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Age-dependent covalent DNA alterations (I-compounds) in rodent tissues: species, tissue and sex specificities
K Randerath1, J G Liehr, A Gladek
1Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030.
Abstract:
I-compounds are non-polar covalent DNA modifications of as yet undetermined structure that tend to accumulate in an age-dependent manner in tissues of untreated animals. They are detectable by 32P-postlabeling assay because of their adduct-like properties and chromatographically resemble DNA nucleotides containing bulky/hydrophobic moieties. To determine which factors may be involved in their formation, I-compounds were examined by 32P-postlabeling in liver and kidney DNA of female and male Sprague-Dawley rats and Syrian hamsters of different ages (1, 4 and 10 months and 1, 2.5 and 9.5 months, respectively). The following results were obtained: (i) Every tissue DNA studied contained characteristic I-compounds. (ii) Patterns and amounts of I-compounds were reproducible among animals of the same kind. (iii) There were pronounced organ and species differences. (iv) I-compound patterns were sex-dependent. (v) I-compound levels increased with age in all tissues studied, except in male hamster kidney, a target organ of estrogen-induced carcinogenesis. The highest levels were observed in liver and kidney of 10-month-old female rats. (vi) The rise of I-compound levels was less steep during the later part of the observation period for female but not male animals. (vii) Gonadectomy decreased I-compound levels in female hamster kidney DNA, while causing a slight increase in male animals later in life. These I-compounds were identical to previously reported DNA modifications that increased in male hamster kidneys after prolonged estrogen treatment. Points, iv, vi and vii strongly implicated sex hormones in I-compound formation. The qualitative effects of species, tissue differentiation, gender and sex hormones on these DNA modifications support the hypothesis that I-compounds are formed by the binding of endogenous electrophiles to DNA. As persistent DNA alterations, they are likely to affect DNA replication and to play a role in spontaneous and chemically induced carcinogenesis and in aging.
Insights
Endogenous DNA modifications, termed I-compounds, accumulate with age and are influenced by sex hormones. Their formation involves electrophilic binding to DNA, potentially impacting aging and cancer development.
Area of Science:
- Biochemistry
- Molecular Biology
- Toxicology
Background:
- I-compounds are non-polar covalent DNA modifications of unknown structure.
- They accumulate in tissues with age and exhibit adduct-like properties.
- These modifications are detectable via 32P-postlabeling assay.
Purpose of the Study:
- To investigate factors influencing the formation of I-compounds.
- To examine organ, species, sex, and age-dependent variations in I-compound levels.
- To explore the role of sex hormones in I-compound generation.
Main Methods:
- 32P-postlabeling assay was used to detect and quantify I-compounds.
- Analysis was performed on liver and kidney DNA from Sprague-Dawley rats and Syrian hamsters of various ages and sexes.
- Effects of gonadectomy on I-compound levels were assessed.
Main Results:
- Characteristic I-compounds were found in all studied tissues, with reproducible patterns within species.
- Significant organ, species, and sex differences in I-compound patterns and levels were observed.
- I-compound levels generally increased with age, with notable influence from sex hormones and gonadectomy.
Conclusions:
- Sex hormones play a significant role in the formation of I-compounds.
- These DNA modifications are likely formed by the binding of endogenous electrophiles to DNA.
- Persistent I-compounds may influence DNA replication, aging, and carcinogenesis.