Journal of Neuroimmune Pharmacology

, Volume 10, Issue 2, pp 245–254 | Cite as

Epigenetic Regulation of Immunological Alterations Following Prenatal Exposure to Marijuana Cannabinoids and its Long Term Consequences in Offspring

  • Elizabeth E. Zumbrun
  • Jessica M. Sido
  • Prakash S. Nagarkatti
  • Mitzi NagarkattiEmail author


Use of marijuana during pregnancy is fairly commonplace and can be expected increase in frequency as more states legalize its recreational use. The cannabinoids present in marijuana have been shown to be immunosuppressive, yet the effect of prenatal exposure to cannabinoids on the immune system of the developing fetus, its long term consequences during adult stage of life, and transgenerational effects have not been well characterized. Confounding factors such as co-existing drug use make the impact of cannabis use on progeny inherently difficult to study in a human population. Data from various animal models suggests that in utero exposure to cannabinoids results in profound T cell dysfunction and a greatly reduced immune response to viral antigens. Furthermore, evidence from animal studies indicates that the immunosuppressive effects of cannabinoids can be mediated through epigenetic mechanisms such as altered microRNA, DNA methylation and histone modification profiles. Such studies support the hypothesis that that parental or prenatal exposure to cannabis can trigger epigenetic changes that could have significant immunological consequences for offspring as well as long term transgenerational effects.


Marijuana Pregnancy Cannabinoids Endocannabinoids CB1 CB2 THC Immune system Epigenetic Transgenerational DNA methylation Histone modification MicroRNA 


Conflict of Interest

The authors declare no conflict of interest.


  1. Aguado T, Carracedo A, Julien B, Velasco G, Milman G, Mechoulam R, Alvarez L, Guzman M, Galve-Roperh I (2007) Cannabinoids induce glioma stem-like cell differentiation and inhibit gliomagenesis. J Biol Chem 282:6854–6862PubMedCrossRefGoogle Scholar
  2. Ansel KM, Djuretic I, Tanasa B, Rao A (2006) Regulation of Th2 differentiation and Il4 locus accessibility. Annu Rev Immunol 24:607–656PubMedCrossRefGoogle Scholar
  3. Araki Y, Wang Z, Zang C, Wood WH 3rd, Schones D, Cui K, Roh TY, Lhotsky B, Wersto RP, Peng W, Becker KG, Zhao K, Weng NP (2009) Genome-wide analysis of histone methylation reveals chromatin state-based regulation of gene transcription and function of memory CD8+ T cells. Immunity 30:912–925PubMedCentralPubMedCrossRefGoogle Scholar
  4. Banerjee A, Singh A, Srivastava P, Turner H, Krishna A (2011) Effects of chronic bhang (cannabis) administration on the reproductive system of male mice. Birth Defects Res B Dev Reprod Toxicol 92:195–205PubMedCrossRefGoogle Scholar
  5. Bari M, Battista N, Pirazzi V, Maccarrone M (2011) The manifold actions of endocannabinoids on female and male reproductive events. Front Biosci 16:498–516CrossRefGoogle Scholar
  6. Barker DJ (2007) The origins of the developmental origins theory. J Intern Med 261:412–417PubMedCrossRefGoogle Scholar
  7. Bar-Oz B, Klein J, Karaskov T, Koren G (2003) Comparison of meconium and neonatal hair analysis for detection of gestational exposure to drugs of abuse. Arch Dis Child Fetal Neonatal Ed 88:F98–F100PubMedCentralPubMedCrossRefGoogle Scholar
  8. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297PubMedCrossRefGoogle Scholar
  9. Behnke M, Smith VC, Committee on Substance A, Committee on F, Newborn, (2013) Prenatal substance abuse: short- and long-term effects on the exposed fetus. Pediatrics 131:e1009–1024PubMedCrossRefGoogle Scholar
  10. Bloch E, Thysen B, Morrill GA, Gardner E, Fujimoto G (1978) Effects of cannabinoids on reproduction and development. Vitam Horm 36:203–258PubMedGoogle Scholar
  11. Bluhm EC, Daniels J, Pollock BH, Olshan AF, Children’s Oncology G (2006) Maternal use of recreational drugs and neuroblastoma in offspring: a report from the children’s oncology group (United States). Cancer Causes Control 17:663–669PubMedCrossRefGoogle Scholar
  12. Bonnin A, de Miguel R, Castro JG, Ramos JA, Fernandez-Ruiz JJ (1996) Effects of perinatal exposure to delta 9-tetrahydrocannabinol on the fetal and early postnatal development of tyrosine hydroxylase-containing neurons in rat brain. J Mol Neurosci 7:291–308PubMedCrossRefGoogle Scholar
  13. Camacho IA, Nagarkatti M, Nagarkatti PS (2004) Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on maternal immune response during pregnancy. Arch Toxicol 78:290–300PubMedCrossRefGoogle Scholar
  14. Chandra LC, Kumar V, Torben W, Stouwe CV, Winsauer P, Amedee A, Molina PE, Mohan M (2014) Chronic administration of Delta9-tetrahydrocannabinol induces intestinal anti-inflammatory microRNA expression during acute SIV infection of rhesus macaques. J VirolGoogle Scholar
  15. Collins SJ, Ulmer J, Purton LE, Darlington G (2001) Multipotent hematopoietic cell lines derived from C/EBPalpha(−/−) knockout mice display granulocyte macrophage-colony-stimulating factor, granulocyte- colony-stimulating factor, and retinoic acid-induced granulocytic differentiation. Blood 98:2382–2388PubMedCrossRefGoogle Scholar
  16. D’Addario C, Di Francesco A, Pucci M, Finazzi Agro A, Maccarrone M (2013) Epigenetic mechanisms and endocannabinoid signalling. FEBS J 280:1905–1917PubMedCrossRefGoogle Scholar
  17. Das SK, Paria BC, Chakraborty I, Dey SK (1995) Cannabinoid ligand-receptor signaling in the mouse uterus. Proc Natl Acad Sci U S A 92:4332–4336PubMedCentralPubMedCrossRefGoogle Scholar
  18. del Arco I, Munoz R, Rodriguez De Fonseca F, Escudero L, Martin-Calderon JL, Navarro M, Villanua MA (2000) Maternal exposure to the synthetic cannabinoid HU-210: effects on the endocrine and immune systems of the adult male offspring. Neuroimmunomodulation 7:16–26PubMedCrossRefGoogle Scholar
  19. DiNieri JA, Wang X, Szutorisz H, Spano SM, Kaur J, Casaccia P, Dow-Edwards D, Hurd YL (2011) Maternal cannabis use alters ventral striatal dopamine D2 gene regulation in the offspring. Biol Psychiatry 70:763–769PubMedCentralPubMedCrossRefGoogle Scholar
  20. Do Y, McKallip RJ, Nagarkatti M, Nagarkatti PS (2004) Activation through cannabinoid receptors 1 and 2 on dendritic cells triggers NF-kappaB-dependent apoptosis: novel role for endogenous and exogenous cannabinoids in immunoregulation. J Immunol 173:2373–2382PubMedCrossRefGoogle Scholar
  21. Dudley KJ, Li X, Kobor MS, Kippin TE, Bredy TW (2011) Epigenetic mechanisms mediating vulnerability and resilience to psychiatric disorders. Neurosci Biobehav Rev 35:1544–1551PubMedCrossRefGoogle Scholar
  22. Fukuchi Y, Shibata F, Ito M, Goto-Koshino Y, Sotomaru Y, Ito M, Kitamura T, Nakajima H (2006) Comprehensive analysis of myeloid lineage conversion using mice expressing an inducible form of C/EBP alpha. EMBO J 25:3398–3410PubMedCentralPubMedCrossRefGoogle Scholar
  23. Gaoni Y, Mechoulam R (1971) The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish. J Am Chem Soc 93:217–224PubMedCrossRefGoogle Scholar
  24. Garcia-Gil L, de Miguel R, Romero J, Perez A, Ramos JA, Fernandez-Ruiz JJ (1999) Perinatal delta9-tetrahydrocannabinol exposure augmented the magnitude of motor inhibition caused by GABA(B), but not GABA(A), receptor agonists in adult rats. Neurotoxicol Teratol 21:277–283PubMedCrossRefGoogle Scholar
  25. Gardiner E, Beveridge NJ, Wu JQ, Carr V, Scott RJ, Tooney PA, Cairns MJ (2012) Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells. Mol Psychiatry 17:827–840PubMedCentralPubMedCrossRefGoogle Scholar
  26. Giusti RM, Iwamoto K, Hatch EE (1995) Diethylstilbestrol revisited: a review of the long-term health effects. Ann Intern Med 122:778–788PubMedCrossRefGoogle Scholar
  27. Goldschmidt L, Richardson GA, Willford J, Day NL (2008) Prenatal marijuana exposure and intelligence test performance at age 6. J Am Acad Child Adolesc Psychiatry 47:254–263PubMedCrossRefGoogle Scholar
  28. Goldschmidt L, Richardson GA, Willford JA, Severtson SG, Day NL (2012) School achievement in 14-year-old youths prenatally exposed to marijuana. Neurotoxicol Teratol 34:161–167PubMedCentralPubMedCrossRefGoogle Scholar
  29. Gray KA, Day NL, Leech S, Richardson GA (2005) Prenatal marijuana exposure: effect on child depressive symptoms at ten years of age. Neurotoxicol Teratol 27:439–448PubMedCrossRefGoogle Scholar
  30. Harbison RD, Mantilla-Plata B (1972) Prenatal toxicity, maternal distribution and placental transfer of tetrahydrocannabinol. J Pharmacol Exp Ther 180:446–453PubMedGoogle Scholar
  31. Hatch EE, Bracken MB (1986) Effect of marijuana use in pregnancy on fetal growth. Am J Epidemiol 124:986–993PubMedGoogle Scholar
  32. Hatch EE, Palmer JR, Titus-Ernstoff L, Noller KL, Kaufman RH, Mittendorf R, Robboy SJ, Hyer M, Cowan CM, Adam E, Colton T, Hartge P, Hoover RN (1998) Cancer risk in women exposed to diethylstilbestrol in utero. JAMA 280:630–634PubMedCrossRefGoogle Scholar
  33. Hatton RD, Harrington LE, Luther RJ, Wakefield T, Janowski KM, Oliver JR, Lallone RL, Murphy KM, Weaver CT (2006) A distal conserved sequence element controls Ifng gene expression by T cells and NK cells. Immunity 25:717–729PubMedCrossRefGoogle Scholar
  34. Hayatbakhsh MR, Kingsbury AM, Flenady V, Gilshenan KS, Hutchinson DM, Najman JM (2011) Illicit drug use before and during pregnancy at a tertiary maternity hospital 2000–2006. Drug Alcohol Rev 30:181–187PubMedCrossRefGoogle Scholar
  35. Hayatbakhsh MR, Flenady VJ, Gibbons KS, Kingsbury AM, Hurrion E, Mamun AA, Najman JM (2012) Birth outcomes associated with cannabis use before and during pregnancy. Pediatr Res 71:215–219PubMedCrossRefGoogle Scholar
  36. Hegde VL, Hegde S, Cravatt BF, Hofseth LJ, Nagarkatti M, Nagarkatti PS (2008) Attenuation of experimental autoimmune hepatitis by exogenous and endogenous cannabinoids: involvement of regulatory T cells. Mol Pharmacol 74:20–33PubMedCentralPubMedCrossRefGoogle Scholar
  37. Hegde VL, Nagarkatti M, Nagarkatti PS (2010) Cannabinoid receptor activation leads to massive mobilization of myeloid-derived suppressor cells with potent immunosuppressive properties. Eur J Immunol 40:3358–3371PubMedCentralPubMedCrossRefGoogle Scholar
  38. Hegde VL, Nagarkatti PS, Nagarkatti M (2011) Role of myeloid-derived suppressor cells in amelioration of experimental autoimmune hepatitis following activation of TRPV1 receptors by cannabidiol. PLoS One 6:e18281PubMedCentralPubMedCrossRefGoogle Scholar
  39. Hegde VL, Tomar S, Jackson A, Rao R, Yang X, Singh UP, Singh NP, Nagarkatti PS, Nagarkatti M (2013) Distinct microRNA expression profile and targeted biological pathways in functional myeloid-derived suppressor cells induced by Delta9-tetrahydrocannabinol in vivo: regulation of CCAAT/enhancer-binding protein alpha by microRNA-690. J Biol Chem 288:36810–36826PubMedCentralPubMedCrossRefGoogle Scholar
  40. Hingson R, Alpert JJ, Day N, Dooling E, Kayne H, Morelock S, Oppenheimer E, Zuckerman B (1982) Effects of maternal drinking and marijuana use on fetal growth and development. Pediatrics 70:539–546PubMedGoogle Scholar
  41. Hollins SL, Zavitsanou K, Walker FR, Cairns MJ (2014) Alteration of imprinted Dlk1-Dio3 miRNA cluster expression in the entorhinal cortex induced by maternal immune activation and adolescent cannabinoid exposure. Transl Psychiatry 4:e452PubMedCentralPubMedCrossRefGoogle Scholar
  42. Hutchings DE, Martin BR, Gamagaris Z, Miller N, Fico T (1989) Plasma concentrations of delta-9-tetrahydrocannabinol in dams and fetuses following acute or multiple prenatal dosing in rats. Life Sci 44:697–701PubMedCrossRefGoogle Scholar
  43. Jackson AR, Nagarkatti P, Nagarkatti M (2014a) Anandamide attenuates Th-17 cell-mediated delayed-type hypersensitivity response by triggering IL-10 production and consequent microRNA induction. PLoS One 9:e93954PubMedCentralPubMedCrossRefGoogle Scholar
  44. Jackson AR, Hegde VL, Nagarkatti PS, Nagarkatti M (2014b) Characterization of endocannabinoid-mediated induction of myeloid-derived suppressor cells involving mast cells and MCP-1. J Leukoc Biol 95:609–619PubMedCentralPubMedCrossRefGoogle Scholar
  45. Jaques SC, Kingsbury A, Henshcke P, Chomchai C, Clews S, Falconer J, Abdel-Latif ME, Feller JM, Oei JL (2014) Cannabis, the pregnant woman and her child: weeding out the myths. J Perinatol Off J Calif Perinatal Assoc 34:417–424CrossRefGoogle Scholar
  46. Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M (2009) Endocannabinoid-mediated control of synaptic transmission. Physiol Rev 89:309–380PubMedCrossRefGoogle Scholar
  47. Kennedy JS, Waddell WJ (1972) Whole-body autoradiography of the pregnant mouse after administration of 14 C- 9 -THC. Toxicol Appl Pharmacol 22:252–258PubMedCrossRefGoogle Scholar
  48. Khare M, Taylor AH, Konje JC, Bell SC (2006) Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod 12:321–333PubMedCrossRefGoogle Scholar
  49. Klegeris A, Bissonnette CJ, McGeer PL (2003) Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. Br J Pharmacol 139:775–786PubMedCentralPubMedCrossRefGoogle Scholar
  50. Klein TW, Friedman H, Specter S (1998) Marijuana, immunity and infection. J Neuroimmunol 83:102–115PubMedCrossRefGoogle Scholar
  51. Klein TW, Lane B, Newton CA, Friedman H (2000) The cannabinoid system and cytokine network. Proc Soc Exp Biol Med Soc Exp Biol Med 225:1–8CrossRefGoogle Scholar
  52. Lombard C, Nagarkatti M, Nagarkatti PS (2005) Targeting cannabinoid receptors to treat leukemia: role of cross-talk between extrinsic and intrinsic pathways in Delta9-tetrahydrocannabinol (THC)-induced apoptosis of Jurkat cells. Leuk Res 29:915–922PubMedCrossRefGoogle Scholar
  53. Lombard C, Nagarkatti M, Nagarkatti P (2007) CB2 cannabinoid receptor agonist, JWH-015, triggers apoptosis in immune cells: potential role for CB2-selective ligands as immunosuppressive agents. Clin Immunol 122:259–270PubMedCentralPubMedCrossRefGoogle Scholar
  54. Lombard C, Hegde VL, Nagarkatti M, Nagarkatti PS (2011) Perinatal exposure to Delta9-tetrahydrocannabinol triggers profound defects in T cell differentiation and function in fetal and postnatal stages of life, including decreased responsiveness to HIV antigens. J Pharmacol Exp Ther 339:607–617PubMedCentralPubMedCrossRefGoogle Scholar
  55. Mackie K (2008) Signaling via CNS cannabinoid receptors. Mol Cell Endocrinol 286:S60–65PubMedCentralPubMedCrossRefGoogle Scholar
  56. Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK (2012a) Dioxin (TCDD) induces epigenetic transgenerational inheritance of adult onset disease and sperm epimutations. PLoS One 7:e46249PubMedCentralPubMedCrossRefGoogle Scholar
  57. Manikkam M, Guerrero-Bosagna C, Tracey R, Haque MM, Skinner MK (2012b) Transgenerational actions of environmental compounds on reproductive disease and identification of epigenetic biomarkers of ancestral exposures. PLoS One 7:e31901PubMedCentralPubMedCrossRefGoogle Scholar
  58. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564PubMedCrossRefGoogle Scholar
  59. McKallip RJ, Lombard C, Fisher M, Martin BR, Ryu S, Grant S, Nagarkatti PS, Nagarkatti M (2002) Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 100:627–634PubMedCrossRefGoogle Scholar
  60. 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 174:3281–3289PubMedCrossRefGoogle Scholar
  61. McKallip RJ, Jia W, Schlomer J, Warren JW, Nagarkatti PS, Nagarkatti M (2006) Cannabidiol-induced apoptosis in human leukemia cells: a novel role of cannabidiol in the regulation of p22phox and Nox4 expression. Mol Pharmacol 70:897–908PubMedCrossRefGoogle Scholar
  62. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR et al (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90PubMedCrossRefGoogle Scholar
  63. Molina PE, Amedee A, LeCapitaine NJ, Zabaleta J, Mohan M, Winsauer P, Vande Stouwe C (2011) Cannabinoid neuroimmune modulation of SIV disease. J Neuroimmune Pharmacol Off J Soc NeuroImmune Pharmacol 6:516–527CrossRefGoogle Scholar
  64. Morinobu A, Kanno Y, O’Shea JJ (2004) Discrete roles for histone acetylation in human T helper 1 cell-specific gene expression. J Biol Chem 279:40640–40646PubMedCrossRefGoogle Scholar
  65. Morris CV, DiNieri JA, Szutorisz H, Hurd YL (2011) Molecular mechanisms of maternal cannabis and cigarette use on human neurodevelopment. Eur J Neurosci 34:1574–1583PubMedCentralPubMedCrossRefGoogle Scholar
  66. Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65PubMedCrossRefGoogle Scholar
  67. Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M (2009) Cannabinoids as novel anti-inflammatory drugs. Future Med Chem 1:1333–1349PubMedCentralPubMedCrossRefGoogle Scholar
  68. Nagarkatti M, Rieder SA, Hegde VL, Kanada S, Nagarkatti P (2010) Do cannabinoids have a therapeutic role in transplantation? Trends Pharmacol Sci 31:345–350PubMedCentralPubMedCrossRefGoogle Scholar
  69. Newbold RR, Padilla-Banks E, Jefferson WN (2006) Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations. Endocrinology 147:S11–17PubMedCrossRefGoogle Scholar
  70. Newsom RJ, Kelly SJ (2008) Perinatal delta-9-tetrahydrocannabinol exposure disrupts social and open field behavior in adult male rats. Neurotoxicol Teratol 30:213–219PubMedCentralPubMedCrossRefGoogle Scholar
  71. Onaivi ES, Sugiura T, Di Marzo V (2006) Endocannabinoids the brain and body’s marijuana and beyond. Taylor & Francis, Boca Raton, In, p 1 online resource (563 p.) illGoogle Scholar
  72. Pandey R, Mousawy K, Nagarkatti M, Nagarkatti P (2009a) Endocannabinoids and immune regulation. Pharmacol Res Off J Ital Pharmacol Soc 60:85–92Google Scholar
  73. Pandey R, Hegde VL, Singh NP, Hofseth L, Singh U, Ray S, Nagarkatti M, Nagarkatti PS (2009b) Use of cannabinoids as a novel therapeutic modality against autoimmune hepatitis. Vitam Horm 81:487–504PubMedCentralPubMedGoogle Scholar
  74. Pandey R, Hegde VL, Nagarkatti M, Nagarkatti PS (2011) Targeting cannabinoid receptors as a novel approach in the treatment of graft-versus-host disease: evidence from an experimental murine model. J Pharmacol Exp Ther 338:819–828PubMedCentralPubMedCrossRefGoogle Scholar
  75. Paradisi A, Pasquariello N, Barcaroli D, Maccarrone M (2008) Anandamide regulates keratinocyte differentiation by inducing DNA methylation in a CB1 receptor-dependent manner. J Biol Chem 283:6005–6012PubMedCrossRefGoogle Scholar
  76. Pertwee RG (2008) Ligands that target cannabinoid receptors in the brain: from THC to anandamide and beyond. Addict Biol 13:147–159PubMedCrossRefGoogle Scholar
  77. Reed CE, Fenton SE (2013) Exposure to diethylstilbestrol during sensitive life stages: a legacy of heritable health effects. Birth Defects Res C Embryo Today 99:134–146PubMedCrossRefGoogle Scholar
  78. Rieder SA, Chauhan A, Singh U, Nagarkatti M, Nagarkatti P (2010) Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression. Immunobiology 215:598–605PubMedCentralPubMedCrossRefGoogle Scholar
  79. Robison LL, Buckley JD, Daigle AE, Wells R, Benjamin D, Arthur DC, Hammond GD (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 63:1904–1911PubMedGoogle Scholar
  80. Rossi S, Bernardi G, Centonze D (2010) The endocannabinoid system in the inflammatory and neurodegenerative processes of multiple sclerosis and of amyotrophic lateral sclerosis. Exp Neurol 224:92–102PubMedCrossRefGoogle Scholar
  81. Sadri-Vakili G, Bouzou B, Benn CL, Kim MO, Chawla P, Overland RP, Glajch KE, Xia E, Qiu Z, Hersch SM, Clark TW, Yohrling GJ, Cha JH (2007) Histones associated with downregulated genes are hypo-acetylated in Huntington’s disease models. Hum Mol Genet 16:1293–1306PubMedCrossRefGoogle Scholar
  82. Sato K, Fukata H, Kogo Y, Ohgane J, Shiota K, Mori C (2009) Neonatal exposure to diethylstilbestrol alters expression of DNA methyltransferases and methylation of genomic DNA in the mouse uterus. Endocr J 56:131–139PubMedCrossRefGoogle Scholar
  83. Schou J, Prockop LD, Dahlstrom G, Rohde C (1977) Penetration of delta-9-tetrahydrocannabinol and 11-OH-delta-9-tetrahydrocannabinol through the blood–brain barrier. Acta Pharmacol Toxicol 41:33–38CrossRefGoogle Scholar
  84. Shirazi J, Shah S, Sagar D, Nonnemacher MR, Wigdahl B, Khan ZK, Jain P (2013) Epigenetics, drugs of abuse, and the retroviral promoter. J Neuroimmune Pharmacol Off J Soc NeuroImmune Pharmacol 8:1181–1196CrossRefGoogle Scholar
  85. Sido JM, Nagarkatti PS, Nagarkatti M (2014) Role of endocannabinoid activation of peripheral CB1 receptors in the regulation of autoimmune disease. International reviews of immunologyGoogle Scholar
  86. Singh NP, Singh US, Nagarkatti M, Nagarkatti PS (2011) Resveratrol (3,5,4′-trihydroxystilbene) protects pregnant mother and fetus from the immunotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Mol Nutr Food Res 55:209–219PubMedCentralPubMedCrossRefGoogle Scholar
  87. Singh NP, Singh UP, Guan H, Nagarkatti P, Nagarkatti M (2012a) Prenatal exposure to TCDD triggers significant modulation of microRNA expression profile in the thymus that affects consequent gene expression. PLoS One 7:e45054PubMedCentralPubMedCrossRefGoogle Scholar
  88. Singh UP, Singh NP, Singh B, Price RL, Nagarkatti M, Nagarkatti PS (2012b) Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10(−/−) mice by attenuating the activation of T cells and promoting their apoptosis. Toxicol Appl Pharmacol 258:256–267PubMedCentralPubMedCrossRefGoogle Scholar
  89. Smita K, Sushil Kumar V, Premendran JS (2007) Anandamide: an update. Fundam Clin Pharmacol 21:1–8PubMedCrossRefGoogle Scholar
  90. Smith CG, Asch RH (1987) Drug abuse and reproduction. Fertil Steril 48:355–373PubMedGoogle Scholar
  91. Suarez I, Bodega G, Fernandez-Ruiz J, Ramos JA, Rubio M, Fernandez B (2004a) Down-regulation of the AMPA glutamate receptor subunits GluR1 and GluR2/3 in the rat cerebellum following pre- and perinatal delta9-tetrahydrocannabinol exposure. Cerebellum 3:66–74PubMedCrossRefGoogle Scholar
  92. Suarez I, Bodega G, Rubio M, Fernandez-Ruiz JJ, Ramos JA, Fernandez B (2004b) Prenatal cannabinoid exposure down- regulates glutamate transporter expressions (GLAST and EAAC1) in the rat cerebellum. Dev Neurosci 26:45–53PubMedCrossRefGoogle Scholar
  93. Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97PubMedCrossRefGoogle Scholar
  94. Suter M, Abramovici A, Showalter L, Hu M, Shope CD, Varner M, Aagaard-Tillery K (2010) In utero tobacco exposure epigenetically modifies placental CYP1A1 expression. Metabc Clin Exp 59:1481–1490CrossRefGoogle Scholar
  95. Tanasescu R, Constantinescu CS (2010) Cannabinoids and the immune system: an overview. Immunobiology 215:588–597PubMedCrossRefGoogle Scholar
  96. Vassoler FM, Johnson NL, Byrnes EM (2013) Female adolescent exposure to cannabinoids causes transgenerational effects on morphine sensitization in female offspring in the absence of in utero exposure. J Psychopharmacol 27:1015–1022PubMedCentralPubMedCrossRefGoogle Scholar
  97. Walker BE, Haven MI (1997) Intensity of multigenerational carcinogenesis from diethylstilbestrol in mice. Carcinogenesis 18:791–793PubMedCrossRefGoogle Scholar
  98. Wang J, Paria BC, Dey SK, Armant DR (1999) Stage-specific excitation of cannabinoid receptor exhibits differential effects on mouse embryonic development. Biol Reprod 60:839–844PubMedCrossRefGoogle Scholar
  99. Wang H, Guo Y, Wang D, Kingsley PJ, Marnett LJ, Das SK, DuBois RN, Dey SK (2004) Aberrant cannabinoid signaling impairs oviductal transport of embryos. Nat Med 10:1074–1080PubMedCrossRefGoogle Scholar
  100. Wang D, D’Costa J, Civin CI, Friedman AD (2006) C/EBPalpha directs monocytic commitment of primary myeloid progenitors. Blood 108:1223–1229PubMedCentralPubMedCrossRefGoogle Scholar
  101. Wei G, Wei L, Zhu J, Zang C, Hu-Li J, Yao Z, Cui K, Kanno Y, Roh TY, Watford WT, Schones DE, Peng W, Sun HW, Paul WE, O’Shea JJ, Zhao K (2009) Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30:155–167PubMedCentralPubMedCrossRefGoogle Scholar
  102. Westerlind KC, Wronski TJ, Ritman EL, Luo ZP, An KN, Bell NH, Turner RT (1997) Estrogen regulates the rate of bone turnover but bone balance in ovariectomized rats is modulated by prevailing mechanical strain. Proc Natl Acad Sci U S A 94:4199–4204PubMedCentralPubMedCrossRefGoogle Scholar
  103. Wu CS, Jew CP, Lu HC (2011) Lasting impacts of prenatal cannabis exposure and the role of endogenous cannabinoids in the developing brain. Futur Neurol 6:459–480CrossRefGoogle Scholar
  104. Yang X, Hegde VL, Rao R, Zhang J, Nagarkatti PS, Nagarkatti M (2014) Histone modifications are associated with Delta9-tetrahydrocannabinol-mediated alterations in antigen-specific T cell responses. J Biol Chem 289:18707–18718PubMedCrossRefGoogle Scholar
  105. Zhu W, Friedman H, Klein TW (1998) Delta9-tetrahydrocannabinol induces apoptosis in macrophages and lymphocytes: involvement of Bcl-2 and caspase-1. J Pharmacol Exp Ther 286:1103–1109PubMedGoogle Scholar
  106. Zhu LX, Sharma S, Stolina M, Gardner B, Roth MD, Tashkin DP, Dubinett SM (2000) Delta-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. J Immunol 165:373–380PubMedCrossRefGoogle Scholar
  107. Zuo T, Liu TM, Lan X, Weng YI, Shen R, Gu F, Huang YW, Liyanarachchi S, Deatherage DE, Hsu PY, Taslim C, Ramaswamy B, Shapiro CL, Lin HJ, Cheng AS, Jin VX, Huang TH (2011) Epigenetic silencing mediated through activated PI3K/AKT signaling in breast cancer. Cancer Res 71:1752–1762PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Elizabeth E. Zumbrun
    • 1
  • Jessica M. Sido
    • 1
  • Prakash S. Nagarkatti
    • 1
  • Mitzi Nagarkatti
    • 1
    Email author
  1. 1.Department of Pathology, Microbiology and ImmunologyUniversity of South Carolina School of MedicineColumbiaUSA

Personalised recommendations