title: 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.
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.
authors.affiliation: 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.|Department of Biology and Wildlife, Center for Alaska Native Health Research, University of Alaska Fairbanks, 902 N. Koyukuk, Fairbanks, AK, 99775, USA.
authors.forename: Andrej
authors.initials: A
authors.lastname: Podlutsky
authors.affiliation: 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.
authors.forename: Marta Noa
authors.initials: MN
authors.lastname: Valcarcel-Ares
authors.affiliation: Department of Biology and Wildlife, Center for Alaska Native Health Research, University of Alaska Fairbanks, 902 N. Koyukuk, Fairbanks, AK, 99775, USA.
authors.forename: Krysta
authors.initials: K
authors.lastname: Yancey
authors.affiliation: Department of Biology and Wildlife, Center for Alaska Native Health Research, University of Alaska Fairbanks, 902 N. Koyukuk, Fairbanks, AK, 99775, USA.
authors.forename: Viktorija
authors.initials: V
authors.lastname: Podlutskaya
authors.affiliation: 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.
authors.forename: Eszter
authors.initials: E
authors.lastname: Nagykaldi
authors.affiliation: 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.
authors.forename: Tripti
authors.initials: T
authors.lastname: Gautam
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.|University of Michigan Geriatrics Center, Ann Arbor, MI, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
authors.affiliation: 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.
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.affiliation: 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.|Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary.
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
authors.affiliation: 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. zoltan-ungvari@ouhsc.edu.|Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary. zoltan-ungvari@ouhsc.edu.
authors.forename: Zoltan
authors.identifier: 0000-0002-6035-6039
authors.initials: Z
authors.lastname: Ungvari
mesh_terms: D000818:Animals; D004260:DNA Repair / Q000502:physiology*; D005347:Fibroblasts / Q000473:pathology*; D013006:Growth Hormone / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008136:Longevity; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000209:etiology*; D011917:Rats, Inbred Lew
chemical_list: D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone
keywords: Cellular resilience; Endocrine; Growth hormone; Insulin-like growth factor-1; Lifespan, health span; Longevity; Stress resistance