PubMed Health⌕ Search

Biomedical subjects

E Randerath

Publications and source records attributed to E Randerath.

At least 37 records · Page 2Linked to original sources
PubMed1994

32P-postlabeling of bile components: bulky adduct-like behavior in polyethyleneimine-cellulose thin layer chromatography.

The 32P-postlabeling assay has been used widely in carcinogen-DNA adduct analysis because of its sensitivity and reproducibility. Cloned T4 polynucleotide kinase (PNK), routinely used in this assay, phosphorylates the 5'-OH groups of adducted nucleotides in the presence of [gamma-32P]ATP. However, as an exception to this property, PNK has been reported to phosphorylate non-adducted carcinogen metabolites, such as tetrol derivatives of benzo[a]pyrene and chrysene. Also, PNK phosphorylates both 5'-OH and 3'-OH groups of safrole-adducted deoxydinucleoside monophosphates having an unmodified purine in the 3'-position. In the present study we show that T4 PNK catalyzed the transfer of [32P]phosphate from [gamma-32P]ATP to rat bile components or purified bile acids (derivatives of 3 alpha-hydroxy-5 beta-cholanic acid) in the absence of nucleic acids or nucleases. However, labeling of the bile acids appeared over 100,000-fold less efficient than labeling of 2'-deoxyadenosine-5'-monophosphate. There was no reaction in the absence of bile components or PNK. Dehydrocholic acid, which lacks hydroxyl groups, was resistant to phosphorylation. On polyethyleneimine-cellulose TLC maps, 32P-labeled rat bile extract gave an array of non-polar radioactive spots which resembled carcinogen-DNA adducts, while 32P-labeled purified bile acids each gave a single spot. These 32P-labeled products liberated 32Pi upon incubation with prostatic acid phosphatases. Two of the radioactive spots obtained from rat bile were identified as phosphorylated taurocholic and taurodeoxycholic acids by co-chromatography with 32P-labeled standards. These findings demonstrate for the first time that PNK is able to phosphorylate natural products other than nucleotides and further emphasize the need to rule out contamination with bile acids and possibly other bulky/hydrophobic alcohols when analyzing DNA samples by 32P-postlabeling.

Adenosine Triphosphate↗
PubMed1993

Flavor constituents in cola drinks induce hepatic DNA adducts in adult and fetal mice.

Mice given one of several widely consumed cola drinks in place of drinking water for up to 8 weeks developed significant levels of covalent liver DNA adducts in a time dependent manner, as measured by 32P-postlabeling. These adducts were not detected in mice given tap water or one of 3 non-cola beverages. Adducts chromatographically identical to those induced by cola drinks were detected in mice treated with extracts of nutmeg or mace, spices from the nutmeg tree (Myristica fragrans Houttuyn), or with myristicin (1-allyl-5-methoxy-3,4-methylenedioxybenzene), the major spice constituent of nutmeg. In addition, small amounts of adducts derived from the hepatocarcinogen safrole (1-allyl-3,4-methylenedioxybenzene), a minor constituent of nutmeg, were observed. Liver DNA adducts were also detected in fetal liver when pregnant mice were intubated with myristicin. Possible implications of these findings for human health are discussed.

Allylbenzene Derivatives↗
PubMed1993

Effects of polychlorinated dibenzofurans on compounds in hepatic DNA of female Sprague-Dawley rats: structure dependence and mechanistic considerations.

Previous work indicated that covalent age-dependent DNA modifications of endogenous origin termed I-compounds may represent useful biomarkers for tumor promotion/carcinogenesis, as various tumor promoters/carcinogens, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and phenobarbital, reduce rat I-compound levels in liver, the target organ. The present study addressed the question as to whether polychlorinated dibenzofurans (PCDFs), which are related to TCDD and its congeners with regard to their toxic and biochemical properties, would also affect hepatic I-compound patterns and levels, and whether such effects would be chemical structure-dependent. Female Sprague-Dawley rats were treated once a week with a single dose (100 micrograms/kg) of 1,2,3,7,8-pentachlorodibenzofuran (1,2,3,7,8-PeCDF), 1,2,4,7,8-PeCDF, 2,3,4,7,8-PeCDF, or 2,3,4,6,7,8-hexachlorodibenzofuran (2,3,4,6,7,8-HeCDF) for 4 weeks and liver DNA was analyzed at the end of the last week by 32P-postlabeling assay. No carcinogen-DNA adducts were detected; however, levels of both non-polar and polar I-compounds were reduced in a structure-dependent manner. Potencies increased in the order, control (100%, 122 modifications in 10(9) DNA nucleotides = 1,2,4,7,8-PeCDF (104%) < 1,2,3,7,8-PeCDF (80%) < 2,3,4,7,8-PeCDF (61%) and 2,3,4,6,7,8-HeCDF (61%). Structure-activity relationships for total I-compounds, therefore, paralleled those reported for Ah receptor agonist activity, i.e., compounds that exhibit high cytosolic Ah receptor binding affinities and are also potent inducers of aryl hydrocarbon hydroxylase activity (1,2,3,7,8-PeCDF, 2,3,4,7,8-PeCDF, and 2,3,4,6,7,8-HeCDF) were active, while 1,2,4,7,8-PeCDF, which is a less potent Ah receptor agonist, was inactive. Polar I-compounds responded to a greater extent than did non-polar ones and, in general, individual I-compounds were affected differentially, thus decreased formation or increased removal of I-compounds played a role in the observed effects of the toxins on DNA. It is proposed that Ah receptor-mediated enzyme induction, particularly of cytochrome P450, is involved in reduced hepatic I-compound formation and that subnormal I-compound levels may contribute to tumor promotion.

Animals↗
PubMed1993

Bulky DNA-adduct formation induced by Ni(II) in vitro and in vivo as assayed by 32P-postlabeling.

Various small oxidation products (e.g. 8-hydroxydeoxyguanosine) can be induced in DNA by nickel compounds. In this study, the 32P-postlabeling assay was applied to determine whether Ni(II) compounds are able to induce bulky DNA-adduct formation in vitro and in vivo. In vitro studies detected two major and several minor adducts in DNA incubated with NiCl2 and H2O2 at 37 degrees C for 1 h. Formation of the two major adducts increased with incubation time (0-24 h) and NiCl2 concentration (0-800 microM). Adduct levels were greatly reduced by hydroxyl free-radical scavengers, i.e. 0.4 M sodium formate or 0.05 M p-nitrosodimethylaniline, and by a singlet oxygen scavenger, 0.05 M sodium azide. The in vitro effects of NiCl2 on DNA were significantly enhanced by (1) addition of 3 mM ascorbic acid, (2) replacement of H2O with D2O in the reaction, and (3) prior denaturation of DNA. Adduct formation presumably involved a Fenton-type reaction, in which DNA crosslinks may arise by reaction with hydroxyl free radicals and singlet oxygen. For in vivo studies, male 6-8 wk old B6C3F1 mice were used. In untreated mice, several I-compounds (putative indigenous DNA modifications that increase with age) were detected in liver, kidney, and lung. Two of these (spots 1 and 2) were chromatographically identical to the two major spots induced by Ni(II) in vitro. The intensities of spots 1 and 2 in kidney and of some other spots in liver and lung were increased 1 and 2 h after i.p. injection with a single dose of 170 mumols/kg NiAc2. The effects of NiAc2 were reduced or undetectable in the three tissues 24 h after treatment. These observations indicate the capacity of Ni(II) to induce and modulate bulky DNA modifications both in vitro and in vivo.

Animals↗
PubMed1993

Enhancement of age-related increases in DNA I-compound levels by calorie restriction: comparison of male B-N and F-344 rats.

Caloric restriction (CR), known to extend median and maximum life spans, improve resistance to carcinogenesis, and significantly retard age-associated degenerative diseases in rodents, was previously reported to modulate levels of indigenous, age-dependent DNA modifications, called I-compounds, in male Brown-Norway (B-N) rats. Since profiles of these adduct-like derivatives are species-, strain-, sex-, and tissue-specific, we explored this apparent CR/I-compound relationship in a comparative study between male B-N and male Fischer 344 (F-344) rats, the latter having a shorter life expectancy and high incidence of renal disease. Control animals were fed NIH-31 diet ad libitum (AL), while the caloric intake of CR animals was limited to 60% of AL, starting at 3.5 months. Liver and kidney DNA from 1, 8, 12, 16, 24 (AL, CR), and 30 (CR only) month old rats was analyzed by 32P-postlabeling. Corresponding tissues from the two strains yielded similar DNA profiles. Total liver I-compound levels displayed 2.3-4.6-fold age-dependent increases from 1 to 24 months, and kidney values at 24 months were 5.2-8 times higher than those at 1 month. In both strains, I-compound levels of CR animals were higher, up to 2-fold, than in age-matched AL rats. Regression analyses indicated linear relationships between most CR relative adduct labeling values (both total and individual fractions) and age, whereas many AL values exhibited this type of link with log age. These findings confirm that a correlation exists between CR and I-compound levels, and, given the above physiological benefits of CR, indicate that I-compounds represent biomarkers of aging with potential utility in intervention studies.

Aging↗
PubMed1993

Biomarkers of aging: correlation of DNA I-compound levels with median lifespan of calorically restricted and ad libitum fed rats and mice.

I-compounds are species-, tissue-, genotype-, gender-, and diet-dependent bulky DNA modifications whose levels increase with animal age. While a few of these DNA modifications represent oxidation products, the majority of I-compounds appear to be derived from as yet unidentified endogenous DNA-reactive intermediates other than reactive oxygen species. Circadian rhythms of certain I-compounds in rodent liver imply that levels of these DNA modifications are precisely regulated. Caloric restriction (CR), the currently most effective method available to retard aging and carcinogenesis, has been previously shown to elicit significant elevations of I-compound levels in tissue DNA from Brown-Norway (BN) and F-344 rats as compared to age-matched ad libitum fed (AL) animals. The present investigation has extended this work by examining liver and kidney DNA I-compound levels in three genotypes of rats (F-344, BN, and F-344 x BN) and two genotypes of mice (C57BL/6N and B6D2F1) under identical experimental conditions in order to determine whether correlations exist between I-compound levels, measured in middle-aged animals, and median lifespan. Levels of a number of liver and kidney I-compounds were found to display genotype- and diet-dependent, statistically significant positive linear correlations with median lifespan in both species. In particular, the longer-lived hybrid F-344 x BN rats and B6D2F1 mice tended to exhibit higher I-compound levels than the parent strains. CR enhanced I-compound levels substantially in both rats and mice. Thus, I-compounds, measured at middle age, reflected the functional capability ('health') of the organism at old age, suggesting their predictive value as biomarkers of aging. The positive linear correlations between levels of certain I-compounds (designated as type I) and lifespan suggest that these modifications may be functionally important and thus not represent endogenous DNA lesions (type II), whose levels would be expected to correlate inversely with lifespan.

Aging↗
PubMed1993

I-compounds--endogenous DNA markers of nutritional status, ageing, tumour promotion and carcinogenesis.

Certain bulky DNA modifications increase with age in laboratory animals without known exposure to carcinogens and are known as indigenous or I-compounds. Most of the spots detected on TLC maps by the nuclease P1-enhanced bisphosphate version or the monophosphate version of the 32P-postlabelling assay fit this definition of I-compounds. Chromatographic profiles and levels of these nucleotides greatly depend on animal species, strain, tissue and gender, but are also influenced by the diet and by chemical exposures. Thus, both genetic and environmental factors contribute to the formation of I-compounds. It appears that they are derived from endogenous DNA-reactive compounds generated during normal nutrient metabolism and that regulatory mechanisms exist which control their levels in tissue DNA.

Aging↗
PubMed1993

Monitoring tobacco smoke-induced DNA damage by 32P-postlabelling.

Adduct levels in smokers are substantial, i.e. about 1 adduct in 10(7) nucleotides in lung DNA of lung cancer patients. Tobacco smoke-associated (TSA) DNA adducts, formed in a dose- and exposure time-dependent manner in smokers' lung, persist for considerable periods of time, consistent with epidemiological evidence showing quantitative associations of smoking with lung cancer risk and mortality. These results support a causal relationship between such adducts and tobacco smoking-induced cancer. TSA adducts were also present in various other target organs for tobacco-smoke carcinogenesis, including kidney, bladder, oesophagus and pancreas.

Animals↗
PubMed1992

Oat lipids-induced covalent DNA modifications (I-compounds) in female Sprague-Dawley rats, as determined by 32P-postlabeling.

Previous studies have shown that the presence of oats in the diet contributes to formation of I-compounds (age-dependent covalent DNA modifications detected by 32P-postlabeling assay) in female Sprague-Dawley rat liver DNA. The current study explored the possible ingredients in oats responsible for the observed effects on DNA. Feeding AIN-76A diet containing 5% oat lipids (obtained by methanol extraction and dissolved in trioctanoin) in place of corn oil for 2 months successfully induced the formation of 3 oats-specific (spots 2-4) and 4 natural ingredient diet-specific I-compounds (spots 6-9) in liver DNA. Barley, an oatlike cereal, induced 3 of these spots at very low intensities but not the 3 oats-specific I-spots. Oral administration of oat lipids to weanling rats of both sexes for 7 days elicited trace amounts of the oats-specific spots and spot 9 in liver DNA. However, when oat lipids were given at 6 or 9 weeks of age, the oats-specific spots were detected at high levels in female but not in male rats. These oats-related DNA modifications were also present in 6-week-old female rats which had received oat lipids p.o. for 2 or 3 days or i.p. for 4 days. Rats given trioctanoin or extracts from natural ingredient Wayne diet (lacking oats) did not show any of these spots. On the other hand, rats treated with extracts from an oats-containing Teklad diet displayed a trace amount of one of these I-compounds. Oat lipids did not induce any extra spots in rat kidney DNA. Feeding of AIN diet supplemented with oats to female Syrian hamsters did not elicit any renal or hepatic DNA alterations, as detected by 32P-postlabeling. Rats fed oat lipids-supplemented AIN diet or Purina diet showed the highest levels of I-compounds overall in liver among all dietary groups and these two groups also had significantly higher hepatic DNA synthesis rates. Oat lipids enhanced kidney DNA synthesis also. The total hepatic or renal cytochrome P-450 contents were not significantly affected by different diets. These results demonstrate a novel link between a natural dietary ingredient and covalent DNA modifications and shed light on the origins of certain I-compounds.

Animals↗
PubMed1992

DNA damage induced by cigarette smoke condensate in vitro as assayed by 32P-postlabeling. Comparison with cigarette smoke-associated DNA adduct profiles in vivo.

Cigarette smoke induces a multitude of bulky/aromatic DNA adducts in vivo as revealed by 32P-postlabeling assay. The formation of such adducts is thought to involve metabolic activation of aromatic chemicals especially polycyclic aromatic hydrocarbons (PAHs) present in tumor-initiating cigarette tar fractions, via cytochrome P450-associated monooxygenases. Because radicals are present in both the gas and particulate (tar) phase of cigarette smoke and in aqueous extracts of cigarette smoke condensate (CSC), we addressed the question as to whether cytochrome P450-independent, possibly free radical-mediated reactions may contribute, also, to formation of cigarette smoke-associated bulky DNA adducts. Rat-lung DNA was incubated with aqueous extracts of CSC in the absence of microsomes under various conditions and analyzed by 32P-postlabeling. Radioactively labeled bulky reaction products were found to accumulate in a time- and CSC concentration-dependent manner. The resulting chromatographic profiles resembled cigarette smoke-associated DNA-adduct patterns observed in vivo. Pretreatment of aqueous CSC extract with radical scavengers/reducing agents (ascorbic acid, glutathione) diminished adduct formation in a concentration-dependent manner. Adduct formation in vitro may involve oxygen-free radicals, which are known to be present in aqueous CSC extracts and could (i) attack DNA directly to produce bulky adducts, (ii) induce radical sites on DNA covalently binding CSC components, or (iii) convert CSC components to DNA-reactive electrophiles. In addition, DNA may react with direct-acting mutagens in CSC. Adduct fractions derived from in vitro and in vivo experiments showed similar chromatographic behavior, suggesting that metabolic activation as well as processes not involving metabolism lead to formation of smoking-induced bulky DNA adducts in vivo.

Animals↗
PubMed1992

Formation of ribonucleotides in DNA modified by oxidative damage in vitro and in vivo. Characterization by 32P-postlabeling.

Oxygen free radicals generated by the interaction of Fe2+ and H2O2 (Fenton reaction) are capable of reacting with DNA bases, which may induce premutagenic and precarcinogenic lesions. Products formed in DNA by such reactions have been characterized as hydroxylated derivatives of cytosine, thymine, adenine, and guanine and imidazole ring-opened derivatives of adenine and guanine. As shown here by 32P-postlabeling, incubation of DNA under Fenton reaction conditions gave rise to additional oxidation products in DNA that were characterized as putative ribonucleosides by enzymatic hydrolysis of the oxidized DNA, 32P-postlabeling, and co-chromatography in multiple systems with authentic markers. Formation of these products in DNA was enhanced by the presence of L-ascorbic acid in the reaction mixtures and their total amounts were similar to those of the major DNA oxidation product, 8-hydroxy-2'-deoxyguanosine. The ribonucleoside guanosine was also formed in kidney DNA of male rats treated with ferric nitrilotriacetate, a renal carcinogen. It is postulated that ribonucleotides alter conformation and function of DNA and thus their presence in DNA may lead to adverse health effects.

Adenosine Triphosphate↗
PubMed1991

Induction of rat liver DNA alterations by chronic administration of peroxisome proliferators as detected by 32P-postlabeling.

The mechanisms of the hepatocarcinogenicity of non-mutagenic peroxisome proliferators, i.e. compounds used as hypolipidemic drugs and industrial plasticizers, are not sufficiently understood. To gain more information on the mechanism of their action, the chronic effects of two structurally diverse peroxisome proliferators on rat-liver DNA were investigated by the 32P-postlabeling assay. Male F-344 rats (1.5 month old) were fed ciprofibrate (0.025%) in the diet for 2, 5, 8, and 16 months or Wy-14643 (0.1%) for 18 months. Liver DNA from individual treated animals (3-4 per group) and age-matched controls was analyzed by the nuclease P1/bisphosphate version of the 32P-postlabeling assay. Three distinct types of exposure-related DNA alterations were observed: (i) A significant reduction of the age-dependent accumulation of I-compounds (putative indigenous DNA modifications) (type 1), (ii) adduct-like DNA derivatives induced by the treatments (type 2), and (iii) as yet structurally uncharacterized radiolabeled material occupying substantial areas of DNA adduct maps and accumulating in an exposure time-dependent manner (type 3). DNA from liver tumors generated by these agents displayed only traces of I-compounds, lacked all but one adduct-like derivatives, and had no type 3 alterations. Thus, in contrast to the non-mutagenicity of peroxisome proliferators in short-term assays, chronic administration of these compounds led to DNA alterations that were detectable by 32P-postlabeling assay.

Affinity Labels↗
PubMed1991

Effects of aging and caloric restriction on I-compounds in liver, kidney and white blood cell DNA of male Brown-Norway rats.

Rodent tissues display species-, strain-, sex- and tissue-specific adduct-like DNA modifications termed I-compounds, which increase with age, are modulated by diet and are presumably derived from indigenous metabolic intermediates. We have explored whether I-compounds are affected by caloric restriction, which is known to extend life span and retard age-related degenerative and neoplastic diseases. Male Brown-Norway rats were fed NIH-31 diet ad libitum (AL). Calorically restricted (CR) rats received 60% of AL consumption, starting at 3.5 months. DNA was analyzed by 32P-postlabeling at 1, 4, 8, 12, 16 and 24 months of age in liver, kidney and white blood cells. I-compounds in AL liver and kidney exhibited complex tissue specific profiles; I-compound levels increased with age, plateaued between 8 and 18 months depending on tissue and diet and were 8.7 (liver) and 27.4 (kidney) modifications in 10(8) nucleotides at 24 months, thereby exceeding the corresponding 1-month values by 3.7- and 16.6-fold. CR resulted in similar profiles but did not diminish age-related increases, rather I-compound levels in CR liver and kidney were increased by about 70% and 30% versus age-matched AL rats. White blood cells exhibited few I-compounds and at low levels; age-related increases were small overall but more pronounced in CR rats. Higher I-compound levels in CR animals, which were presumably a consequence of metabolic effects elicited by CR, thus correlated with extended life span and, therefore, may be beneficial, in agreement with previous findings showing an association between reduced I-compound levels and hepatocarcinogenesis as well as organ susceptibility to diseases.

Aging↗
PubMed1991

Short-term effects of the tumor promoting polychlorinated biphenyl mixture, Aroclor 1254, on I-compounds in liver, kidney and lung DNA of male Sprague-Dawley rats.

The effects of a tumor promoting polychlorinated biphenyl mixture, Aroclor 1254, on I-compounds (tissue, species and sex dependent DNA modifications that increase with age in untreated rodents) were studied by 32P-postlabeling in male Sprague-Dawley rat liver, kidney, and lung DNA. Aroclor 1254 was dissolved in corn oil and intraperitoneally (i.p.) injected (2 x 500 mg/kg, 2 weeks apart) into 3-month-old rats. Control rats were given corn oil. Groups of 3 animals were sacrificed at 2 and 6 weeks after the second injection of corn oil or Aroclor 1254. At both time points Aroclor 1254-treated rats had significantly lower body weights and higher liver weights while kidney and lung weights were unaffected. Thymidine incorporation into liver and lung DNA was significantly increased at both time points, while kidney DNA showed a small decrease at 2 weeks. Treatment resulted in significant reductions (ranging from 29 to 100%) of each of nine liver I-spots at 2 and 6 weeks. In treated rats there was no decrease in kidney I-spots at 2 weeks, while the levels of only two out of ten kidney spots were reduced by 42-91% at 6 weeks. At 2 weeks three out of seven and at 6 weeks four out of seven lung I-spots were lowered by 51-100% in the Aroclor 1254-treated rats. Thus the effects decreased in the order liver greater than lung greater than kidney. Since Aroclor 1254 has been reported to be a tumor promoter in liver and lung but not kidney, these results suggest a correlation between organ specific promotion of carcinogenesis by Aroclor 1254 and the reduction of DNA I-compounds.

Animals↗
PubMed1991

DNA adduct formation in liver and kidney of male Syrian hamsters treated with estrogen and/or alpha-naphthoflavone.

Chronic administration of estrogens to male Syrian hamsters induces kidney tumors. Co-administration of estrogen plus alpha-naphthoflavone (ANF) suppresses this kidney carcinogenesis but induces liver tumors instead. In an attempt to elucidate the mechanism of the switch from estrogen-induced kidney to liver carcinogenesis in response to ANF treatment, patterns of kidney and liver DNA adducts were investigated by 32P-postlabeling analysis and compared to controls. Chronic treatment of hamsters with ANF alone or in combination with estradiol resulted in a flavone-specific DNA adduct pattern in livers of these animals. These spots, adducts 1 and 2, on 32P-postlabeling maps were taken as evidence of covalent ANF-DNA modifications. The kidney-specific estrogen-induced indirect DNA adducts, observed previously in hamsters treated chronically with estrogen, occurred in renal but not hepatic DNA of animals treated with estradiol alone or in combination with ANF. Pretreatment of hamsters with ANF for 3 days decreased by 75-80% the hepatic and renal diethylstilbestrol (DES)-DNA adducts, which are formed after injection of a single large dose of DES. It is concluded from these changes in DNA adduct patterns and levels that estrogen quinone-DNA adduction may play an etiological role in estrogen-induced kidney cancer. The prevention of estrogen-induced kidney tumors by ANF co-treatment may be a consequence of the decrease in renal concentrations of these adducts in response to ANF. Hepatic concentrations of estrogen quinone-DNA adducts also decrease, but ANF-DNA adducts, observed only in liver, may assume an etiological role in the induction of hepatomas.

Animals↗
PubMed1991

Sexual dimorphism of the chromatographic profiles of I-compounds (endogenous deoxyribonucleic acid modifications) in rat liver.

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 P1-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 male-specific I-compounds were observed. In female rats, the total level amounted to 112 I-compounds in 10(9) 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 androgen-imprinting 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.

Animals↗