Investigating the effect of methadone on lifespan up to the fourth generation, fertility, whole body malondialdehyde level and brain tissue damage in the first generation of Drosophila
Subject Areas : biology
Zahra Rostami
1
,
Majid Hassanpourezatti
2
1 - Master's degree, Department of Biology, Faculty of Basic Sciences, Shahed University, Tehran, Iran.
2 - Assistant Professor, Department of Biology, Faculty of Basic Sciences, Shahed University, Tehran, Iran
Keywords: Methadone, Drosophila, Heredity, Malondialdehyde, Fertility, Lifespan, Brain,
Abstract :
Objective: Preliminary documentation shows that the use of opioids can affect
the lifespan and function of the reproductive system. In this study, the effect of oral methadone consumption by parents and the first generation on the level of malondialdehyde in the whole body, brain tissue damage in the first generation, and life span, and the fertility of flies and the transmission of the effect up to four generations have been investigated.
Materials and methods: During the laying period and the first generation,
parent flies (10 of each sex) were treated orally with methadone (0.1, 1, 5, 10 and 100 micromol) and the positive control group was treated with metronidazole (1 and 2 mg in liters) were placed. The number of live flies and offspring in each group were counted weekly for a maximum of 94 days. The concentration of malondialdehyde was measured in whole body homogenates (30 of each gender) using a commercial kit. Areas without cells were counted in brain tissue sections after hematoxylin-eosin staining.
Findings: 10 and 100 micromol doses of methadone led to death and 5 micromol doses caused complete sterility of flies. The life span and the number of offspring of flies in a sex-dependent manner decreased after oral administration of doses of 0.1 and 1 μmol/L methadone. The content of malondialdehyde increased to 0.6 μmol/mg only in male flies under the effect of methadone (1 μmol), and the number of cell-free areas in a section prepared from brain tissue increased to 60 compared to 15 in the control group. The effects observed in female flies were different from males.
Conclusion: Using methadone by the parents and the first generation of flies by stimulating the production of fat peroxidation products in the body and brain damage reduces the lifespan and reduces reproduction in the first generation and its transfer to the next generation.
1. Bachi K, Sierra S, Volkow ND, Goldstein RZ & Alia-Klein N. Is biological aging accelerated in drug addiction? Current opinion in behavioral sciences. 2017; 13: 34–39.
2. Hulse GK, Milne E, English DR & Holman CD. The relationship between maternal use of heroin and methadone and infant birth weight. Addiction. 1997; 92: 1571-9.
3. Neppl TK, Diggs ON & Cleveland MJ. The intergenerational transmission of harsh parenting, substance use, and emotional distress: Impact on the third-generation child. Psychology of addictive behaviors: Journal of the Society of Psychologists in Addictive Behaviors. 2020; 34: 852-863.
4. Sohal RS, Mockett RJ & Orr WC. Mechanisms of aging: an appraisal of the oxidative stress hypothesis. Free radical biology & medicine. 2002; 33: 575-586.
5. Ajayi AF & Akhigbe RE. Codeine-induced sperm DNA damage is mediated predominantly by oxidative stress rather than apoptosis. Redox Rep. 2020; 25(1): 33-40.
6. Guan Q, Velho RV, Sehouli J & Mechsner S. Endometriosis and opioid receptors: Are opioids a possible/promising treatment for endometriosis? Int J Mol Sci. 2023; 24(2): 1633.
7. Kovacs GG, Horvath MC, Majtenyi K, Lutz MI, Hurd YL & Keller E. Heroin abuse exaggerates age-related deposition of hyperphosphorylated tau and p62-positive inclusions. Neurobiol Aging. 2015; 36(11): 3100-3107.
8. Gil P, Fariñas F, Casado A & López-Fernández E. Malondialdehyde: a possible marker of ageing. Gerontology. 2002; 48(4): 209-14.
9. Rao KS & Loeb LA. DNA damage and repair in brain: relationship to aging. Mutat Res.1992; 275(3-6): 317-29.
10. Khazaee-Pool M, Moeeni M, Ponnet K, Fallahi A, Jahangiri L & Pashaei T. Perceived barriers to methadone maintenance treatment among Iranian opioid users. Int J Equity Health. 2018; 17(1): 75.
11. Arezoomandan M, Zhiani R, Mehrzad J, Motavalizadehkakhky A, Eshrati S & Arezoomandan R. Inflammatory, oxidative stress and cognitive functions in patients under maintenance treatment with methadone or buprenorphine and healthy subjects. J Clin Neurosci. 2022; 101: 57-62.
12. Rahimi Mehdi Abad F, Khalili P, Jalali F, Pirsadeghi A, Esmaeili Nadimi A, Manshoori A & et al. Maternal opioid use is reflected on leukocyte telomere length of male newborns. PloS One. 2021; 16(12): e0261013.
13. Bashore RA, Ketchum JS, Staisch KJ, Barrett CT & Zimmermann EG. Heroin addiction and pregnancy. West J Med. 1981; 134(6): 506-514.
14. Farid WO, Dunlop SA, Tait RJ & Hulse GK. The effects of maternally administered methadone, buprenorphine and naltrexone on offspring: review of human and animal data. Curr Neuropharmacol. 2008; 6(2): 125-50.
15. Jansson LM, Dipietro J & Elko A. Fetal response to maternal methadone administration. Am J Obstet Gynecol. 2005; 193(3 Pt 1): 611-7.
16. Prosser J, Cohen LJ, Steinfeld M, Eisenberg D, London ED & Galynker II. Neuropsychological functioning in opiate-dependent subjects receiving and following methadone maintenance treatment. Drug Alcohol Depend. 2006; 84(3): 240-7.
17. Santoro C, Hall LM & Zukin RS. Characterization of two classes of opioid binding sites in Drosophila melanogaster head membranes. J Neurochem. 1990; 54(1): 164-70.
18. Birgül N, Weise C, Kreienkamp HJ & Richter D. Reverse physiology in drosophila: identification of a novel allatostatin-like neuropeptide and its cognate receptor structurally related to the mammalian somatostatin/galanin/opioid receptor family. EMBO J. 1999; 18(21): 5892-900.
19. Obata F, Fons CO & Gould AP. Early-life exposure to low-dose oxidants can increase longevity via microbiome remodelling in Drosophila. Nat Commun. 2018; 9(1): 975.
20. Wu W, Yao H, Dwivedi I, Negraes PD, Zhao HW, Wang J, Trujillo CA, Muotri AR & Haddad GG. Methadone Suppresses Neuronal Function and Maturation in Human Cortical Organoids. Front Neurosci. 2020; 14: 593248.
21. Tekieh E, Kazemi M, Dehghani L, Bahramyian S, Sadogi M, Zardooz H & et al. Effects of Oral Morphine on the Larvae, Pupae and Imago Development in Drosophila Melanogaster. Cell Journal(Yakhteh), 2011; 13: 149-154.
22. Cammaerts MC, Cammaerts R & Rachidi Z. Effects of buprenorphine and methadone, two analgesics used for suppressing humans’ addiction to morphine; a study using ants as biological models. Int j pharm Sci. Invent. 2015: 4: 1-19.
23. Siddique YH, Naz F & Jyoti S. Effect of curcumin on lifespan, activity pattern, oxidative stress, and apoptosis in the brains of transgenic Drosophila model of Parkinson’s disease. Biomed Res Int. 2014; 2014: 606928.
24. Mossman JA, Mabeza RMS, Blake E, Mehta N & Rand DM. Age of Both Parents Influences Reproduction and Egg Dumping Behavior in Drosophila melanogaster. J Hered. 2019; 110(3): 300-309.
25. Murashov AK, Pak ES, Mar J, O’Brien K, Fisher-Wellman K & Bhat KM. Paternal Western diet causes transgenerational increase in food consumption in Drosophila with parallel alterations in the offspring brain proteome and microRNAs. FASEB J. 2023; 37(6): e22966.
26. Chandrashekara KT, Popli S & Shakarad MN. Curcumin enhances parental reproductive lifespan and progeny viability in Drosophila melanogaster. Age (Dordr). 2014; 36(5): 9702.
27. Trindade de Paula M, Poetini Silva MR, Machado Araujo S, Cardoso Bortolotto V, Barreto Meichtry L, Zemolin AP & et al. High-Fat Diet Induces Oxidative Stress and MPK2 and HSP83 Gene Expression in Drosophila melanogaster. Oxid Med Cell Longev. 2016; 2016: 4018157.
28. Kang J, Shin S, Perrimon N & Shen J. An Evolutionarily Conserved Role of Presenilin in Neuronal Protection in the Aging Drosophila Brain. Genetics. 2017; 206(3): 1479-1493.
29. Nash TR, Chow ES, Law AD, Fu SD, Fuszara E, Bilska A & et al. Daily blue-light exposure shortens lifespan and causes brain neurodegeneration in Drosophila. NPJ Aging Mech Dis. 2019; 5: 8.
30. Ma L, Ma J & Xu K. Effect of spaceflight on the circadian rhythm, lifespan and gene expression of Drosophila melanogaster. PloS One. 2015; 10(3): e0121600.
31. Drummer OH, Opeskin K, Syrjanen M & Cordner SM. Methadone toxicity causing death in ten subjects starting on a methadone maintenance program. Am J Forensic Med Pathol. 1992; 13(4): 346-50.
32. Reece AS. Differing age related trajectories of dysfunction in several organ systems in opiate dependence. Aging Clin Exp Res. 2012; 24(1): 85-96.
33. Zarulli V, Barthold Jones JA, Oksuzyan A, Lindahl-Jacobsen R, Christensen K & Vaupel JW. Women live longer than men even during severe famines and epidemics. Proc Natl Acad Sci U S A. 2018; 115(4): E832-E840.
34. Foo JC, Skorodumov I, Spanagel R & Meinhardt MW. Sex- and age-specific effects on
the development of addiction and compulsive-like drinking in rats. Biol Sex Differ. 2023; 14(1): 44.
35. Tahergorabi Z, Rahmani H, Williams J & Moodi M. The effect of methadone on blood glucose, lipids and glucose-modulating hormones in methadone-dependent Wistar rats. Toxicol Res. 2019; 36(3): 221-226.
36. McCance-Katz EF, Sullivan LE & Nallani S. Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review. Am J Addict. 2010; 19(1): 4-16.
37. Nylander E, Zelleroth S, Nyberg F, Grönbladh A & Hallberg M. The effects of morphine, methadone, and fentanyl on mitochondria: A live cell imaging study. Brain Res Bull. 2021; 171: 126-134.
38. Mazahery C, Valadkhan S & Levine AD. Transcriptomic Analysis Reveals Receptor Subclass-Specific Immune Regulation of CD8+ T Cells by Opioids. Immunohorizons. 2020; 4(7): 420-429.
39. Salarian A, Kadkhodaee M, Zahmatkesh M, Seifi B, Bakhshi E, Akhondzadeh S, Adeli S, Askari H & Arbabi M. Opioid Use Disorder Induces Oxidative Stress and Inflammation: The Attenuating Effect of Methadone Maintenance Treatment. Iran J Psychiatry. 2018; 13(1): 46-54.
40. Long J, Wang X, Gao H, Liu Z, Liu C, Miao M & et al. Malonaldehyde acts as a mitochondrial toxin: Inhibitory effects on respiratory function and enzyme activities in isolated rat liver mitochondria. Life Sci. 2006; 79(15): 1466-72.
41. Pinchuk I, Weber D, Kochlik B, Stuetz W, Toussaint O, Debacq-Chainiaux F & et al. Gender- and age-dependencies of oxidative stress, as detected based on the steady state concentrations of different biomarkers in the MARK-AGE study. Redox Biol. 2019; 24: 101204.
42. Mutlu-Türkoğlu U, Ilhan E, Oztezcan S, Kuru A, Aykaç-Toker G & Uysal M. Age-related increases in plasma malondialdehyde and protein carbonyl levels and lymphocyte DNA damage in elderly subjects. Clin Biochem. 2003; 36(5): 397-400.
43. Das P, Choudhari AR, Singh AK & Singh R. Correlation among routine semen parameters, sperm viabilty and malondialdehyde levels in human subjects with different fertility potential. Indian J Physiol Pharmacol. 2009; 53(3): 253-8.
44. Jové M, Mota-Martorell N, Pradas I, Martín-Gari M, Ayala V & Pamplona R. The Advanced Lipoxidation End-Product Malondialdehyde-Lysine in Aging and Longevity. Antioxidants (Basel). 2020; 9(11): 1132.
45. Okada K, Blount JD, Sharma MD, Snook RR & Hosken DJ. Male attractiveness, fertility and susceptibility to oxidative stress are influenced by inbreeding in Drosophila simulans.
J Evol Biol. 2011; 24(2): 363-71.
46. Omelyanchuk LV, Shaposhnikov MV & Moskalev AA. Drosophila nervous system as a target of aging and anti-aging interventions. Front Genet. 2015; 6: 89.
47. Zhu J, Wang S, Liu Y, Wang F, Li Q, Li Z, Sun Y, Li W & Wang W. The influence of methadone on cerebral gray matter and functional connectivity. Ann Palliat Med. 2021; 10(9): 9497-9507.
48. Zheng J, Mutcherson R & Helfand SL. Calorie restriction delays lipid oxidative damage in Drosophila melanogaster. Aging Cell. 2005; 4(4): 209-16.
49. Yalçınkaya E, Cakıroğlu Y, Doğer E, Budak O, Cekmen M & Calışkan E. Effect of follicular fluid NO, MDA and GSH levels on in vitro fertilization outcomes. J Turk Ger Gynecol Assoc. 2013; 14(3): 136-41.
50. Ayala A, Muñoz MF & Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev. 2014; 2014: 360438.
51. Ruffing DM & Domino EF. Effects of selected opioid agonists and antagonists on DMT- and LSD-25-induced disruption of food-rewarded bar pressing behavior in the rat. Psychopharmacology (Berl).1981; 75(3): 226-230.
52. Hoyer-Fender S. Transgenerational effect of drug-mediated inhibition of LSD1 on eye pigment expression in Drosophila. BMC Ecol. 2020; 20(1): 62.
53. Moinaddini F, Amirinejad M, Haghpanah T, Abedini M, Yoosefi F & Nematollahi-Mahani SN. Opioid replacement therapy with methadone or buprenorphine effects on male mice reproduction. Psychopharmacology (Berl). 2023; 240(1): 77-86.
DOI: 10.1007/s00213-022-06274-7
54. Tahmasbpour Marzouni E, Ilkhani H, Beigi Harchegani A, Shafaghatian H, Layali I & et al. Epigenetic Modifications, A New Approach to Male Infertility Etiology: A Review. Int J Fertil Steril. 2022; 16(1): 1-9.
55. Wang Y, Li W, Li Q, Yang W, Zhu J & Wang W. White matter impairment in heroin addicts undergoing methadone maintenance treatment and prolonged abstinence: a preliminary DTI study. Neurosci Lett. 2011; 494(1): 49-53.
56. Subirán N, Casis L & Irazusta J. Regulation of male fertility by the opioid system. Mol Med. 2011; 17(7-8): 846-53.