An Unexpected Pathway From Cannabidiol To Genotoxicity – PPARγ: CBD To GENOTOX!!!

I was just learning this morning that CBD is well documented to trigger and act via PPAR gamma receptors which are well known to physicians as used in a class of diabetes drugs called the thiazolidinediones (pioglitazone and its congeners).

So I thought I should just check if this was involved in pregnancy and gestation.

Sure enough – BINGO!!!

Another strike of GOLD!!!

So I wrote this to add in the references…

Cannabidiol is known to interact with the (Peroxisome Proliferation Activated Receptor) PPARγ pathway 1-8.

PPARγ is known to be a very important transcription factor in metabolic regulation and is also the master regulator of the adipogenic differentiation pathway.

It also plays a key role in the reproductive tract with actions on the corpus luteum and developing gametes.

It has been documented in a rich literature to have a major effect on developing embryos and the reproductive tract 9-32.


1 De Filippis, D. et al. Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis. PLoS One 6, e28159, doi:10.1371/journal.pone.0028159 (2011).
2 Esposito, G. et al. Cannabidiol reduces Abeta-induced neuroinflammation and promotes hippocampal neurogenesis through PPARgamma involvement. PLoS One 6, e28668, doi:10.1371/journal.pone.0028668 (2011).
3 Hegde, V. L., Singh, U. P., Nagarkatti, P. S. & Nagarkatti, M. Critical Role of Mast Cells and Peroxisome Proliferator-Activated Receptor gamma in the Induction of Myeloid-Derived Suppressor Cells by Marijuana Cannabidiol In Vivo. J Immunol 194, 5211-5222, doi:10.4049/jimmunol.1401844 (2015).
4 Hind, W. H., England, T. J. & O’Sullivan, S. E. Cannabidiol protects an in vitro model of the blood-brain barrier from oxygen-glucose deprivation via PPARgamma and 5-HT1A receptors. Br J Pharmacol 173, 815-825, doi:10.1111/bph.13368 (2016).
5 O’Sullivan, S. E. & Kendall, D. A. Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory disease. Immunobiology 215, 611-616, doi:10.1016/j.imbio.2009.09.007 (2010).
6 O’Sullivan, S. E., Sun, Y., Bennett, A. J., Randall, M. D. & Kendall, D. A. Time-dependent vascular actions of cannabidiol in the rat aorta. European journal of pharmacology 612, 61-68, doi:10.1016/j.ejphar.2009.03.010 (2009).
7 Ramer, R. et al. COX-2 and PPAR-gamma confer cannabidiol-induced apoptosis of human lung cancer cells. Mol Cancer Ther 12, 69-82, doi:10.1158/1535-7163.MCT-12-0335 (2013).
8 Scuderi, C., Steardo, L. & Esposito, G. Cannabidiol promotes amyloid precursor protein ubiquitination and reduction of beta amyloid expression in SHSY5YAPP+ cells through PPARgamma involvement. Phytother Res 28, 1007-1013, doi:10.1002/ptr.5095 (2014).
9 Adaikalakoteswari, A. et al. Low Vitamin B12 in Pregnancy Is Associated With Adipose-Derived Circulating miRs Targeting PPARgamma and Insulin Resistance. The Journal of clinical endocrinology and metabolism 102, 4200-4209, doi:10.1210/jc.2017-01155 (2017).
10 Anghebem-Oliveira, M. I. et al. Type 2 diabetes-associated genetic variants of FTO, LEPR, PPARg, and TCF7L2 in gestational diabetes in a Brazilian population. Arch Endocrinol Metab 61, 238-248, doi:10.1590/2359-3997000000258 (2017).
11 Casamadrid, V., Amaya, C. A. & Mendieta, Z. H. Body Mass Index in Pregnancy Does Not Affect Peroxisome Proliferator-activated Receptor Gamma Promoter Region (-359 to -260) Methylation in the Neonate. Ann Med Health Sci Res 6, 38-43, doi:10.4103/2141-9248.180272 (2016).
12 Cawyer, C. et al. Attenuation of hyperglycemia-induced apoptotic signaling and anti-angiogenic milieu in cultured cytotrophoblast cells. Hypertens Pregnancy 35, 159-169, doi:10.3109/10641955.2015.1122035 (2016).
13 Drew, P. D. & Kane, C. J. Peroxisome Proliferator-Activated Receptor-gamma Agonists: Potential Therapeutics for Neuropathology Associated with Fetal Alcohol Spectrum Disorders. J Clin Cell Immunol 7, doi:10.4172/2155-9899.1000469 (2016).
14 Gao, F., Hu, W., Li, Y., Shen, H. & Hu, J. Mono-2-ethylhexyl phthalate inhibits human extravillous trophoblast invasion via the PPARgamma pathway. Toxicology and applied pharmacology 327, 23-29, doi:10.1016/j.taap.2017.04.014 (2017).
15 Hasby Saad, M., El-Anwar, N., Lotfy, S., Fouda, M. & Hasby, E. Human placental PPAR-gamma & SOX2 expression in serologically proved toxoplasmosis. Parasite Immunol, e12529, doi:10.1111/pim.12529 (2018).
16 Hu, W. et al. Activation of Peroxisome Proliferator-Activated Receptor Gamma and Disruption of Progesterone Synthesis of 2-Ethylhexyl Diphenyl Phosphate in Human Placental Choriocarcinoma Cells: Comparison with Triphenyl Phosphate. Environ Sci Technol 51, 4061-4068, doi:10.1021/acs.est.7b00872 (2017).
17 Kurzynska, A., Chojnowska, K., Bogacki, M. & Bogacka, I. PPAR ligand association with prostaglandin F2alpha and E2 synthesis in the pig corpus luteum-An in vitro study. Anim Reprod Sci 172, 157-163, doi:10.1016/j.anireprosci.2016.07.014 (2016).
18 Lecoutre, S. et al. Depot- and sex-specific effects of maternal obesity in offspring’s adipose tissue. The Journal of endocrinology 230, 39-53, doi:10.1530/JOE-16-0037 (2016).
19 Lendvai, A., Deutsch, M. J., Plosch, T. & Ensenauer, R. The peroxisome proliferator-activated receptors under epigenetic control in placental metabolism and fetal development. Am J Physiol Endocrinol Metab 310, E797-810, doi:10.1152/ajpendo.00372.2015 (2016).
20 Lin, Y., Bircsak, K. M., Gorczyca, L., Wen, X. & Aleksunes, L. M. Regulation of the placental BCRP transporter by PPAR gamma. J Biochem Mol Toxicol 31, doi:10.1002/jbt.21880 (2017).
21 Maekawa, M. et al. Polyunsaturated fatty acid deficiency during neurodevelopment in mice models the prodromal state of schizophrenia through epigenetic changes in nuclear receptor genes. Transl Psychiatry 7, e1229, doi:10.1038/tp.2017.182 (2017).
22 Mahendra, J. et al. Evidence Linking the Role of Placental Expressions of Peroxisome Proliferator-Activated Receptor-gamma and Nuclear Factor-Kappa B in the Pathogenesis of Preeclampsia Associated With Periodontitis. J Periodontol 87, 962-970, doi:10.1902/jop.2016.150677 (2016).
23 Marginean, C. et al. The role of TGF-beta1 869 T > C and PPAR gamma2 34 C > G polymorphisms, fat mass, and anthropometric characteristics in predicting childhood obesity at birth: A cross-sectional study according the parental characteristics and newborn’s risk for child obesity (the newborns obesity’s risk) NOR study. Medicine (Baltimore) 95, e4265, doi:10.1097/MD.0000000000004265 (2016).
24 Meher, A. P. et al. Placental DHA and mRNA levels of PPARgamma and LXRalpha and their relationship to birth weight. J Clin Lipidol 10, 767-774, doi:10.1016/j.jacl.2016.02.004 (2016).
25 Papamitsou, T., Toskas, A., Papadopoulou, K., Economou, Z. & Sioga, A. Expression of peroxisome proliferator activation receptors (PPARs) and TNFalpha in placenta tissues in unexplained recurrent pregnancy loss: an immunohistochemical study. Histology and histopathology 31, 1029-1036, doi:10.14670/HH-11-734 (2016).
26 Roberti, S. L. et al. Critical role of mTOR, PPARgamma and PPARdelta signaling in regulating early pregnancy decidual function, embryo viability and feto-placental growth. Molecular human reproduction, doi:10.1093/molehr/gay013 (2018).
27 Shapiro, A. L. et al. Nicotinamide Promotes Adipogenesis in Umbilical Cord-Derived Mesenchymal Stem Cells and Is Associated with Neonatal Adiposity: The Healthy Start BabyBUMP Project. PLoS One 11, e0159575, doi:10.1371/journal.pone.0159575 (2016).
28 Singh, S. P. et al. Gestational Exposure to Sidestream (Secondhand) Cigarette Smoke Promotes Transgenerational Epigenetic Transmission of Exacerbated Allergic Asthma and Bronchopulmonary Dysplasia. J Immunol 198, 3815-3822, doi:10.4049/jimmunol.1700014 (2017).
29 Sonanez-Organis, J. G. et al. HIF-1alpha and PPARgamma during physiological cardiac hypertrophy induced by pregnancy: Transcriptional activities and effects on target genes. Gene 591, 376-381, doi:10.1016/j.gene.2016.06.025 (2016).
30 Wang, L. L., Yu, Y., Guan, H. B. & Qiao, C. Effect of Human Umbilical Cord Mesenchymal Stem Cell Transplantation in a Rat Model of Preeclampsia. Reprod Sci 23, 1058-1070, doi:10.1177/1933719116630417 (2016).
31 Wu, Y., Ruan, Y., Shen, L. & Gong, Q. Protective effects of PPAR-gamma against pregnancy-induced hypertension by differential ETR expression in rat models. J Cell Biochem 119, 3118-3128, doi:10.1002/jcb.26454 (2018).
32 Xu, Y. et al. An M1-like Macrophage Polarization in Decidual Tissue during Spontaneous Preterm Labor That Is Attenuated by Rosiglitazone Treatment. J Immunol 196, 2476-2491, doi:10.4049/jimmunol.1502055 (2016).

Source: Email to from Stuart Reece April 2018

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