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Research ArticleToxicology

Perinatal Exposure to Δ9-Tetrahydrocannabinol Triggers Profound Defects in T Cell Differentiation and Function in Fetal and Postnatal Stages of Life, Including Decreased Responsiveness to HIV Antigens

Catherine Lombard, Venkatesh L. Hegde, Mitzi Nagarkatti and Prakash S. Nagarkatti
Journal of Pharmacology and Experimental Therapeutics November 2011, 339 (2) 607-617; DOI: https://doi.org/10.1124/jpet.111.181206
Catherine Lombard
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Venkatesh L. Hegde
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Mitzi Nagarkatti
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Prakash S. Nagarkatti
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Abstract

Marijuana abuse is very prominent among pregnant women. Although marijuana cannabinoids have been shown to exert immunosuppression in adults, virtually nothing is known about the effects of marijuana use during pregnancy on the developing immune system of the fetus and during postnatal life. We noted that murine fetal thymus expressed high levels of the cannabinoid receptors CB1 and CB2. Moreover, perinatal exposure to Δ9-tetrahydrocannabinol (THC) had a profound effect on the fetus as evidenced by a decrease in thymic cellularity on gestational days 16, 17, and 18 and postgestational day 1 and marked alterations in T cell subpopulations. These outcomes were reversed by CB1/CB2 antagonists, suggesting that THC-mediated these effects through cannabinoid receptors. Thymic atrophy induced in the fetus correlated with caspase-dependent apoptosis in thymocytes. Thymic atrophy was the result of direct action of THC and not based on maternal factors inasmuch as THC was able to induce T cell apoptosis in vitro in fetal thymic organ cultures. It is noteworthy that perinatal exposure to THC also had a profound effect on the immune response during postnatal life. Peripheral T cells from such mice showed decreased proliferative response to T cell mitogen as well as both T cell and antibody response to HIV-1 p17/p24/gp120 antigens. Together, our data demonstrate for the first time that perinatal exposure to THC triggers profound T cell dysfunction, thereby suggesting that the offspring of marijuana abusers who have been exposed to THC in utero may be at a higher risk of exhibiting immune dysfunction and contracting infectious diseases including HIV.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of Environmental Health Sciences [Grants R01-ES009098, R01-ES019313]; the National Institutes of Health National Institute on Drug Abuse [Grant R01-DA016545]; and the National Institutes of Health National Center for Complementary and Alternative Medicine [Grant P01-AT003961].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.181206.

  • ABBREVIATIONS:

    THC
    Δ9-tetrahydrocannabinol
    CB
    cannabinoid receptor
    CFA
    complete Freund's adjuvant
    FITC
    fluorescein isothiocyanate
    FTOC
    fetal thymic organ culture
    GD
    gestational day
    mAb
    monoclonal antibody
    PD
    postnatal day
    Con A
    concanavalin A
    PE
    phycoerythrin
    TUNEL
    terminal deoxynucleotidyl transferase dUTP nick end labeling
    ANOVA
    analysis of variance
    PBS
    phosphate-buffered saline
    DMSO
    dimethyl sulfoxide
    RT-PCR
    reverse transcription-polymerase chain reaction
    SR141716A
    5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide
    AM630
    1-[2-(morpholin-4-yl)ethyl]-2-methyl-3-(4-methoxybenzoyl)-6-iodoindole
    LPS
    lipopolysaccharide
    LN
    lymph node
    ELISA
    enzyme-linked immunosorbent assay
    SP
    single positive
    DP
    double positive
    DN
    double negative
    HU-210
    (6aR,10aR)- 9-(hydroxymethyl)- 6,6-dimethyl- 3-(2-methyloctan-2-yl)- 6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol.

  • Received March 2, 2011.
  • Accepted August 8, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 339 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 2
1 Nov 2011
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Research ArticleToxicology

Effect of Perinatal Exposure to THC on T Cell Functions

Catherine Lombard, Venkatesh L. Hegde, Mitzi Nagarkatti and Prakash S. Nagarkatti
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 607-617; DOI: https://doi.org/10.1124/jpet.111.181206

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Research ArticleToxicology

Effect of Perinatal Exposure to THC on T Cell Functions

Catherine Lombard, Venkatesh L. Hegde, Mitzi Nagarkatti and Prakash S. Nagarkatti
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 607-617; DOI: https://doi.org/10.1124/jpet.111.181206
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