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The GH/IGF-1 axis in a critical period early in life determines cellular DNA repair capacity by altering transcriptional regulation of DNA repair-related genes: implications for the developmental origins of cancer

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Abstract

Experimental, clinical, and epidemiological findings support the concept of developmental origins of health and disease (DOHAD), suggesting that early-life hormonal influences during a sensitive period around adolescence have a powerful impact on cancer morbidity later in life. The endocrine changes that occur during puberty are highly conserved across mammalian species and include dramatic increases in circulating GH and IGF-1 levels. Importantly, patients with developmental IGF-1 deficiency due to GH insensitivity (Laron syndrome) do not develop cancer during aging. Rodents with developmental GH/IGF-1 deficiency also exhibit significantly decreased cancer incidence at old age, marked resistance to chemically induced carcinogenesis, and cellular resistance to genotoxic stressors. Early-life treatment of GH/IGF-1-deficient mice and rats with GH reverses the cancer resistance phenotype; however, the underlying molecular mechanisms remain elusive. The present study was designed to test the hypothesis that developmental GH/IGF-1 status impacts cellular DNA repair mechanisms. To achieve that goal, we assessed repair of γ-irradiation-induced DNA damage (single-cell gel electrophoresis/comet assay) and basal and post-irradiation expression of DNA repair-related genes (qPCR) in primary fibroblasts derived from control rats, Lewis dwarf rats (a model of developmental GH/IGF-1 deficiency), and GH-replete dwarf rats (GH administered beginning at 5 weeks of age, for 30 days). We found that developmental GH/IGF-1 deficiency resulted in persisting increases in cellular DNA repair capacity and upregulation of several DNA repair-related genes (e.g., Gadd45a, Bbc3). Peripubertal GH treatment reversed the radiation resistance phenotype. Fibroblasts of GH/IGF-1-deficient Snell dwarf mice also exhibited improved DNA repair capacity, showing that the persisting influence of peripubertal GH/IGF-1 status is not species-dependent. Collectively, GH/IGF-1 levels during a critical period during early life determine cellular DNA repair capacity in rodents, presumably by transcriptional control of genes involved in DNA repair. Because lifestyle factors (e.g., nutrition and childhood obesity) cause huge variation in peripubertal GH/IGF-1 levels in children, further studies are warranted to determine their persisting influence on cellular cancer resistance pathways.

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Acknowledgement

This work was supported by grants from the American Heart Association (to MNVA, AC and ZU), the National Center for Complementary and Alternative Medicine (R01-AT006526 to ZU), the National Institute on Aging (R01-AG047879; R01-AG038747; 3P30AG050911-02S1 to AC, WES and ZU, AG019899 and AG024824 to RAM), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS056218 to AC), the National Institute of General Medical Sciences (UL1GM118991, TL4GM118992, and RL5GM118990 to AP and VP), the Arkansas Claude Pepper Older Americans Independence Center at University of Arkansas Medical Center (to ZU; P30 AG028718), the Oklahoma Center for the Advancement of Science and Technology (to AC, ZU), the Oklahoma IDeA Network for Biomedical Research Excellence (to AC), and the Reynolds Foundation (to ZU and AC) and by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103395 (to AP and KY). The content is solely the responsibility of the authors and does not necessarily reflect the official views of the NIH.

Author contribution

AP, AC, and ZU designed research; MNVA, AP, KV, VP, EN, TG, and RAM performed experiments; AP, MNVA, AC, RAM, WES, and ZU analyzed and interpreted data; AP, AC, and ZU wrote the paper; MNVA, WES, RAM revised the manuscript.

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Authors and Affiliations

  1. Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, 975 N. E. 10th Street-BRC 1303, Oklahoma City, OK, 73104, USA

    Andrej Podlutsky, Marta Noa Valcarcel-Ares, Eszter Nagykaldi, Tripti Gautam, William E. Sonntag, Anna Csiszar & Zoltan Ungvari

  2. Department of Biology and Wildlife, Center for Alaska Native Health Research, University of Alaska Fairbanks, 902 N. Koyukuk, Fairbanks, AK, 99775, USA

    Andrej Podlutsky, Krysta Yancey & Viktorija Podlutskaya

  3. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    Richard A. Miller

  4. University of Michigan Geriatrics Center, Ann Arbor, MI, USA

    Richard A. Miller

  5. Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary

    Anna Csiszar & Zoltan Ungvari

Authors
  1. Andrej Podlutsky
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  2. Marta Noa Valcarcel-Ares
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  3. Krysta Yancey
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  4. Viktorija Podlutskaya
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  5. Eszter Nagykaldi
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  6. Tripti Gautam
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  7. Richard A. Miller
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  8. William E. Sonntag
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  9. Anna Csiszar
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  10. Zoltan Ungvari
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Corresponding author

Correspondence to Zoltan Ungvari.

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The authors declare that they have no conflict of interest.

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Podlutsky, A., Valcarcel-Ares, M.N., Yancey, K. et al. The GH/IGF-1 axis in a critical period early in life determines cellular DNA repair capacity by altering transcriptional regulation of DNA repair-related genes: implications for the developmental origins of cancer. GeroScience 39, 147–160 (2017). https://doi.org/10.1007/s11357-017-9966-x

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  • DOI: https://doi.org/10.1007/s11357-017-9966-x

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