Open Access Open Access  Restricted Access Subscription or Fee Access

Elevated levels of DNA methylation at the OPRM1 promoter in blood and sperm from male opioid addicts

Vesselin M. Chorbov, PhD, Alexandre A. Todorov, PhD, Michael T. Lynskey, PhD, Theodore J. Cicero, PhD

Abstract


Objective: The OPRM1 gene was studied for DNA methylation in opioid dependence and possible paternal contribution to epigenetic inheritance of altered methylation profiles.
Participants and methods: DNA was extracted from blood and sperm from 13 male opioid addicts and 21 male control subjects. DNA methylation was determined by pyrosequencing in 24 CpG sites at the OPRM1 promoter region.
Results: The authors found significantly increased overall methylation in blood DNA from addicted subjects (Kruskal-Wallis [K-W] p = 0.013). Seven CpG sites showed significantly hypermethylated blood DNA from cases when compared with blood DNA from controls (p < 0.05 at CpGs 5, 9, 10, 11, 18, 23, and 24). In spermderived DNA from addicts, the methylation was significantly increased at CpG 2 (p = 0.012), and overall methylation did not reach significant difference (K-W p = 0.523).
Conclusions: Increased DNA methylation in the OPRM1 gene is associated with opioid dependence. Hypermethylated CpG sites located in OPRM1 promoter may potentially block the binding of Sp1 and other transcription activators, thus leading to OPRM1 silencing. The increased DNA methylation in sperm may suggest a way of epigenetic heritability of opioid abuse or dependence phenotypes.


Keywords


OPRM1, DNA methylation, CpG island, opioid dependence

Full Text:

PDF

References


Cadoret RJ, Troughton E, O’Gorman TW, et al.: An adoption study of genetic and environmental factors in drug abuse. Arch Gen Psychiatry. 1986; 43(12): 1131-1136.

Kendler KS, Jacobson KC, Prescott CA, et al.: Specificity of genetic and environmental risk factors for use and abuse/dependence of cannabis, cocaine, hallucinogens, sedatives, stimulants, and opiates in male twins. Am J Psychiatry. 2003; 160(4): 687-695.

Eriksson PS, Ronnback L, Hansson E: Do persistent morphine effects involve interactions with the genome? Drug Alcohol Depend. 1989; 24(1): 39-43.

Champagne F, Meaney MJ: Like mother, like daughter: Evidence for non-genomic transmission of parental behavior and stress responsivity. Prog Brain Res. 2001; 133: 287-302.

Uhl GR, Drgon T, Johnson C, et al.: Molecular genetics of addiction and related heritable phenotypes: Genome-wide association approaches identify “connectivity constellation” and drug target genes with pleiotropic effects. Ann N Y Acad Sci. 2008; 1141: 318-381.

Bird AP, Wolffe AP: Methylation-induced repression–Belts, braces, and chromatin. Cell. 1999; 99(5): 451-454.

Fahrner JA, Eguchi S, Herman JG, et al.: Dependence of histone modifications and gene expression on DNA hypermethylation in cancer. Cancer Res. 2002; 62(24): 7213-7218.

Herman JG, Baylin SB: Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003; 349(21): 2042-2054.

Antequera F: Structure, function and evolution of CpG island promoters. Cell Mol Life Sci. 2003; 60(8): 1647-1658.

Nielsen DA, Yuferov V, Hamon S, et al.: Increased OPRM1 DNA methylation in lymphocytes of methadone-maintained former heroin addicts. Neuropsychopharmacology. 2009; 34(4): 867-873.

Nielsen DA, Hamon S, Yuferov V, et al.: Ethnic diversity of DNA methylation in the OPRM1 promoter region in lymphocytes of heroin addicts. Hum Genet. 2010; 127(6): 639-649.

Hwang CK, Song KY, Kim CS, et al.: Evidence of endogenousμ opioid receptor regulation by epigenetic control of the promoters. Mol Cell Biol. 2007; 27(13): 4720-4736.

Agirregoitia E, Valdivia A, Carracedo A, et al.: Expression and localization of δ-, κ-, and μ-opioid receptors in human spermatozoa and implications for sperm motility. J Clin Endocrinol Metab. 2006; 91(12): 4969-4975.

Cicero TJ, Davis LA, LaRegina MC, et al.: Chronic opiate exposure in the male rat adversely affects fertility. Pharmacol Biochem Behav. 2002; 72(1-2): 157-163.

Cicero TJ, Meyer ER, Wiest WG, et al.: Effects of chronic morphine administration on the reproductive system of the male rat. J Pharmacol Exp Ther. 1975; 192(3): 542-548.

Houshdaran S, Cortessis VK, Siegmund K, et al.: Widespread epigenetic abnormalities suggest a broad DNA methylation erasure defect in abnormal human sperm. PLoS One. 2007; 2(12): e1289.

McLellan AT, Luborsky L, Woody GE, et al.: An improved diagnostic evaluation instrument for substance abuse patients. The Addiction Severity Index. J Nerv Ment Dis. 1980; 168(1): 26-33.

Benjamini Y, Hochberg Y: Controlling the false discovery rate: A practical and powerful approach to multiple testing. J R Stat Soc B. 1995; 57(1): 289-300.

Oakes CC, La Salle S, Smiraglia DJ, et al.: Developmental acquisition of genome-wide DNA methylation occurs prior to meiosis in male germ cells. Dev Biol. 2007; 307(2): 368-379.

Li H, Liu H, Wang Z, et al.: The role of transcription factors Sp1 and YY1 in proximal promoter region in initiation of transcription of the opioid receptor gene in human lymphocytes. J Cell Biochem. 2008; 104(1): 237-250.

Hwang CK, Kim CS, Kim do K, et al.: Up-regulation of the μ-opioid receptor gene is mediated through chromatin remodeling and transcriptional factors in differentiated neuronal cells. Mol Pharmacol. 2010; 78(1): 58-68.

Weber M, Schubeler D: Genomic patterns of DNA methylation: Targets and function of an epigenetic mark. Curr Opin Cell Biol. 2007; 19(3): 273-280.

Tian M, Broxmeyer HE, Fan Y, et al.: Altered hematopoiesis, behavior, and sexual function in μ opioid receptor-deficient mice. J Exp Med. 1997; 185(8): 1517-1522.

Novikova SI, He F, Bai J, et al.: Maternal cocaine administration in mice alters DNA methylation and gene expression in hippocampal neurons of neonatal and prepubertal offspring. PLoS One. 2008; 3(4): e1919.

Renthal W, Nestler EJ: Chromatin regulation in drug addiction and depression. Dialogues Clin Neurosci. 2009; 11(3): 257-268.




DOI: https://doi.org/10.5055/jom.2011.0067

Refbacks

  • There are currently no refbacks.