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Explaining Contemporary Patterns of Cannabis Teratology
Clinical Pediatrics: Open Access

Clinical Pediatrics: Open Access
Open Access

ISSN: 2572-0775

+44 1223 790975

Short Communication - (2019) Volume 4, Issue 1

Explaining Contemporary Patterns of Cannabis Teratology

Albert Stuart Reece1* and Gary Kenneth Hulse2
1Division of Psychiatry, University of Western Australia, Australia
2School of Medical and Health Sciences, Edith Cowan University, Australia
*Corresponding Author: Albert Stuart Reece, Division of Psychiatry, University of Western Australia, Australia, Tel: (617) 3844-4000 Email:

Abstract

Cannabis has been shown to be teratogenic in cells, animals and humans. Particular targets of prenatal exposure include brain, heart and blood vessels and chromosomal segregation. Three longitudinal clinical studies report concerning cortical dysfunction persisting into adolescence and beyond, which are pertinent to the autism epidemic. Increased rates of congenital heart defects, gastroschisis, anencephaly and others have been reported. The pattern of neuroteratology seen after cannabis exposure strongly suggests a spectrum of dysfunction from mild to moderate to very severe. Downs syndrome, atrial septal defect (secundum type), ventricular septal defect and anotia / microtia were noted to be more common in prenatally cannabis exposed children in a large US epidemiological study which would appear to have been confirmed by recent experience in Colorado and other USA states. Studies in cells, together with the above mentioned epidemiology, implicate cannabidiol, cannabichromene, cannabidivarin and other cannabinoids in significant genotoxicity and / or epigenotoxicity. Notch signalling has recently been shown to be altered by cannabinoids, which is highly pertinent to morphogenesis of the neuraxis and cardiovasculature, and also to congenital and inheritable cancer induction. It is felt that subtle neurobehavioural psychosocial and educational deficits will likely be the most common expression of cannabinoid teratology at the population level. The far reaching implications of this wide spectrum of neuroteratological, pediatric cardiological and other defects and deficits should be carefully considered in increasingly liberal paradigms. Hence it is shown that the disparate presentations of cannabis teratology relate directly and closely to the distribution of CB1R’s across the developing embryo and account for the polymorphous clinical presentations.

Keywords: Cannabis; Gastroschisis; Pediatric Epidemiology; Congenital Heart Disease; Notch Signalling; Neurobehavioral Teratology

Introduction

At a time when up to 24% of Californian teenage mothers test positive for cannabis, it is of concern that the complex literature relating to the teratology of cannabis seems to have created mixed messages in both professional and popular fora, leading the teratogenic effects of cannabis to be overlooked and the impact of increasing cannabis consumption to be underestimated. It is therefore important to reiterate that a number of independent and well-designed studies have similarly indicated major teratogenic effects associated with both maternal and paternal cannabis use.

In reviewing the teratology of prenatal cannabis exposure (PCE) this paper will concisely consider neurobehavioural effects, cardiovascular effects including gastroschisis (which is thought to have a vascular aetiopathology), immune effects, chromosomal effects, genetic and epigenetic effects, mitochondrial effects, the effects of the various different exogenous cannabinoids, and notch signalling.

Neurobehavioural Teratology

Indeed, despite the existence of a conflicting literature on the teratogenic effects of cannabis, there is also a growing body of studies which indicate major teratogenic effects associated with prenatal cannabis exposure. Furthermore, since there is not always an established neurodevelopmental phenotype related to PCE, the absence of an overt teratogenic effect does not exclude the existence of covert effects or vulnerabilities which become manifest during the postnatal development when individuals are in contact with various stressors.This can be explained by a vulnerability/stress model or again a double hit hypothesis [1-6]. Therefore, it becomes urgent to remind the profession of the latest findings suggesting major teratogenic effects in relation to PCE, especially in the context of a recent increase of cannabis consumption in many western countries. It therefore becomes important to note that the published literature shows a high degree of concordance that a variety of neurological effects are seen with increased frequency after prenatal cannabis exposure including: impairment of foetal development, elevated rates of prematurity, earlier births, smaller heads which have been shown to persist life long, and which necessarily includes smaller brain [7].

Such a pattern fits with the moderate to high concentration of cannabinoid type 1 receptors (CB1R) which has been shown to exist in the foetal brain from early in development including in the cerebral, cerebellar, orbitofrontal and hippocampal cortices, parts of the midbrain and the limbic system. The CB1R is the major cannabinoid receptor found throughout the body. Indeed two papers have issued from the Centres for Disease Control (CDC) births defects monitoring program the National Births Defects Prevention Network (NBDPN) which document rates of anencephaly elevated respectively to 1.7 (95%C.I. 0.9-3.4) and 1.9 (1.1-3.2) times above background [8].

The effects of PCE have been studied longitudinally in three major cohort studies from Canada (Ottawa), USA (Pittsburgh) and The Netherlands and there is again a remarkable level of concordance between the three showing impaired brain growth and development, impaired intellectual acuity and academic ability, reduced attention span, and lower scores on a broad spectrum of school tests [1]. Many of these changes persisted and were detectable right throughout the schooling career through primary and secondary school and into their early twenties [7]. These findings of impaired executive and cognitive functioning are supported by other studies which have shown structural and functional damage including decreased frontal cortical thickness and a higher rate of disconnection of major white matter tracts of over 84% in key junctional nodal areas of the cerebral cortex (splenium to precuneus and in the fimbria of the fornix). Microcephaly has also been demonstrated in PCE neonates [9].

In this connection it is noteworthy that the largely supratentorial distribution of CB1R’s in the foetal brain closely parallels the observed pattern of functional disability after PCE, which is largely restricted to the supratentorial brain. The pathology of anencephaly illustrates this feature particularly clearly wherein the brain stem is usually spared, and simultaneously has the lowest concentration of CB1R’s whereas the other parts of the brain which are richer in CB1R’s become effectively “chemically amputated”.

Indeed further thought shows that the above mentioned neuroteratological manifestations of PCE including impaired cortical and destabilized affective function and an increased rate of drug dependency – which is mediated by the limbic system – also appear to closely follow the distribution of CB1R’s across these structures. Indeed a clear sequence is documented by the extant literature from subtle forms of affective and intellectual impairment at one end to more severe impacts such as smaller heads, microcephaly and anencephaly at the other end of the spectrum. This spectrum of disorders can be further extended to include neurologically induced foetal loss both before and after birth including spontaneous and induced terminations of pregnancy.

Several exogenous agents are known to cause anencephaly including the anticonvulsant valproate, various serotonin uptake receptor antagonists and folic acid deficiency in addition to genetic disorders including ciliopathies and a prior history of an anencephalic pregnancy [10-17]. That cannabis can act to effectively amputate the forebrain strongly suggests a spectrum of neuroteratological cannabis related manifestations. In such a conceptual paradigm both the fact and the severity of cannabis neuroteratology is underscored by the inclusion of anencephaly within the cannabis-related neonatalperinatal- pediatric disease spectrum. This important neuroteratological spectrum carries a major public health message which is not widely appreciated.

Implications of High Density Mitochondrial CB1R’s

Importantly high density CB1R’s together with their complete transduction machinery including intracellular cascades have been identified on mitochondria of many organs including the brain. Various major brain functions including memory, thinking, wakefulness and attention have been shown to be dependent on these mitochondrial activities [18]. Inhibition of the CB1R’s on these brain mitochondria has been shown to be causally linked with a stimulation of the aging processes of the brain by impairing the metabolic crosstalk between mitochondria and nuclei, stimulation of the mitochondrial stress response, and impairment of mitochondrial and nuclear DNA repair [18,19]. Since these processes can also be expected to act in utero the direct and profound implication is that molecular, neuronal and genetic aging is induced at the foetal stage, even prior to birth. Such a suggestion would be formally testable by investigating molecular and epigenetic biomarkers of aging from foetal and placental tissues.

Cardiovascular Pathologies

Cannabis use in adults has also been shown to be linked with significantly elevated rates of stroke, cardiac arrest, testicular cancer, chronic lung disease and hepatic fibrosis and cirrhosis [20-24]. Parts of the membranous interventricular septum and both the atrioventricular valves are derived from the endocardial cushions which are known to express high levels of CB1R’s from as early as 9 weeks of gestation [25]. Perivascular CB1R also plays a key role in regulating the neurovascular coupling of the neural stem cell niche and is directly responsible for the elevated Blood Oxygen Level Dependent (BOLD) signal shown on MRI with increased local brain metabolism and neural activity. In 2007 American Academy of Paediatrics and the American Heart Association in a major position statement linked PCE to a doubled incidence of the two congenital heart defects ventricular septal defect (VSD) and Ebsteins anomaly and noted that the relationship was likely causal [26].

Increasing cannabis use in Colorado is the most obvious explanatory cause for the increased rates of Coloradan: VSD by 35%, atrial septal defects by 262% and all major congenital defects by 70% from 2000-2013 (Figure 1) data cited April 2018, Colorado Respond to Children with Special Needs (CRCSN) program. Over this period drug use data from the National Survey of Drug Use and Health indicates that the use of other drugs in Colorado was falling and/or at very low levels likely too low to impact the population prevalence of these issues. It is noted en passant that the CRCSN Program have recently revised the totality of their birth defect data 2000-2013 in October 2018, for reasons which remain unclear at the time of writing. Data on selected defects including both the earlier data release and data subsequent to October 2018 is included in (Figure 2). From this Figure one notes a rise in several congenital anomalies in Colorado, all of which have been previously shown to be linked with PCE [9,26].

clinical-pediatrics-teen-cannabls

Figure 1: Colorado-Congenital Anomaly Rate and Teen Cannabls Use.

clinical-pediatrics-congenital-anomaly

Figure 2: Congenital Anomaly Rates in Colorado.

Since cardiovascular structures are formed early in gestation they are particularly vulnerable to CB1R-mediated effects. Early in pregnancy some women may not be aware that they are pregnant. Cannabinoids are lipid soluble and are known to have a very protracted half-life in fat stores, so that even immediate cessation in a regular cannabis consumer would not protect her foetus from exposure due to the residual effects of on board cannabinoids leaching out of her endogenous stores. Various studies also implicate paternal cannabis exposure in foetal teratogenesis. For some defects, for example for transposition of the great arteries, paternal exposure has shown to be more important than maternal exposure [27].

The rate of gastroschisis is known to have risen in areas where cannabis use has increased, such as Northern Canada, Mexico, Northern New South Wales in Australia, and North Carolina and Washington state in USA, and likely also reflects vasoactive cannabinoid exposure. CB1R’s are known to exist in high density on foetal arterial and venous vessels. Cannabinoids acting via CB1R’s have also been linked with both vasospasm and arteritis [25]. Concordant with this view one notes that seven studies uniformly document an increased incidence of gastroschisis after PCE and another two studies show increased severity of the deformity. Careful multivariate analyses from Canada have shown a three-fold elevation of gastroschisis risk after prenatal cannabis exposure. These findings also suggest that the vasoactive properties of cannabis have not been widely appreciated as a potential cause of subsequent teratological malformations.

Immune Dysfunction

It is well established that cannabinoids play a large role as immunomodulators with CB1R’s most often up-regulating, and CB2R’s down-regulating immune responses [28-34]. Endocannabinoid receptors are widely distributed on all cell types of the immune system including endothelial cells and the microglia which are the macrophages of the brain. This is important as microglia play a direct role in synaptic pruning and the disposal of unwanted dendrites and sculpt the neural network for increased focus, attention and concentration. Deficits of such function have been linked with impaired memory, brain development and the onset of numerous major mental disorders including autism and schizophrenia [33]. PCE has been shown to result in activation of the microglia of the brain [33]. Moreover the demonstration that PCE can lead to alteration of the methylation state of DNA on immune cells has long lasting implications not only for immune development, but also for brain development and maturation, and has been linked with the subsequent development of opioid addiction in a rodent model [35]. Chromosomal Mis-segregation Disorders from Damage to the Mitotic Spindle [9]. Tetrahydrocannabinol has also been shown to interfere with the key elements of cytoskeletal framework including actin and tubulin polymerization [36]. Tubulin polymers form the microtubule “rails” of the mitotic spindle along which the chromosomes slide during cell division, and chromosomal mis-segregation is a major cause of serious genetic damage and anomalies of chromosomal ploidy. Hence it becomes important that Down’s syndrome, which is one of the chromosomal mis-segregation disorders, has been previously linked with PCE by prior studies [9], and was recently found to be increased 35% in Colorado from 74 cases in 2001 to 100 in 2013 (October 2018 data release). Official Canadian Government reports demonstrate a clear association across Canadian provinces between cannabis use on the one hand [37] and elevated rates of total congenital defects, gastroschisis, orofacial clefts and cardiovascular defects on the other [38]. Similar data has also been published for eastern Australia [39].

Other Cannabinoids

Cannabidiol is the second most commonly occurring natural cannabinoid. Hence it would appear to be deeply implicated also in the above impressive series of epidemiological studies. One notes that cannabidiol at high concentration has also been shown by several investigators to bind CB1R’s [40-42], which further implicates cannabidiol in the above pathophysiological cascades. Cannabidiol has also been shown to have important interactions with PPARγ (Peroxisome Proliferator Activated Receptor) which is a major nuclear receptor impacting metabolic, immune and adipose function on immune, adipose and hepatic cells in particular [43-46]. Cannabidiol, cannabinol, cannabidivarin and cannabichromene have also been implicated in major genetic and epigenetic damage to cells in vitro [35,47-54].

Notch Signalling

It was also recently shown that endocannabinoids interact with the notch signalling system in many tissues [55-58], and indeed that reciprocal signalling occurs [59], opening the way for feed-forward information loops and relays. This is a profoundly important finding and highly relevant to foetal morphogenesis, as it is well established that notch is a major morphogen controlling body formation and involved in the cellular specification particularly of the brain and cardiovasculature [60].

Notch is also an important signaling molecule involved in cancer induction. This is likely of particular relevance to the demonstrated links between PCE and the four cancers: acute lymphatic leukaemia, acute myelomonocytic leukaemia, neuroblastoma and rhabdomyosarcoma [36,61-66].

These considerations demonstrate that a careful consideration of the distribution of the major cannabinoid endoreceptor CB1R clearly explains much of the cardiovascular, neuropsychiatric and behavioural teratology which has been described in the extant literature as it relates to prenatal cannabinoid exposure from both paternal and maternal sources.

Higher concentration cannabis and systematic under-reporting in exclusively self-report studies consistently underestimate future trends [8]. Increased PCE consequent upon the intersection of elevated cannabis use prevalence, rising cannabis concentration and the frequently asymptotic cannabis genotoxicity dose-response relationships will result in predictable increases in brain and organ damage from which the child’s recovery is likely permanently compromised.

References

  1. Calvigioni D, Hurd YL, Harkany T, Keimpema E (2014) Neuronal substrates and functional consequences of prenatal cannabis exposure. Eur Child Adolesc Psychiatry 23: 931-941.
  2. Gilbert MT, Sulik KK, Fish EW, Baker LK, Dehart DB, et al. (2016) Dose-dependent teratogenicity of the synthetic cannabinoid CP-55,940 in mice. Neurotoxicol Teratol 58: 15-22.
  3. Jansson LM, Jordan CJ, Velez ML (2018) Perinatal Marijuana Use and the Developing Child. JAMA 320: 545-546.
  4. Maccarrone M, Guzman M, Mackie K, Doherty P, Harkany T (2014) Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies. Nat Rev Neurosci 15: 786-801.
  5. Richardson KA, Hester AK, McLemore GL (2016) Prenatal cannabis exposure - The "first hit" to the endocannabinoid system. Neurotoxicol Teratol 58: 5-14.
  6. Wu CS, Jew CP, Lu HC (2011) Lasting impacts of prenatal cannabis exposure and the role of endogenous cannabinoids in the developing brain. Future Neurol 6: 459-480.
  7. Brents L (2017) Correlates and consequences of Prenatal Cannabis Exposure (PCE): Identifying and Characterizing Vulnerable Maternal Populations and Determining Outcomes in Exposed Offspring In: Preedy V.R (eds.) Handbook of Cannabis and Related Pathologies: Biology, Pharmacology, Diagnosis and Treatment. London: Academic Press, pp: 160-170.
  8. Van Gelder MM, Donders AR, Devine O, Roeleveld N, Reefhuis J, et al. (2014) Using bayesian models to assess the effects of under-reporting of cannabis use on the association with birth defects, national birth defects prevention study, 1997-2005. Paediatr Perinat Epidemiol 28: 424-433.
  9. Forrester MB, Merz RD (2007) Risk of selected birth defects with prenatal illicit drug use, Hawaii, 1986-2002. J Toxicol Environ Health A 70: 7-18.
  10. Agopian AJ, Tinker SC, Lupo PJ, Canfield MA, Mitchell LE, et al (2013) Proportion of neural tube defects attributable to known risk factors. Birth Defects Res A Clin Mol Teratol 97: 42-46.
  11. Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM, et al. (2007) Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 356: 2684-2692.
  12. Badano JL, Mitsuma N, Beales PL, Katsanis N (2006) The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 7: 125-148.
  13. Centers for Disease Control (1991) Use of folic acid for prevention of spina bifida and other neural tube defects--1983-1991. MMWR Morb Mortal Wkly Rep 40: 513-516.
  14. Cowchock S, Ainbender E, Prescott G, Crandall B, Lau L, et al. (1980) The recurrence risk for neural tube defects in the United States: a collaborative study. Am J Med Genet 5: 309-314.
  15. Kaneko KJ, Kohn MJ, Liu C, DePamphilis ML (2007) Transcription factor TEAD2 is involved in neural tube closure. Genesis 45: 577-587.
  16. Reefhuis J, Devine O, Friedman JM, Louik C, Honein MA, et al. (2015) Specific SSRIs and birth defects: Bayesian analysis to interpret new data in the context of previous reports. BMJ 351: h3190.
  17. Shaffer LG, Marazita ML, Bodurtha J, Newlin A, Nance WE (1990) Evidence for a major gene in familial anencephaly. Am J Med Genet 36: 97-101.
  18. Hebert-Chatelain E, Desprez T, Serrat R, Bellocchio L, Soria-Gomez E, et al. (2016) A cannabinoid link between mitochondria and memory. Nature 539: 555-559.
  19. Wolff V, Schlagowski AI, Rouyer O, Charles AL, Singh F, et al. (2015) Tetrahydrocannabinol induces brain mitochondrial respiratory chain dysfunction and increases oxidative stress: a potential mechanism involved in cannabis-related stroke. Biomed Res Int 2015: 323706.
  20. Gurney J, Shaw C, Stanley J, Signal V, Sarfati D (2015) Cannabis exposure and risk of testicular cancer: a systematic review and meta-analysis. BMC Cancer 15: 897.
  21. Sarafian TA, Habib N, Oldham M, Seeram N, Lee RP, et al. (2006) Inhaled marijuana smoke disrupts mitochondrial energetics in pulmonary epithelial cells in vivo. Am J Physiol Lung Cell Mol Physiol 290: L1202-1209.
  22. Menahem S (2017) Cardiovascular Effects of Cannabis Usage. In: V.R.P (editors) Handbook of Cannabis and Related Pathologies: Biology, Pharmacology and Treatment. New York: Academic Press, pp: 481-485.
  23. Barber PA (2017) Cannabis and Stroke. In: V.R P (editors). Handbook of Cannabis and Related Pathologies: Biology, Pharmacology and Treatment. New York: Academic Press, pp: 486-493.
  24. Tashkin DP (2017) Cannabis Smoking and the Lung. In: V.R. P (editors) Handbook of Cannabis and Related Pathologies: Biology, Pharmacology and Treatment. New York: Academic Press, pp: 494-504.
  25. Pacher P, Steffens S, Hasko G, Schindler TH, Kunos G (2018) Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly. Nat Rev Cardiol 15: 151-166.
  26. Jenkins KJ, Correa A, Feinstein JA, Botto L, Britt AE, et al. (2007) Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 115: 2995-3014.
  27. Wilson PD, Loffredo CA, Correa-Villasenor A, Ferencz C (1998) Attributable fraction for cardiac malformations. Am J Epidemiol 148: 414-423.
  28. Cabral GA (2006) Drugs of abuse, immune modulation, and AIDS. J Neuroimmune Pharmacol 1: 280-295.
  29. Eisenstein TK, Meissler JJ, Wilson Q, Gaughan JP, Adler MW (2007) Anandamide and Delta9-tetrahydrocannabinol directly inhibit cells of the immune system via CB2 receptors. J Neuroimmunol 189: 17-22.
  30. Klein TW, Cabral GA (2006) Cannabinoid-induced immune suppression and modulation of antigen-presenting cells. J Neuroimmune Pharmacol 1: 50-64.
  31. Klein TW, Newton C, Larsen K, Lu L, Perkins I, et al. (2003) The cannabinoid system and immune modulation. Journal of leukocyte biology 74: 486-496.
  32. McKallip RJ, Nagarkatti M, Nagarkatti PS (2005) Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. J Immunol 174: 3281-3289.
  33. Cutando L, Maldonado R, Ozaita A (2017) Microglial Activation and Cannabis Exposure. In: V. P (eds.) Handbook of Cannabis and Related Pathologies: Biology, Pharmacology, Diagnosis and Treatment. New York: Academic Press, pp: 401-412.
  34. Hernandez-Cervantes R, Mendez-Diaz M, Prospero-Garcia O, Morales-Montor J (2017) Immunoregulatory Role of Cannabinoids during Infectious Disease. Neuroimmunomodulation 24: 183-199.
  35. Zumbrun EE, Sido JM, Nagarkatti PS, Nagarkatti M (2015) Epigenetic Regulation of Immunological Alterations Following Prenatal Exposure to Marijuana Cannabinoids and its Long Term Consequences in Offspring. J Neuroimmune Pharmacol 10: 245-254.
  36. Reece AS, Hulse GK (2016) Chromothripsis and epigenomics complete causality criteria for cannabis- and addiction-connected carcinogenicity, congenital toxicity and heritable genotoxicity. Mutat Res 789: 15-25.
  37. Leos-Toro C, Reid JL, Madill CL, Rynard VL, Manske SR, Hammond D (2017) Cannabis in Canada - Tobacco Use in Canada: Patterns and Trends, 2017 (editors) Special Supplement. In: PROPEL, Centre for Population Health Impact, Waterloo Uo, eds. Cannabis in Canada: Patterns and Trends. Waterloo, Ontario: University of Waterloo, pp: 1-23.
  38. Public Health Agency of Canada HC. 2013 Congenital Anomalies in Canada, 2013. A Perinatal Health Surveillance Report.. In: Public Health Agency of Canada HC, (editors) Ottawa: Health Canada, pp: 1-119.
  39. Queensland Maternal and Perinatal Quality Council (2018). Queensland Mothers and Babies 2014 and 2015. In: Health Q, (eds.) Brisbane: Queensland Health, pp: 1-70.
  40. Hwang YS, Kim YJ, Kim MO, Kang M, Oh SW, et al. (2017) Cannabidiol upregulates melanogenesis through CB1 dependent pathway by activating p38 MAPK and p42/44 MAPK. Chem Biol Interact 273: 107-114.
  41. Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM (2015) Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol 172: 4790-4805.
  42. Stanley CP, Hind WH, Tufarelli C, O'Sullivan SE (2015) Cannabidiol causes endothelium-dependent vasorelaxation of human mesenteric arteries via CB1 activation. Cardiovasc Res 107: 568-578.
  43. De Filippis D, Esposito G, Cirillo C, Cipriano M, De Winter BY, et al. (2011) Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis. PLoS One 6: e28159.
  44. Esposito G, Scuderi C, Valenza M, Togna GI, Latina V, et al. (2011) Cannabidiol reduces Abeta-induced neuroinflammation and promotes hippocampal neurogenesis through PPARgamma involvement. PLoS One 6: e28668.
  45. O'Sullivan SE, Kendall DA (2010) Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory disease. Immunobiology 215: 611-616.
  46. Ramer R, Heinemann K, Merkord J, Rohde H, Salamon A, et al. (2013) COX-2 and PPAR-gamma confer cannabidiol-induced apoptosis of human lung cancer cells. Mol Cancer Ther 12: 69-82.
  47. Szutorisz H, Hurd YL (2016) Epigenetic Effects of Cannabis Exposure. Biol Psychiatry 79: 586-594.
  48. Todd SM, Zhou C, Clarke DJ, Chohan TW, Bahceci D, et al. (2017) Interactions between cannabidiol and Delta(9)-THC following acute and repeated dosing: Rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway. Eur Neuropsychopharmacol 27: 132-145.
  49. Russo C, Ferk F, Mišík M, Ropek N, Nersesyan A, et al. (2018) Low doses of widely consumed cannabinoids (cannabidiol and cannabidivarin) cause DNA damage and chromosomal aberrations in human-derived cells. Arch Toxicol.
  50. DeLong GT, Wolf CE, Poklis A, Lichtman AH (2010) Pharmacological evaluation of the natural constituent of Cannabis sativa, cannabichromene and its modulation by Delta(9)-tetrahydrocannabinol. Drug Alcohol Depend 112: 126-133.
  51. Hatoum NS, Davis WM, Elsohly MA, Turner CE (1981) Perinatal exposure to cannabichromene and Δ9-tetrahydrocannabinol: Separate and combined effects on viability of pups and on male reproductive system at maturity. Toxicology letters 8: 141-146.
  52. Maor Y, Yu J, Kuzontkoski PM, Dezube BJ, Zhang X, et al. (2012) Cannabidiol inhibits growth and induces programmed cell death in kaposi sarcoma-associated herpesvirus-infected endothelium. Genes Cancer 3: 512-520.
  53. Pucci M, Rapino C, Di Francesco A, Dainese E, D'Addario C, et al. (2013) Epigenetic control of skin differentiation genes by phytocannabinoids. Br J Pharmacol 170: 581-591.
  54. Murphy SK, Itchon-Ramos N, Visco Z, Huang Z, Grenier C, et al. (2018) Cannabinoid exposure and altered DNA methylation in rat and human sperm. Epigenetics.
  55. Lu T, Newton C, Perkins I, Friedman H, Klein TW (2006) Cannabinoid treatment suppresses the T-helper cell-polarizing function of mouse dendritic cells stimulated with Legionella pneumophila infection. J Pharmacol Exp Ther 319: 269-276.
  56. Newton CA, Chou PJ, Perkins I, Klein TW (2009) CB(1) and CB(2) cannabinoid receptors mediate different aspects of delta-9-tetrahydrocannabinol (THC)-induced T helper cell shift following immune activation by Legionella pneumophila infection. J Neuroimmune Pharmacol 4: 92-102.
  57. Tanveer R, Gowran A, Noonan J, Keating SE, Bowie AG, et al. (2012) The endocannabinoid, anandamide, augments Notch-1 signaling in cultured cortical neurons exposed to amyloid-beta and in the cortex of aged rats. J Biol Chem 287: 34709-34721.
  58. Xapelli S, Agasse F, Sarda-Arroyo L, Bernardino L, Santos T, et al. (2013) Activation of type 1 cannabinoid receptor (CB1R) promotes neurogenesis in murine subventricular zone cell cultures. PLoS One 8: e63529.
  59. Kim D, Lim S, Park M, Choi J, Kim J, et al. (2014) Ubiquitination-dependent CARM1 degradation facilitates Notch1-mediated podocyte apoptosis in diabetic nephropathy. Cellular signalling 26: 1774-1782.
  60. Sadler TW (2015) Medical Embryology. 13th (eds.) Philadelphia, USA: Wolters Kluwer.
  61. Grufferman S, Schwartz AG, Ruymann FB, Maurer HM (1993) Parents' use of cocaine and marijuana and increased risk of rhabdomyosarcoma in their children. Cancer Causes Control 4: 217-224.
  62. Kuijten RR, Bunin GR, Nass CC, Meadows AT (1990) Gestational and familial risk factors for childhood astrocytoma: results of a case-control study. Cancer Res 50: 2608-2612.
  63. Robison LL, Buckley JD, Daigle AE, Wells R, Benjamin D, et al. (1989) Maternal drug use and risk of childhood nonlymphoblastic leukemia among offspring. An epidemiologic investigation implicating marijuana (a report from the Childrens Cancer Study Group). Cancer 63: 1904-1911.
  64. Trivers KF, Mertens AC, Ross JA, Steinbuch M, Olshan AF, et al. (2006) Parental marijuana use and risk of childhood acute myeloid leukaemia: a report from the Children's Cancer Group (United States and Canada). Paediatric and perinatal epidemiology 20: 110-118.
  65. Wen WQ, Shu XO, Steinbuch M, Severson RK, Reaman GH, et al. (2000) Paternal military service and risk for childhood leukemia in offspring. Am J Epidemiol 151: 231-240.
  66. Reece AS (2009) Chronic toxicology of cannabis. Clin Toxicol (Phila) 47: 517-24.
Citation: Reece AS, Hulse GK (2019) Explaining Contemporary Patterns of Cannabis Teratology. Clin Pediatr OA 4: 146.

Copyright: © 2019 Reece AS, et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.
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