent with the prevalence of heavy alcohol use, heavy episodic drinking and alcohol use disorders in this region 26 . 0123456789();: PrimerIn 40% of the 162 countries evaluated, >25% of women who consumed any alcohol during pregnancy drank at 'bing...

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Potential roles of imprinted genes in the teratogenic effects of alcohol on the placenta, somatic growth, and the developing brain

Cited by 11 publications

References 171 publications

Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis

Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis

Patterns of Cannabis- and Substance-Related Congenital General Anomalies in Europe: A Geospatiotemporal and Causal Inferential Study

Fetal alcohol spectrum disorders

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