Toxicity Potentials of Dolutegravir-Base Antiretroviral Therapy on the Ovary and Uterus of Adult Wistar Rats

Ogbe, O.C.; Ataman, J.E; Ezeuko, V.C

doi:10.62951/ijhm.v2i2.383

Authors

Ogbe, O.C. University of Benin
Ataman, J.E University of Benin
Ezeuko, V.C University of Benin

DOI:

https://doi.org/10.62951/ijhm.v2i2.383

Keywords:

HIV, Hormonal assay, Ovary and uterus, Oxidative stress, TLD

Abstract

Background: Human immunodeficiency virus (HIV) remains a critical global health issue, with 88.4 million infections and 42.3 million AIDS-related deaths to date. In 2024 alone, 39.9 million individuals are living with HIV, 630,000 deaths occurred, and 1.3 million new infections were recorded. Tenofovir Disoproxil Fumarate/Lamivudine/Dolutegravir (TLD) is a widely used antiretroviral therapy, but its reproductive and oxidative effects remain underexplored in female models, particularly in the South-South region of Nigeria.Objective: This study aimed to evaluate the reproductive toxicity and oxidative stress effects of TLD on the ovaries and uterus of adult female Wistar rats.Methods: Ten adult female Wistar rats (156–187g) were divided into control and treatment groups (n=5). The control group received standard diet and distilled water, while the treated group received daily doses of TLD (Tenofovir 5 mg, Lamivudine 5 mg, and Dolutegravir 0.8 mg/kg body weight) for 90 days. At the end of the treatment, animals in estrus phase were sacrificed for biochemical, histological, and hormonal analysis.Results: The treated group showed a significant reduction in body weight but no significant changes in ovarian or uterine weight. Oxidative stress analysis revealed decreased MDA and increased SOD, GPx, and CAT in the uterus. Hormonal levels were not significantly different. Histologically, the treated group displayed impaired follicular development, atretic follicles, cysts, enlarged endometrial cavities, and thicker endometria.Conclusion: TLD administration induced notable reproductive alterations in female Wistar rats, highlighting potential implications for its use in women of reproductive age.

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References

Abraham, G. E., & Saxena, B. N. (1981). Assay of estrogens. Pharmacology & Therapeutics, 12(2), 247–253.

Agarwal, A., Aponte-Mellado, A., Premkumar, B. J., Shaman, A., & Gupta, S. (2012). The effects of oxidative stress on female reproduction: A review. Reproductive Biology and Endocrinology, 10, 49. https://doi.org/10.1186/1477-7827-10-49

Al-Gubory, K. H., Fowler, P. A., & Garrel, C. (2010). The roles of cellular reactive oxygen species, oxidative stress and antioxidants in pregnancy outcomes. International Journal of Biochemistry & Cell Biology, 42(10), 1634–1650. https://doi.org/10.1016/j.biocel.2010.06.001

Aufrère, M. B., & Benson, H. (1976). Progesterone: An overview and recent advances. Journal of Pharmaceutical Sciences, 65(6), 783–800.

Awodele, O., Olayemi, S. O., Nwite, J. A., & Adeyemo, T. A. (2012). Investigation of the levels of oxidative stress parameters in HIV and HIV-TB co-infected patients. Journal of Infection in Developing Countries, 6(1), 79–85. https://doi.org/10.3855/jidc.2104

Awodele, O., Popoola, T. D., Idowu, O., Bashua, B. M., Awolola, N. A., & Okunowo, W. O. (2018). Investigations into the risk of reproductive toxicity following exposure to highly active antiretroviral drugs in rodents. Tokai Journal of Experimental and Clinical Medicine, 43(2), 54–63.

Azu, O. O., Naidu, E. C., Naidu, J. S., Masia, T., Nzemande, N. F., Chuturgoon, A., & Singh, S. (2014). Testicular histomorphologic and stereological alterations following short‐term treatment with highly active antiretroviral drugs (HAART) in an experimental animal model. Andrology, 2(5), 772–779. https://doi.org/10.1111/andr.262

Buege, J. A., & Aust, S. D. (1978). Microsomal lipid peroxidation. In Methods in enzymology (Vol. 52, pp. 302–310). Academic Press.

Bujan, L., Hollander, L., Coudert, M., Gilling-Smith, C., Vucetich, A., Guibert, J., Vernazza, P., Ohl, J., Weigel, M., Englert, Y., & Semprini, A. E. (2007). Safety and efficacy of sperm washing in HIV-1-serodiscordant couples where the male is infected: Results from the European CREAThE network. Journal of Acquired Immune Deficiency Syndromes, 21(14), 1909–1914.

Centers for Disease Control and Prevention. (2018). HIV transmission - HIV basics - HIV/AIDS. https://www.cdc.gov/hiv/basics/transmission.html

Cohen, G., Dembiec, D., & Marcus, J. (1970). Measurement of catalase activity in tissue extracts. Analytical Biochemistry, 34, 30–38.

Cribbs, S. K., Guidot, D. M., Martin, G. S., Lennox, J., & Brown, L. A. (2014). Antiretroviral therapy is associated with decreased alveolar glutathione levels even in healthy HIV-infected individuals. PLoS ONE, 9(2), e88630. https://doi.org/10.1371/journal.pone.0088630

Danzer, H., & Braunstein, G. D. (1976). Serum human luteinizing hormone levels through normal pregnancy. American Journal of Obstetrics and Gynecology, 126, 678–681.

Dorfman, R. I., & Shipley, R. A. (1956). Androgens (p. 59). Chapman & Hall.

Drury, R. A. B., & Wallington, E. A. (1980). General staining procedures. In R. A. B. Drury & E. A. Wallington (Eds.), Carleton's Histological Techniques (pp. 125–150). Oxford University Press.

Ellman, G. L. (1959). Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics, 82(1), 70–77.

Iorjiim, W. M., Omale, S., Bagu, G. D., Gyang, S. S., & Alemika, E. T. (2020). Reproductive and oxidative stress toxicity of dolutegravir-based combination antiretroviral therapy in Drosophila melanogaster. Journal of Advances in Medical and Pharmaceutical Sciences, 22(6), 26–40. https://doi.org/10.9734/jamps/2020/v22i630190

Joint United Nations Programme on HIV/AIDS. (2024). Fact sheet 2024: Global HIV statistics. https://www.unaids.org

Jones, D. P. (2008). Radical-free biology of oxidative stress. American Journal of Physiology-Cell Physiology, 295(4), C849–C868. https://doi.org/10.1152/ajpcell.00283.2008

Kosasa, T. S. (1981). Measurement of human luteinizing hormone. Journal of Reproductive Medicine, 26, 201–206.

Kwara, A., Flanigan, T., & Carter, E. (2005). Highly active antiretroviral therapy (HAART) in adults with tuberculosis: Current status. International Journal of Tuberculosis and Lung Disease, 9(3), 248–257.

Mandas, A., Iorio, E. L., Congiu, M. G., Balestrieri, C., Mereu, A., Cau, D., Dessì, S., & Curreli, N. (2009). Oxidative imbalance in HIV-1 infected patients treated with antiretroviral therapy. BioMed Research International, 2009, 749575. https://doi.org/10.1155/2009/749575

Martin, J. A., Sastre, J., de la Asunción, J. G., Pallardó, F. V., & Viña, J. (2001). Hepatic γ-cystathionase deficiency in patients with AIDS. JAMA, 285(11), 1444–1445.

Masiá, M., Padilla, S., Fernández, M., Rodríguez, C., Moreno, A., Oteo, J. A., ... & Gutiérrez, F. (2016). Oxidative stress predicts all-cause mortality in HIV-infected patients. PLoS ONE, 11(4), e0153456. https://doi.org/10.1371/journal.pone.0153456

Misra, H. P., & Fridovich, I. (1972). The role of superoxide anion in the autooxidation of epinephrine and simple assay for superoxide dismutase. Journal of Biological Chemistry, 247, 3170–3175.

Morse, C. G., & Kovacs, J. A. (2006). Metabolic and skeletal complications of HIV infection: The price of success. JAMA, 296(7), 844–854.

National Research Council of the National Academies. (2011). Guide for the care and use of laboratory animals (8th ed.). National Academies Press.

Nkechi, O. F., Chinedu, O. C., Ositadinma, I. M., Ebere, A. J., Michael, E., & Priscilla, E. I. (2013). Impact of HIV and Mycobacterium tuberculosis co-infections on antioxidant status in Nigeria. Pakistan Journal of Nutrition, 12(5), 496–500.

Nyman, M. (1959). Serum hemoglobin; Methodological and clinical studies. Scandinavian Journal of Clinical and Laboratory Investigation, 11, 1–169.

Odell, W. D., Parlow, A. F., Swerdloff, R. S., Wabh, P. C., & Jacobs, H. S. (1981). Estimation of FSH test assay. Journal of Clinical Investigation, 47, 25–51.

Ohihoin, A. G., Ohihoin, E. N., Ujomu, I., Bakare, A., Olanrewaju, O., Okafor, A., ... & Taylor-Robinson, S. D. (2023). Contemporary anti-retroviral drugs (ARVDs) disrupt follicular development in female Wistar rats. Journal of Experimental Pharmacology, 15, 267–278.

Ohihoin, A. G., Ogbeifun, H. E., Ohihoin, E., Bakare, A., Mbarie, I., Herbertson, E., ... & Taylor-Robinson, S. D. (2025). Efavirenz-based highly active antiretroviral therapy disrupts folliculogenesis: Evidence from 48 women of reproductive age. Cureus, 17(2), e79597. https://doi.org/10.7759/cureus.79597

Salmen, S., & Berrueta, L. (2012). Immune modulators of HIV infection: The role of reactive oxygen species. Journal of Clinical & Cellular Immunology, 3(121), 2. https://doi.org/10.4172/2155-9899.1000121

Sattler, F. R., He, J., Letendre, S., Wilson, C., Sanders, C., Heaton, R., ... & McCutchan, J. A. (2015). Abdominal obesity contributes to neurocognitive impairment in HIV-infected patients with increased inflammation and immune activation. Journal of Acquired Immune Deficiency Syndromes, 68(3), 281–288.

Sax, P. E., Erlandson, K. M., Lake, J. E., McComsey, G. A., Orkin, C., Esser, S., ... & Waters, L. (2020). Weight gain following initiation of antiretroviral therapy: Risk factors in randomized comparative clinical trials. Clinical Infectious Diseases, 71(6), 1379–1389.

Semprini, A. E., Macaluso, M., Hollander, L., Vucetich, A., Duerr, A., Mor, G., ... & Jamieson, D. J. (2013). Safe conception for HIV-discordant couples: Insemination with processed semen from the HIV-infected partner. American Journal of Obstetrics and Gynecology, 208(5), 402.e1–402.e9.

Vaishnav, Y. N., & Wong-Staal, F. (1991). The biochemistry of acquired immunodeficiency syndrome. Annual Review of Biochemistry, 60(1), 577–630.

Van Leeuwen, E., Wit, F. W., Repping, S., Schattenkerk, J. K. M. E., Reiss, P., van der Veen, F., & Prins, J. M. (2008). Effects of antiretroviral therapy on semen quality. Journal of Acquired Immune Deficiency Syndromes, 22(5), 637–642.

World Health Organization. (2018). Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: Interim guidelines. https://apps.who.int/iris/handle/10665/273632

World Health Organization. (2019). WHO recommends dolutegravir as preferred HIV treatment option in all populations. https://www.who.int/news/item/22-07-2019-who-recommends-dolutegravir-as-preferred-hiv-treatment-option-in-all-populations