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Growth hormone increases DNA damage in ovarian follicles and macrophage infiltration in the ovaries

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Abstract

Evidence points to an important role of the growth hormone (GH) in the aging process and longevity. GH-deficient mice are smaller, live longer than normal littermates, and females have an increased ovarian reserve. The aim of the study was to evaluate the role of GH in the ovarian reserve by evaluating DNA damage, macrophage infiltration, and granulosa cell number in primordial and primary follicles. Experiment 1 used GH-deficient Ames dwarf mice (df/df, n = 12) and their normal littermates (N/df, n = 12), receiving GH or saline injections. Experiment 2 included transgenic mice overexpressing bovine GH (bGH) (n = 6) and normal mice (N, n = 6). DNA damage (anti-γH2AX) and macrophage counting (anti-CD68) were evaluated by immunofluorescence. Female df/df mice had lower γH2AX foci intensity in both oocytes and granulosa cells of primordial and primary follicles (p < 0.05), indicating fewer DNA double-strand breaks (DSBs). GH treatment increased DSBs in both df/df and N/df mice. Inversely, bGH mice had a higher quantity of DSBs in both oocytes and granulosa cells of primordial and primary follicles (p < 0.05). Df/df mice showed ovarian tissue with less macrophage infiltration than N/df mice (p < 0.05) and GH treatment increased macrophage infiltration (p < 0.05). In contrast, bGH mice had ovarian tissue with more macrophage infiltration compared to normal mice (p < 0.05). The current study shows that GH increases DNA DSBs in oocytes and granulosa cells and raises macrophage infiltration in the ovaries, pointing to the role of the GH/IGF-I axis in maintenance of oocyte DNA integrity and ovarian macrophage infiltration in mice.

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Funding

This work was supported by CAPES, CNPq, FAPERGS, and NIH/NIA grants R15 AG059190, R03 AG059846, and R56 AG061414 (MMM).

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Authors and Affiliations

  1. Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, RS, Brazil

    Tatiana D. Saccon & Driele N. Garcia

  2. Faculdade de Veterinária, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil

    Monique T. Rovani

  3. Faculdade de Nutrição, Universidade Federal de Pelotas, Pelotas, RS, Brazil

    Jorgea Pradiee, Carlos C. Barros & Augusto Schneider

  4. Instituto de Biologia, Universidade Federal de Pelotas, Pelotas, RS, Brazil

    Rafael G. Mondadori & Luis Augusto X. Cruz

  5. Departments of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL, USA

    Yimin Fang, Samuel McFadden & Andrzej Bartke

  6. Department of Animal, Dairy and Veterinary Sciences, Center for Integrated BioSystems, School of Veterinary Medicine, Utah State University, Logan, UT, USA

    Jeffrey B. Mason

  7. College of Medicine, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL, USA

    Michal M. Masternak

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  1. Tatiana D. Saccon
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Contributions

TDS performed sample analysis, interpreted data, and wrote the manuscript; MTR, DNG, JP, and LAXC performed sample analysis and data interpretation; RGM, CCB, AB, JBM, MMM, and AS designed the experiments, provided reagents and equipment, and data interpretation; YF and SM performed animal experiments and sample collection. All authors revised and edited the final manuscript draft.

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Correspondence to Augusto Schneider.

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Saccon, T.D., Rovani, M.T., Garcia, D.N. et al. Growth hormone increases DNA damage in ovarian follicles and macrophage infiltration in the ovaries. GeroScience 44, 1071–1081 (2022). https://doi.org/10.1007/s11357-021-00380-8

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