Genetic and reproductive toxicity of lamivudine, tenofovir disoproxil fumarate, efavirenz and their combination in the bone marrow and testicular cells of male mice

Adekunle A. Bakare 1 , Kehinde M. Akinseye 1 , 2 , Bayonle A. Aminu 1 , 3 , Francis C. Ofoegbu 1 , Saheed O. Anifowose 1 , 4 , Stork Abruda 1 , Opeoluwa M. Fadoju 1 , Olusegun I. Ogunsuyi 1 , 5 , Ifeoluwa T. Oyeyemi 6 , Okunola A. Alabi 7 , Olusola M. Adetona 8 , and Chibuisi G. Alimba 1 , 9
  • 1 Cell Biology and Genetics Unit, Department of Zoology, University of Ibadan, Ibadan, Nigeria
  • 2 Department of Molecular Biosciences, University of Kansas, Lawrence
  • 3 Department of Environmental Health, College of Medicine, University of Cincinnati, 670056, Cincinnati
  • 4 Department of Zoology, King Saud University, Riyadh, Saudi Arabia
  • 5 Department of Biological Sciences, Mountain Top University, Ibafo, Nigeria
  • 6 Department of Biological Sciences, University of Medical Sciences, Nigeria
  • 7 Department of Biology, Federal University of Technology, Akure, Nigeria
  • 8 Department of Anatomy, College of Medicine, University of Ibadan, Ibadan, Nigeria
  • 9 Leibniz Research Centre for Working Environment and Human Factors (IfADo), Technical University of Dortmund, 44139, Dortmund, Germany

Abstract

The combination of antiretroviral (ARV) drugs: lamivudine, tenofovir disoproxil fumarate (TDF) and efavirenz is among the preferred first-line regimens for adolescents and adults infected with HIV. However, knowledge on in vivo genetic and reproductive toxicity of each of these drugs and their combination is limited. We evaluated the genotoxicity of lamivudine, TDF, efavirenz and their combination utilizing the mouse micronucleus (MN) and sperm morphology tests. Histopathological analysis of the testes of exposed mice was also carried out. 0.016, 0.032, 0.064 and 0.129 mg/kg bwt of lamivudine, TDF and the combination; and 0.032, 0.064, 0.129 and 0.259 mg/kg bwt of efavirenz corresponding to 0.125, 0.250, 0.500 and 1.000 x the human therapeutic daily dose (HTD) of each of the ARVs and their combinations were administered to mice for 5 consecutive days. Data on MN showed a significant increase (p < 0.05) across the tested doses of TDF, efavirenz and the combination, with the combination inducing lower frequency of MN than TDF and efavirenz. Lamivudine did not evoke significant induction of MN. Significant increase in frequency of abnormal sperm cells were observed in the tested samples, however, the combination induced the highest number of abnormal spermatozoa. The ARVs and their combination induced pathological lesions such as vacuolation and necrosis in mice testes. These findings suggest that the individual ARVs and their combination are potentially capable of activating genetic alterations in the bone marrow and germ cells of male mice thereby raising concern for long term use by HIV patients.

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