Biomedical subjects

B A Carnes

Publications and source records attributed to B A Carnes.

At least 19 recordsLinked to original sources

PubMed1992

In vivo protection by the aminothiol WR-2721 against neutron-induced carcinogenesis.

The ability of the compound S-2-(aminopropylamino)ethylphosphorothioic acid, designated WR-2721, to protect against neutron-induced carcinogenesis was investigated. Both sexes of the B6CF1 mouse were injected i.p. with 400 mg/kg of WR-2721 30 min prior to being irradiated by 10 cGy of neutrons. Neoplastic mortality in the groups receiving thiol was either reduced or delayed relative to irradiated mice not given protector. However, the time at which the protective effect of WR-2721 was expressed depended on the sex of the animal. Thiol-related shifts in the time of neoplastic death in females occurred only in the first half of the lifespan. Once a female survived to the mean age at death, no difference in the pattern of mortality could be detected between control and WR-2721-treated mice exposed to neutrons. Irrespective of thiol treatment, the timing of tumour-related death was nearly identical during the first half of life for males exposed to neutrons. In the last half of the lifespan, survival of thiol-protected males was enhanced relative to saline-injected males and even exceeded that observed in the control population.

Amifostine↗

PubMed1992

The comparative tumorigenic effects of fission neutrons and cobalt-60 gamma rays in the B6CF1 mouse.

In the period from 1971 to 1986, both sexes of the B6CF1 (C57BL/6 x BALB/c) mouse were exposed at 110 +/- 7 days of age to single, 24 once-weekly or 60 once-weekly doses of fission neutrons or 60Co gamma rays. A small group of males was also exposed to gamma rays for 22 h/day, 5 days/week, for either 23 or 59 weeks, the elapsed times for the 24 and 60 once-weekly series. All mice were followed for their natural lifetimes. A gross pathology report is available on 32,000 animals, and a histopathology record is available on about 19,000. About 85% died with or from one or more neoplastic diseases. The principal tumors observed at death were of lymphoreticular (45-60%), vascular (20%), or pulmonary (35-50%) origin. From 4 to 10% died with fibrosarcomas, hepatocellular tumors, ovarian tumors, and tumors of the Harderian, adrenal, and pituitary glands. Dose-response equations (linear and linear-quadratic) were fitted to the data for deaths from and occurrences of eight different individual or groups of tumors. Equations were constrained through the control intercepts and fitted separately for the two sexes, the two radiation qualities, and all exposure patterns for the two intervals of 600-799 days and 800-999 days from first exposure. RBE values were derived from the ratios of linear coefficients of dose-response curves. RBE values increased as dose was protracted, largely due to the reduced effectiveness of protracted gamma irradiation; however, about 28% of the increase can be attributed to the increase in neutron-induced injury caused by dose protraction. Highest RBE values were seen for tumors of epithelial tissue origin and the lowest for tumors of connective tissue origin. The range for significant values was from about 2 to over 50. Nonneoplastic diseases accounted for about 5% of all deaths, and 10% were classified as from unknown causes. Neither category responded to differences in radiation quality or exposure patterns.

Age Factors↗

PubMed1991

Protection against late effects of radiation by S-2-(3-aminopropylamino)-ethylphosphorothioic acid.

We have demonstrated that S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR2721) administered to mice 30 min prior to a relatively low dose of ionizing radiation is effective in protecting against radiation-induced carcinogenesis and subsequent life shortening. Female C57BL/6JANL x BALB/cJANL F1 mice, 200 per group, were exposed to gamma radiation at a dose of 206 cGy. Additional groups of 200 animals were sham treated, given injections of 400 mg/kg of WR2721, or administered WR2721 and the irradiated with 60Co photons at doses of 206 cGy or 417 cGy. Mice were treated at 110 days of age. They were housed five to a cage and were checked daily throughout life. All deceased animals were necropsied, and tissues were removed and fixed for histopathological analysis. Over 90% of the animal deaths were due to tumor involvement. WR2721 afforded significant protection (P = 0.0016) against radiation-induced malignancies (i.e., a total of 164 tumor codes were used) following a dose of 206 cGy. Protection against lymphoreticular tumors in particular was significant (P = 0.0165). Subsequent survival time in WR2721-protected animals (compared with matched irradiated controls) was extended by 65 days. Mice irradiated with 417 cGy following administration of WR2721 exhibited a response similar to those irradiated without the protector at a dose of 206 cGy (P = 0.26). Cumulative survival curves for unirradiated mice were unaffected by a single dose of WR2721. These data indicate a potential novel benefit for radioprotectors in cancer therapy. WR2721 and similar aminothiols may be effective adjuvants for reducing the risk of therapy-induced secondary cancers in patients who have an excellent prognosis for cure and long-term survival.

Amifostine↗

PubMed1991

Protection by WR-151327 against late-effect damage from fission-spectrum neutrons.

The mutagenic and carcinogenic properties of fission-spectrum neutrons (KERMA-weighted mean energy of 0.85 MeV) from Argonne National Laboratory's JANUS reactor are substantially greater than those of low-LET radiation sources such as X-ray and 60Co photons. However, in contrast to the vast amount of work focused on chemical protection against damage induced by low-LET radiation, studies on the prevention of carcinogenic damage induced by fission neutrons have been limited. We have investigated the protective properties of the thiophosphorate compound S-3-(3-methylaminopropylamino)propylphosphorothioic acid (WR-151327) against carcinogenesis and life shortening in the B6CF1 hybrid mouse strain. Male and female mice, 200 of each sex per experimental group, were irradiated individually at 110 days of age. WR-151327 was administered intraperitoneally at a dose of 580 mg/kg 30 min prior to irradiation with a dose of 10 cGy. Animals were housed five to a cage; cage locations in holding rooms were controlled by computer and randomized. Mice were checked daily and all deceased animals were necropsied. A neutron dose of 10 cGy significantly altered the patterns of death of male and female animals compared to corresponding unirradiated control groups (logrank P values of 0.01 and 0.07, respectively). This was evidenced by a shortening of the life span due to tumor induction in the irradiated groups. WR-151327, when administered 30 min prior to irradiation, effectively protected both male and female animals from these effects. The life curves of irradiated male and female animals and those of corresponding unirradiated control groups were not significantly different (logrank P values of 0.63 and 0.25, respectively).

Animals↗

PubMed1991

Issues about neutron effects: the JANUS program.

The impact of the biological end point selected as a synoptic measurement of mortality for the detection of protraction effects and the estimation of RBE values was investigated. Life shortening was chosen as an end point because it summarizes, in a single index, the cumulative effect of all injuries experienced by an organism. Cumulative mortality at a single time point and the hazard function (age-specific failure rate) were chosen to incorporate progressively more information, respectively, about the distribution of mortality through time. Data for both sexes of the B6CF1 mouse exposed to fission neutrons from the JANUS biomedical research reactor and 60Co gamma rays were analyzed. Three basic patterns of exposure were compared: single exposures, 24 equal once-weekly exposures, and 60 equal once-weekly exposures. The interpretation of results was influenced by the biological end point used as the synoptic measurement. An augmented response with protraction of the neutron exposure depended on the accumulated dose using the life-shortening response while this effect was nonexistent when cumulative mortality or the hazard function was used. A reduced effectiveness of protracted gamma-ray exposures was apparent for all end points. The hazard function analyses suggest that the time domain must be considered in the detection of protraction effects for either radiation quality and the subsequent estimation of RBE values.

Animals↗

PubMed1991

Responses of the beagle to protracted irradiation. I. Effect of total dose and dose rate.

The effects of protracted exposure to 60Co gamma rays on survival and tumor induction in the beagle were investigated. Total accumulated doses of 450, 1050, 1500, and 3000 cGy were given at rates of 3.8, 7.5, 12.8, and 26.3 cGy/day. Hazard models were used to identify trends in mortality associated with radiation exposure. The probability of an acute death (related to hematopoietic aplasia) was positively associated with the total dose received and the rate at which the dose was delivered. Once an animal survived the initial hematopoietic effects of radiation exposure, the risk of death from causes other than cancer, while elevated, was far less responsive than the neoplastic end points. No relationship between tumor or chronic nontumor deaths and dose rate could be identified. However, survival curves for tumor mortality did separate into a pattern clearly dependent on the accumulated dose.

Animals↗

PubMed1990

In search of Methuselah: estimating the upper limits to human longevity.

Estimates of the upper limits to human longevity have important policy implications that directly affect forecasts of life expectancy, active life expectancy, population aging, and social and medical programs tied to the size and health status of the elderly population. In the past, investigators have based speculations about the upper limits of human longevity on observations of past trends in mortality. Here the estimate of the upper bound is based on hypothesized reductions in current mortality rates necessary to achieve a life expectancy at birth from 80 to 120 years and an expectation of life at age 50 from 30 to 70 years. With the use of conditional probabilities of death from complete life tables for the United States, reductions in mortality required to achieve extreme longevity (that is, 80 to 120 years) were compared with those resulting from hypothetical cures for all cardiovascular diseases, ischemic heart disease, diabetes, and cancer. Results indicate that in order for life expectancy at birth to increase from present levels to what has been referred to as the average biological limit to life (age 85), mortality rates from all causes of death would need to decline at all ages by 55%, and at ages 50 and over by 60%. Given that hypothetical cures for major degenerative diseases would reduce overall mortality by 75%, it seems highly unlikely that life expectancy at birth will exceed the age of 85.

Female↗

PubMed1989

Blood responses under chronic low daily dose gamma irradiation: I. Differential preclinical responses of irradiated male dogs in progression to either aplastic anemia or myeloproliferative disease.

Male beagles chronically exposed to low daily doses of 60Co gamma rays (7.5 cGy/22h/day) show one of three hematopoietic patterns, which reflect three different distinctly responding subgroups: (1) low radioresistance with progressing aplastic anemia and shortened survival (-S-AA subgroup); (2) high radioresistance with a complex of progressing myeloproliferative disorders (+R-MPD group); or (3) high radioresistance with other nonMPD syndromes (+R-nonMPD group). Blood cell levels (granulocytes, monocytes, erythrocytes, lymphocytes, and platelets) were assessed and fitted to a flexible polynomial spline model, thus defining the (a) initial suppressive and (b) subsequent recovery phases for the subgroups. Results showed that relative to the overall magnitude of blood cell loss as well as to the maximum rate of suppression during the initial phase, the subgroups were generally ranked -S-AA much greater than +R-MPD greater than +R-nonMPD. Relative to the overall strength of the recovery response, the subgroups were generally ranked +R-MPD greater than +R-nonMPD much much greater than -S-AA. In terms of overall maintenance levels of circulating blood cells during the recovery phase, however, the +R-nonMPD subgroup consistently exhibited stronger responses than the +R-MPD subgroup. These results tend to support our contention that selected subgroups of dogs have strong propensities to specific hematopathologies (i.e. aplastic anemia and myeloid leukemia) under chronic irradiation and that these pathology-prone animals exhibit a series of marked differential hematopoietic responses during early preclinical phases, which serve effectively to prognosticate subsequent pathological progression.

Adaptation, Physiological↗

PubMed1989

DNA damage and repair in rodent and human cells after exposure to JANUS fission spectrum neutrons: a minor fraction of single-strand breaks as revealed by alkaline elution is refractory to repair.

We have examined the induction and repair of breaks induced in the DNA of Chinese hamster V79 and human P3 epithelial teratocarcinoma cells by JANUS fission-spectrum neutrons (mean energy 0.85 MeV) and 60Co gamma radiation in the biological dose range, using alkaline filter elution methods. Fission-spectrum neutrons induce fewer immediate single-strand breaks (ssb) per gray of absorbed dose than do gamma rays, as measured by alkaline elution methods. Previous survival measurements have indicated incomplete recovery after neutron exposures. The present data demonstrate that whereas most ssb caused by exposure to fission-spectrum neutrons can be rapidly repaired by both cell lines, a small but statistically significant fraction of the ssb induced by exposure to 6 Gy of neutrons is refractory to repair. In contrast, all measurable ssb induced by 3 Gy gamma rays are rapidly repaired.

Animals↗

PubMed1989

Dose-response modeling of life shortening in a retrospective analysis of the combined data from the JANUS program at Argonne National Laboratory.

Life shortening was investigated in both sexes of the B6CF1 (C57BL/6 x BALB/c) mouse exposed to fission neutrons and 60Co gamma rays. Three basic exposure patterns for both neutrons and gamma rays were compared: single exposures, 24 equal once-weekly exposures, and 60 equal once-weekly exposures. Ten different dose-response models were fitted to the data for animals exposed to neutrons. The response variable used for all dose-response modeling was mean after-survival. A simple linear model adequately described the response to neutrons for females and males at doses less than or equal to 80 cGy. At higher neutron dose levels a linear-quadratic equation was required to describe the life-shortening response. An effect of exposure pattern was observed prior to the detection of curvature in the dose response for neutrons and emerged as a potentially significant factor at neutron doses in the range of 40-60 cGy. Augmentation of neutron injury with dose protraction was observed in both sexes and began at doses as low as 60 cGy. The life-shortening response for all animals exposed to gamma rays (22-1918 cGy) was linear and inversely dependent upon the protraction period (1 day, 24 weeks, 60 weeks). Depending on the exposure pattern used for the gamma-ray baseline, relative biological effectiveness (RBE) values ranged from 6 to 43. Augmentation, because it occurred only at higher levels of neutron exposure, had no influence on the estimation of RBEm.

Animals↗

PubMed1989

Protection by WR1065 and WR151326 against fission-neutron-induced mutations at the HGPRT locus in V79 cells.

The radioprotectors WR1065 and WR151326, each at a concentration of 4 mM, protect against cell killing and mutagenesis at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus in V79 Chinese hamster fibroblast cells exposed to fission-spectrum neutrons (mean energy of 0.85 MeV) from the JANUS reactor. Significant protection against neutron-induced cell lethality occurred only when the radioprotectors were present during irradiation; e.g., D0's and n's were 82 Gy, 1.27 for control cells; 97 Gy, 1.51 for WR1065-protected cells; and 120 Gy, 1.00 for WR151326-protected cells, respectively. Mutation induction by JANUS fission-spectrum neutrons was linear over the dose range tested giving rise to a mutation frequency of 109.3 x 10(-6)/Gy. In comparison with 60Co gamma rays (mutation frequency 8.7 X 10(-6)/Gy), JANUS neutrons, at a dose rate of 24 cGy/min, were over 12 times more effective in inducing HGPRT mutations. Both WR1065 and WR151326 afforded protection against the induction of mutants by neutrons, even when they were administered up to 3 h after irradiation; i.e., mutation frequencies were 40.9, 48.8 and 68.6 X 10(-6)/Gy for WR1065 present during, present immediately after, or added 3 h after irradiation, respectively; and 61.7, 47.8, and 68.5 X 10(-6)/Gy for WR151326 present at the same times.

Animals↗

PubMed1988

Comparative developmental and phenotypic properties of altered hepatocyte foci and hepatic tumors in rats.

Previous investigations in this laboratory have provided evidence that histochemically detectable altered hepatocyte foci and hepatic tumors appearing in rats given a single neonatal treatment with a low dose of carcinogen followed by chronic dietary phenobarbital administration are developmentally independent. The present investigation further evaluates developmental relationships among these lesions. Altered hepatocyte foci were divided into two subclasses consisting of foci that were detectable by histochemical as well as by hematoxylin-eosin staining [designated hist(+)/morph(+) foci] and those foci that were detectable solely by histochemical staining [designated hist(+)/morph(-) foci]. The developmental and phenotypic properties of the hist(+)/morph(-) foci, hist(+)/morph(+) foci, and hepatic tumors were compared in rats initiated once neonatally with different doses of diethylnitrosamine and promoted with dietary phenobarbital from weaning. The morph(+) and morph(-) lesion subclasses were distinguishable on the basis of several developmental characteristics. Hist(+)/morph(+) foci were present at low frequency until at least 150 days after initiation. Although the development of hist(+)/morph(-) foci was essentially complete at that point, the rate of appearance of hist(+)/morph(+) increased significantly. The diethylnitrosamine dose response of the hist(+)/morph(+) foci followed the histochemical marker patterns of the tumor lesion class more closely than that of the hist(+)/morph(-) group. The rates of expression of the hist(+)/morph(+) foci increased with the increasing level of histochemical complexity, whereas the rates of expression of the hist(+)/morph(-) foci groups were inversely correlated to their complexity level. Although the average focus size or diameter in the hist(+)/morph(+) groups was greater than that of the hist(+)/morph(-) foci, the focus growth rates of morph(+) and morph(-) subsets matched for histochemical phenotype were comparable. The complexity level and individual marker distribution patterns of the hist(+)/morph(+) focus class were more similar to tumor patterns than to the distribution patterns of the hist(+)/morph(-) lesion class. The results suggest the following. (a) The development of lesion classes with successively greater deviation from normalcy does not occur via lineal progression from less to more deviated forms within a given lesion class. The three lesion classes appear to develop independently, with the developmental characteristics of each lesion class determined at the time of initiation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1988

Genetic injury in hybrid male mice exposed to low doses of 60Co gamma-rays or fission neutrons. III. Frequencies of abnormal sperm and reciprocal translocations measured during and following long-term weekly exposures.

Male B6CF1 mice were exposed to either fission neutrons or 60Co gamma-rays at once-weekly doses approaching occupational levels for periods up to 60 weeks. Both during and after the irradiation sequence, the mice were screened to determine the incidence of abnormal epididymal sperm and of reciprocal chromosome translocations in metaphase spermatocytes. Abnormal sperm frequencies equilibrated with dose/week by 10 weeks and also showed an additive nonlinear seasonal increment. The relative biological effectiveness (RBE) for these damages is 12 +/- 1. After exposures ended, sperm frequencies in gamma-irradiated mice quickly returned to near-normal levels. Neutron-irradiated males showed a significantly elevated level of abnormalities for approximately 30 weeks--a paradoxical finding--as no clear evidence of cumulative injury was seen during exposure. When assayed at 10 and 25 weeks of exposure but not later, translocation frequencies demonstrated an increment, significant in the neutron series, attributed to irradiated spermatocytes. Dose-response analysis with cumulative dose up to the 60-week maximum gave an RBE of 45 +/- 10. Post exposure, the incidence of translocations subsided slightly, but the RBE remained above 30.

Animals↗

PubMed1988

Skeletal changes in multiparous mice fed a nutrient-sufficient diet containing cadmium.

Female mice were given nutrient-sufficient, purified diets containing either 0.25, 5, or 50 ppm Cd. One-half of the females were bred for 6 consecutive 42-day rounds of pregnancy/lactation (PL mice); remaining females were non-pregnant controls (NP mice). PL mice and NP controls were sacrificed after 1, 2, 4, or 6 consecutive rounds of pregnancy/lactation. No consistent, cadmium-dependent decreases in body weight, femur calcium content, or calcium/dry weight (Ca/DW) ratio occurred among the NP mice during the 252 days of cadmium exposure. In contrast, significant, cadmium-dependent decreases in body weight (3-11%), femur calcium content (15-27%), and Ca/DW ratio (5-7%) occurred in the multiparous mice exposed to 50 vs 0.25 ppm Cd. In addition, among the PL mice, the effect of cadmium was dose-dependent, with femur calcium contents decreasing significantly as the cadmium exposure level increased from 0.25 to 5 then 50 ppm Cd (P less than 0.05). Results demonstrate that dietary cadmium exposure had a greater effect on the skeletons of dams exposed to cadmium during the stresses of pregnancy and lactation than in non-pregnant controls. The results provide evidence that the combination of cadmium exposure and multiparity may have played a role in the etiology of Itai-Itai disease in Japan.

Administration, Oral↗

PubMed1988

Kidney changes in multiparous mice fed a nutrient-sufficient diet containing cadmium.

Female mice were given nutrient-sufficient, purified diets containing cadmium at either 0.25, 5, or 50 ppm, as described in the accompanying publication. One-half of the females were bred for 6 consecutive 42-day rounds of pregnancy/lactation (PL mice); remaining females were non-pregnant controls (NP mice). PL mice and NP controls were sacrificed after 1, 2, 4, or 6 consecutive rounds of pregnancy/lactation. At all levels of dietary cadmium and after all reproductive rounds, kidney cadmium concentrations were 2-5-fold higher in PL than NP mice. After 6 rounds of reproduction, the mean concentration of cadmium in the kidneys of PL mice exposed to dietary cadmium at 50 ppm was 115 micrograms Cd/g kidney, close to the critical concentration for cadmium-induced renal damage (200 micrograms/g). No consistent increases in the concentrations of amino acids, protein, or cadmium in urine were observed in the NP or PL mice in our study, indicating that cadmium-induced renal dysfunction had not yet appeared. Very small increases in kidney concentrations of zinc and copper were observed with large increases in kidney cadmium concentrations. Threshold cadmium concentrations below which the concentrations of zinc and copper were relatively constant and independent of cadmium concentration were identified; they were 7.2 micrograms Cd/g kidney for zinc and 13 micrograms Cd/g kidney for copper. In this study, cadmium-induced decreases in bone-mineral content occurred in the PL mice exposed to cadmium at 5 and 50 ppm (see accompanying publication). Data presented here indicate that the latter bone changes occurred in the absence of cadmium-induced renal dysfunction of the type that results in increased aminoaciduria/proteinuria. They suggest that the bone disease of Itai-Ital patients may also have started prior to the onset of this type of renal dysfunction.

Administration, Oral↗

PubMed1988

Female reproduction and pup survival and growth for mice fed a cadmium-containing purified diet through six consecutive rounds of gestation and lactation.

Female CF1 mice were bred for 6 consecutive, 42-d rounds of gestation-lactation. Their purified diets contained cadmium added at either 0.25, 5.0, or 50.0 ppm Cd; at each cadmium level, the diets were either sufficient or deficient in certain vitamins, minerals, and fat. The deficient diet at 5 ppm cadmium was designed to simulate conditions implicated in the etiology of itai-itai disease among multiparous women in Japan. Fertility, litter size, pup survival, and pup growth (weaning weight) are reported for mice on the six diets during each of the six rounds of gestation/lactation. Except for fertility, decreases in reproductive measures that occurred in response to dietary deficiencies or cadmium during round 1 of reproduction were repeated, unchanged in magnitude, in each successive round. For sufficient diet groups, 50 ppm cadmium had no effect on fertility or pup survival during lactation, but caused a 15% decrease in litter size at birth and a 25% decrease in pup growth. Dietary deficiencies alone decreased all four measures of reproductive performance: fertility by 12%, litter size by 30%, pup survival by 18%, and pup growth by 42%. In addition, dietary deficiencies strikingly decreased the incidence of consecutive pregnancies. Combined effects of 50 ppm cadmium and dietary deficiencies were additive for all reproductive measures except fertility; for fertility, cadmium caused no decrease in the fertility of sufficient-diet animals, but caused a striking 45% decrease in deficient-diet animals. Relating our results to humans, women who contracted itai-itai disease (analogous to mice on the deficient, 5 ppm cadmium diet), in addition to their characteristic bone disease, could have experienced decreases in fertility and in growth of their offspring related to their dietary deficiencies. In addition, their diet-related decreases in fertility could have been enhanced by their combined exposure to cadmium.

Animals↗

PubMed1987

Phenotypically selective promotion of diethylnitrosamine-initiated altered hepatocyte foci by dietary phenobarbital or a topically applied coal-derived organic mixture in male and female rats.

Relative frequencies of diethylnitrosamine (DEN)-initiated foci of altered hepatocytes appearing in response to promotion by either dietary phenobarbital or a topically applied coal-derived organic mixture (CDM) were investigated in male and female rats. The focus population was examined for two histochemical markers, elevated gamma-glutamyl transpeptidase [GG(+)] and iron exclusion [FE(-)], giving rise to 3 detectable focus phenotypes, i.e., GG(+) foci, FE(-) foci, and GG(+)/(FE(-) foci. Frequencies of the 3 phenotypes were quantitated through the use of serial frozen sectioning and computer-assisted image analysis. In agreement with our prior observations, cutaneous exposure to CDM or dietary phenobarbital promoted the expression of DEN-initiated foci. However, the current data showed that this promoting effect of CDM occurred only in females and was restricted to foci with the GG(+)/FE(-) phenotype. Dietary phenobarbital, on the other hand, promoted both the GG(+) and GG(+)/FE(-) phenotypes and was effective in both males and females, although a sex-related differential in the promoting efficiency of phenobarbital was also observed. The pronounced heterogeneity in the responses of the 3 focus phenotypes suggests that each phenotype is the consequence of a specific type of genomic alteration with a specific capacity to undergo phenotypic expression in response to a given promoting stimulus.

Administration, Topical↗

PubMed1987

Effects of rat strain, diet composition, and phenobarbital on hepatic gamma-glutamyl transpeptidase histochemistry and on the induction of altered hepatocyte foci and hepatic tumors by diethylnitrosamine.

To extend our ongoing characterization of modulatory influences on hepatic tumorigenesis, we examined effects of rat strain (Sprague-Dawley versus Fischer), diet composition (semipurified diet versus standard nonpurified laboratory chow), and dietary phenobarbital on the production of gamma-glutamyl transpeptidase (GGT)-positive hepatocyte foci and hepatic tumors initiated by diethylnitrosamine. In addition to GGT-positive foci, we observed, under certain conditions, the appearance of extensive hepatic GGT staining not associated with focal lesions. This elevated nonfocal GGT was found in rats of both strains fed the nonpurified rather than the purified diet, but the level of staining was higher in Fischer than in Sprague-Dawley rats. Enhancement of this nonfocal staining by dietary phenobarbital appeared insignificant. By comparison, frequencies of GGT-positive foci were generally higher in rats fed the semipurified rather than the nonpurified diet, and the frequencies of GGT-positive foci were invariably higher in Sprague-Dawley than in Fischer rats. Moreover, dietary phenobarbital generally enhanced focus production. Assessments of focus and tumor yields among these experimental groups showed that differences in focus frequencies did not correspond closely to differences in subsequent tumor formation. These results document the need to consider the influences of diet and rat strain on experimental end points in designing protocols for hepatocarcinogenesis studies, especially those involving GGT histochemistry. The data also raise questions about the mechanistic relevance of GGT induction to hepatocarcinogenesis and support our prior evidence against the putative lineal relationship between foci and tumors.

Animals↗