| 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
|
|---|---|
| Published in |
GeroScience, February 2017
|
| DOI | 10.1007/s11357-017-9966-x |
| Pubmed ID | |
| Authors |
Andrej Podlutsky, Marta Noa Valcarcel-Ares, Krysta Yancey, Viktorija Podlutskaya, Eszter Nagykaldi, Tripti Gautam, Richard A. Miller, William E. Sonntag, Anna Csiszar, Zoltan Ungvari |
| 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. |
X Demographics
The data shown below were collected from the profiles of 2 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 1 | 50% |
| Romania | 1 | 50% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 50% |
| Scientists | 1 | 50% |
Mendeley readers
The data shown below were compiled from readership statistics for 51 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 51 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Bachelor | 10 | 20% |
| Student > Master | 10 | 20% |
| Researcher | 7 | 14% |
| Student > Ph. D. Student | 6 | 12% |
| Student > Doctoral Student | 3 | 6% |
| Other | 5 | 10% |
| Unknown | 10 | 20% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 12 | 24% |
| Biochemistry, Genetics and Molecular Biology | 10 | 20% |
| Agricultural and Biological Sciences | 6 | 12% |
| Environmental Science | 3 | 6% |
| Nursing and Health Professions | 3 | 6% |
| Other | 8 | 16% |
| Unknown | 9 | 18% |
Attention Score in Context
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#18,507,485
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Outputs from GeroScience
#423
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#226,437
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Outputs of similar age from GeroScience
#1
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