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Sexual Dimorphism of the Chromatographic Profiles of I-Compounds (Endogenous Deoxyribonucleic Acid Modifications) in Rat Liver^*

Laboratory of Biochemical Risk Analysis, National Institute of Environmental Health Sciences, Research Triangle Park North Carolina 27709
The Division of Toxicology, Department of Pharmacology, Baylor College of Medicine Houston, Texas 77030

Address requests for reprints to: Dr. George Lucier, Laboratory of Biochemical Risk Analysis, National Institute of Environmental and Health Sciences, National Institutes of Health, P.O. Box 12233, Research Triangle Park, North Carolina 27709.

Abstract

DNA of all tissues studied thus far in untreated mammals contains as yet structurally unidentified, covalent modifications termed I (indigenous)-compounds, which are detectable by the ³²P postlabeling assay for DNA adducts and increase with age. The purpose of this study was to determine the effects of sex, gonadectomy, and androgen administration on I-compound profiles and levels in order to gain insight into the factors involved in the biosynthesis of these DNA modifications. Liver DNA from various groups of 6-month-old Sprague- Dawley rats (untreated or gonadectomized males and females; animals with or without gonadectomy treated with testosterone propionate) was analyzed by a nuclease Pl-enhanced version of the ³²P postlabeling assay. Hepatic I-compound profiles of untreated animals exhibited pronounced sexual dimorphism. In addition to a number of I-compounds that differed quantitatively between sexes, 7 female-specific and 1 malespecific I-compounds were observed. In female rats, the total level amounted to 112 I-compounds in 109 DNA nucleotides and exceeded the level in males by 3-fold. Castration feminized and ovariectomy masculinized I-compound profiles and levels. Neonatal testosterone propionate failed to restore the male pattern of I-compounds lost by neonatal castration, so that an androgenimprinting mechanism did not appear to be involved in the maintenance of the male I-compound phenotype and the suppression of the female pattern. Testosterone propionate administered to intact female animals lowered total I-compound levels significantly. The results indicate that estrogens play a dominant role in regulating sex-dependent formation of I-compounds in rat liver. The dependence of I-compound formation on both age and sex hormones suggests that the levels of these DNA modifications are developmentally controlled. (Endocrinology 129: 3093–3100, 1991)

Footnotes

^* This work was supported in part by USPHS Grants R37-CA-32157 awarded by the NCI, R01-AG-07750 awarded by the NIA, and P42-ES-04917 awarded by the NIEHS.

Received April 27, 1991.