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P Grasso

Publications and source records attributed to P Grasso.

At least 19 recordsLinked to original sources
PubMed1992

Structural response of the hamster Sertoli cell to hypophysectomy: a correlative morphometric and endocrine study.

Reproductively active hamsters were hypophysectomized and examined 6 or 20 days later in a combined morphometric and endocrine study of the Sertoli cell to determine 1) the morphological and endocrine effects of hypophysectomy of both short- and long-term duration, 2) if regression of Sertoli cells after hypophysectomy in a seasonal breeder resembles regression due to seasonal changes, and 3) if effects of hypophysectomy in a seasonal breeder are equivalent to the effects of hypophysectomy in a nonseasonal breeder. Six days after hypophysectomy, at a period when germ cell degeneration is first noted, there was a significant decrease in testis weight, interstitial space, tubule diameter and length, volume of seminiferous tubule, and tubular lumen. There were no significant changes in Sertoli cell nuclear and cytoplasmic volume although cell surface area was decreased significantly. Most organelles exhibited no significant change in volume or surface area except for secondary lysosomes which expectedly increased in volume as the result of phagocytosis of germinal cells. Thus at an early time period when functional changes in germ cells and Leydig cells are clearly evident (Russell et al. [1992] Endocrinology), the Sertoli cell shows minimal changes. Twenty days after hypophysectomy, the cell, nuclear and cytoplasmic volumes and surface area of the Sertoli cells, and volumes and surface areas of nearly all organelles were significantly decreased from values measured in normal and in short-term hypophysectomized hamsters. The exceptions were the total volumes of lipid which increased significantly and lysosomes which were similar to normal but significantly lower than short-term hypophysectomized animals. The long-term hypophysectomized hamster Sertoli cell, like that of the short-day hamster (Sinha Hikim et al. [1989b] Endocrinology, 125:1829-1843) is structurally regressed as a whole rather than exhibiting selective decreases in cellular and subcellular components. The size of the Sertoli cell in pituitary-intact, long- and short-term hypophysectomized animals showed positive and significant correlations with the volumes and surface areas of all its cytoplasmic organelles except the volume of lipid which showed a negative, significant correlation. Comparisons of long-term hypophysectomized hamsters (in long-day light exposure) and short-day exposed animals (Sinha Hikim et al. [1989b] (Endocrinology, 125:1829-1843) suggested that hypophysectomy, in general, resulted in similar, but slightly more severe regressive changes in the testis and germ cell population than those seen during seasonal regression.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Stabilization of follicle-stimulating hormone-receptor complexes may involve calcium-dependent transglutaminase activation.

Calcium-dependent transglutaminase (TGase) activity, determined by incorporation of [1,4-14C]diaminobutane dihydrochloride (putrescine) into casein, was demonstrated in a light membrane fraction prepared from bovine calf testicular homogenates. Purification of these membranes by sucrose density gradient centrifugation produced a follicle-stimulating hormone (FSH) receptor-enriched fraction containing TGase activity which cosolubilized with the FSH receptor and could be incorporated with detergent-solubilized receptor into liposomes. In the present study, we show that calcium increases specific binding of FSH to receptor in a concentration-related manner, and is associated with an increase (13.2-fold at 20 mM) in the affinity (Ka) of the receptor with no significant (P greater than 0.05) change in receptor concentration. Treatment of the light membrane fraction with monodansylcadaverine (MDC, 1 mM), a specific inhibitor of TGase, did not affect specific binding of FSH, but resulted in only a 3.9-fold increase in Ka at 20 mM calcium with no change in receptor concentration. Specific binding of FSH to receptor at 4 degrees C was also enhanced by calcium. Scatchard analysis of competitive binding inhibition data showed a Ka at 20 mM calcium similar to that observed with MDC. Dissociation of [125I]hFSH-receptor complexes formed at 30 degrees C in the presence of calcium was significantly less than dissociation of complexes formed at 30 degrees C in the absence of calcium. When [125I]hFSH-receptor complexes were formed at 30 degrees C in the presence of calcium and dissociated in calcium-deficient buffer, dissociation increased 3-fold. Similar results were obtained in the presence of MDC.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Alcohol and cancer.

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Alcohol Drinking↗
PubMed1992

Synthetic human follicle-stimulating hormone-beta-(1-15) peptide-amide binds Ca2+ and possesses sequence similarity to calcium binding sites of calmodulin.

To determine the basis for the previously demonstrated calcium requirement for specific binding of FSH to receptor, 11 overlapping peptide amides representing the entire primary structure of human FSH (hFSH)-beta-subunit were tested for their ability to bind 45Ca2+ as an approach to identifying possible calcium binding regions of the hormone. hFSH-beta-(1-15)-peptide amide bound significant amounts of 45Ca2+. This peptide contains an amino acid sequence similar to that found in the loop structures of the calcium-binding domains of calmodulin. The affinity of hFSH-beta-(1-15)-peptide amide for calcium (Kd = 1.2 +/- 0.3 mM) was similar to that previously reported for a synthetic peptide corresponding to calmodulin binding site III. No such sequence is predicted in the recently deduced primary structure of the FSH receptor. FSH-beta-(1-15) may, therefore, be associated with the calcium requirement for specific binding of FSH to receptor. The calcium binding property of this calmodulin-like peptide also correlates well with its ability to induce uptake of calcium into liposomes via transmembrane channel formation, as previously reported by this laboratory.

Amino Acid Sequence↗
PubMed1992

Structural manifestations of the rat Sertoli cell to hypophysectomy: a correlative morphometric and endocrine study.

Although the Sertoli cell is a key cell mediating the actions of FSH- and LH-stimulated testosterone (T) in the testis, there is little information to indicate how this cell responds structurally to hormonal insufficiency. The present study used morphometric techniques to study the structural manifestations of the Sertoli cell in adult rats hypophysectomized for 6 and 28 days. Six days posthypophysectomy, a period when germ cell degeneration is first evident, tubular diameter and length, testis weights, volume of the interstitium, and volume of most parameters that comprise the interstitium (except blood vessels) showed significant regressive features. However, virtually no parameter relating to the volume and surface area of the Sertoli cell or its subcellular components was significantly reduced compared with that in the normal animal. Thus, at a time when germ cell degeneration is seen in the testis, the Sertoli cell showed no significant structural response to the changing endocrine status of the animal. In contrast, 28 days after hypophysectomy, virtually all parameters relating to the Sertoli cell and its organelles were significantly decreased compared with those in normal animals. Plasma and tissue testosterone, PRL, and FSH showed a very significant decrease 6 days after hypophysectomy compared with intact animals, but at 28 days there was no further significant decrease in the levels of these hormones. There was no correlation of most organelle volumes and surface areas with endocrine parameters. The size of the Sertoli cell showed positive and significant correlations with the volumes and surface areas of all of its cytoplasmic organelles, except the lipid volume. Short term hypophysectomy resulted in no significant change in either the concentration (femtomoles per mg protein) or the content (femtomoles per testis) of FSH receptors, nor was there a significant change in the number of FSH receptors per cell. However, 28 days after hypophysectomy only the content, not the concentration, of FSH receptors decreased significantly along with a decrease in the number of FSH receptors per cell. Although the marked degenerative changes that are seen in the testis 6 days after hypophysectomy parallel endocrine decline, the Sertoli cell responded slowly from a structural standpoint compared with the Leydig cell. After long term hypophysectomy, significant morphometric changes were observed in all of its structural parameters.

Animals↗
PubMed1992

Correlation of follicle-stimulating hormone (FSH)-receptor complex internalization with the sustained phase of FSH-induced calcium uptake by cultured rat Sertoli cells.

We have previously reported that synthetic peptide amides corresponding to regions of the beta-subunit of human FSH [hFSH-beta-(1-15) and hFSH-beta-(51-65)] have the ability to bind calcium and to facilitate its entry into liposomes. In the present study, we have examined the ability of synthetic peptides corresponding to the entire primary structure of hFSH-beta-subunit, to induce calcium influx in cultured rat Sertoli cells. Calcium (as 45Ca2+) uptake in response to 50 microM hFSH-beta-(1-15), hFSH-beta-(21-35), or hFSH-beta-(51-65) peptide amides was 2.5-, 2.4-, and 2.0-fold higher, respectively, than basal uptake. Pretreatment of Sertoli cells for 5 min with phenylarsine oxide (PAO, 80 microM), an inhibitor of receptor-mediated endocytosis, significantly (P < 0.05) reduced 45Ca2+ influx in response to hFSH-beta-(1-15), hFSH-beta-(21-35), and hFSH-beta-(51-65). A delay of 20 min was required, however, before the inhibitory effect of PAO on 45Ca2+ uptake was observed. Specific binding of [125I] hFSH to receptor at 4 C was unaffected by PAO. After 2 h at 37 C, however, approximately 1.6-fold more [125I]hFSH specifically bound at 4 C could be dissociated from the cell surfaces of PAO-pretreated Sertoli cell monolayers, compared to untreated monolayers. This result is consistent with an inhibitory effect of PAO on FSH receptor internalization. Chloroquine (at 100 microM), a lysosomotropic agent known to block FSH degradation, also significantly (P < 0.05) inhibited FSH-induced 45Ca2+ uptake. Extending our earlier studies, these results suggest that the sustained (> 20 min) phase of FSH-induced calcium uptake, also seen in response to synthetic hFSH-beta-(1-15), hFSH-beta-(21-35), and hFSH-beta-(51-65) peptide amides, may occur as a consequence of FSH-receptor complex internalization and FSH degradation. Vesicular uptake of extracellular calcium, which accompanies internalization of FSH-receptor complexes, and release of channel-forming peptides by lysosomal hydrolysis of FSH suggests a novel mechanism whereby FSH increases intracellular calcium levels in Sertoli cells.

Animals↗
PubMed1991

Effects on 4080 rats of chronic ingestion of N-nitrosodiethylamine or N-nitrosodimethylamine: a detailed dose-response study.

Four thousand eighty inbred rats were maintained from weaning on various different concentrations of N-nitrosodiethylamine (NDEA) or N-nitrosodimethylamine (NDMA). The principal aim was to characterize the dose-response relationship for the effects of these agents on esophageal cancer (NDEA) or on various types of liver cancer (NDEA and NDMA), although NDEA also caused a few tumors of the nasopharynx and NDMA also caused a few tumors of the lung. The numbers of tumors of mesenchymal and Kupffer cells in the liver were too few to allow easy characterization of the dose-response relationships, and although NDMA induced large numbers of bile duct neoplasms, NDEA did not. Thus, the four principal dose-response relationships studied were of NDEA on esophageal or liver cells and of NDMA on bile duct or liver cells. At doses sufficiently high for the median time to death from the disease of interest to be estimated, relationships were observed of the general form (Dose rate) x (median)n = constant where n was about 2.3 for the first three relationships and about 1 for the last one (NDMA on liver cell tumors). By contrast, at doses sufficiently low for longevity to be nearly normal (median survival about 2.5 years), there remained no material dependence on the dose rate of the age distribution of the induced neoplasms. At these low dose rates, the number of liver (but not of esophageal) neoplasms induced by treatment was simply proportional to the dose rate. This finding is not surprising, since the background incidence of liver (but not of esophageal) neoplasms was appreciable. The linear relationship observed at low dose rates (below 1 ppm) suggests that under these experimental conditions, among rats allowed to liver their natural life span, a dose of 1 ppm of NDEA or NDMA in the drinking water will cause about 25% to develop a liver neoplasm, a dose of 0.1 ppm will cause about 2.5% to do so, and a dose of 0.01 ppm will cause about 0.25% to do so, etc., with no indication of any "threshold." (At these low dose rates, the incidence of liver neoplasms appears likely to exceed greatly that of esophageal neoplasms.) In addition, even quite low dose rates of the test agents caused a variety of nonneoplastic liver abnormalities (e.g., hyperplastic nodules, or shrinkage of hepatocytes) at a frequency roughly proportional to the dose rate.

Animals↗
PubMed1991

Dose and time relationships for tumor induction in the liver and esophagus of 4080 inbred rats by chronic ingestion of N-nitrosodiethylamine or N-nitrosodimethylamine.

A Weibull analysis is presented of the dose and time relationships for the effects on 4080 inbred rats of chronic ingestion in the drinking water of 16 different doses of N-nitrosodimethylamine (NDMA) or N-nitrosodiethylamine (NDEA). The sites chiefly affected were the liver (by both agents) and the esophagus (by NDEA only). Since the experiment continued on into extreme old age, effects became measurable at doses of only 0.01 to 0.02 mg/kg/day, which is an order of magnitude lower than previously achieved. (After only 2 years of treatment, however, the TD50 doses needed to halve the proportion of tumorless survivors would have been about 0.06 mg/kg/day of NDEA, or about 0.12 mg/kg/day of NDMA.) The general pattern of response was that the natural logarithm of the probability of remaining tumorless was given by the product of two terms, the first (the "Weibull b value") depending on the dose rate but not on the duration of exposure and the second depending not on dose at all but only on duration. For all types of tumor the dependence on duration was fairly similar (and for each the second term was taken to be -t7, where t = years of treatment), but for different types of tumor the dependence on dose rate was quite different. For esophageal tumors, the "Weibull b value" was approximately proportional to the cube of the dose rate of NDEA (males 21 d3, females 11 d3, where d = dose rate in mg/kg adult body weight/day), and the background incidence was unmeasurably low. For liver tumors induced by NDEA, the b value was approximately proportional to the fourth power of dose rate + 0.04 mg/kg/day [males, 19 (d + 0.04)4; females, 32 (d + 0.04)4], although the relationships were somewhat different for the different cell types of liver tumor. This one formula implies both approximate linearity at low doses and an approximately cubic relationship within the higher range of doses that was studied. For liver tumors induced by NDMA, the Weibull b value was approximately proportional to the sixth power of dose rate + 0.1 mg/kg/day [males, 37 (d + 0.1)6; females, 51 (d + 0.1)6], again with some variation between liver cell types, and again implying approximate linearity at low doses. These algebraic formulae should, of course, be trusted only in the range of doses where they were derived, and particularly not above it.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed1991

Chronic nitrosamine ingestion in 1040 rodents: the effect of the choice of nitrosamine, the species studied, and the age of starting exposure.

In parallel with a larger experiment on 4080 rats fed 16 different concentrations of N-nitrosodiethylamine (NDEA) or N-nitrosodimethylamine (NDMA) from 6 weeks of age, a variety of smaller experiments on a total of 1040 rodents were undertaken and are the subject of the present report. Three separate subjects were addressed. Studies of 16 different concentrations of N-nitrosopyrrolidine and N-nitrosopiperidine given from age 6 weeks onwards to small groups of rats yielded dose-response relationships for the effects of N-nitrosopyrrolidine on liver tumors and for those of N-nitrosopiperidine on tumors of the liver and upper gastrointestinal tract that resembled those seen for NDMA and NDEA, respectively, except that N-nitrosopyrrolidine and N-nitrosopiperidine were less potent [the respective dose rates needed to halve the proportion of tumorless survivors after 2 years of treatment being approximately 0.4 (males) and 0.6 (females) mg/kg adult body weight/day for each agent]. Alternatively, it was estimated that the risks to rats from lifelong exposure to 1 microgram/kg adult body weight/day of each agent might be about 0.1%, and that the risks to rats from lower doses would be proportionately less. Studies of 16 different concentrations of NDEA on small groups of female mice and female hamsters yielded the types of dose response that would be expected for upper gastrointestinal tumors, liver cell tumors, and Kupffer cell tumors in mice (no other types of liver tumor being produced, in contrast with previous reports) and for tracheal and liver cell tumors in hamsters (no clear effect on upper gastrointestinal tumors being apparent in hamsters). The dose rates needed to halve the proportion of tumorless survivors after 2 years of treatment were approximately 0.3 mg/kg adult body weight/day, i.e., 5 times that for the same agent in rats. In part, however, this may be because treatment started at an older age in these species. Studies were undertaken of the effects on esophageal and liver tumorigenesis of starting the treatment of rats with NDEA at 3 or at 20 weeks of age instead of at 6 weeks of age (as in the main experiment). Earlier treatment resulted in slightly greater dosage rates, if dosage was measured in mg/kg/day, and hence in a correspondingly more rapid yield of esophageal tumors, but the effect was not large. By contrast, an earlier start to treatment resulted, after a fixed duration of treatment, in animals having a 3-fold higher incidence rate of liver tumors, while a later start resulted in a 2-fold decrease.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed1991

Sulfhydryl groups are involved in the interaction of FSH with its receptor.

FSH has recently been reported to possess thioredoxin-like activity, presumably explained by the homology between a region of FSH-beta subunit and the active site of thioredoxin. The homologous sequence lies within a receptor binding region, which suggests a possible role for sulfhydryl groups in the formation of an active hormone-receptor complex and subsequent signal transduction. In order to determine the relevance of sulfhydryl groups on FSH-receptor interaction, we studied the effect of N-ethylmaleimide (NEM) and glutathione on FSH binding. The results indicate that free sulfhydryl groups, probably derived from the FSH receptor, are involved in ligand-receptor interaction.

Animals↗
PubMed1991

Immunotoxicity of tri-n-butyltin oxide (TBTO) and tri-n-butyltin chloride (TBTC) in the rat.

In a 1-month feeding trial, pure and commercial tri-n-butyltin oxide (TBTO) and tri-n-butyltin chloride (TBTC) were fed to rats at concentrations of 5 ppm and 25 ppm. At all times, the mean body weight gain and the food consumption was significantly less in rats treated with 25 ppm pure TBTO or pure TBTC as compared to control rats or rats receiving commercial TBTO. Histological examination of the thymus of rats treated for 7 days with TBTO showed atrophy with severe lymphocytic depletion in the cortex. After 28 days of exposure, most of the lesions reversed and the thymus became markedly smaller than in control rats, both in absolute terms and in relation to body weight. Seven days of exposure to TBTO increased liver weight but this change was reversed during a further 3-week exposure. Tin concentrations were the highest in livers and kidneys. Concentrations in the thymus were less than one-fifth of hepatic values. Changes in the rats treated with the commercial TBTO were very similar. Rats treated with TBTC showed lower tin levels and less immunotoxicity as compared to those treated with TBTO.

Animals↗
PubMed1991

Evidence for and possible mechanisms of non-genotoxic carcinogenesis in rodent liver.

Doses of chemicals which induce hepatocellular necrosis usually induce hepatic tumours if the dosing is frequent and is maintained for long periods. Such necrosis is usually evident within 48 h of the first administration. Similarly, chemicals that lead to marked proliferation of peroxisomes in the liver also usually induce hepatic tumours on pretracked regular dosing. For both of these phenomena failure to produce a certain level of effect, or to maintain it for sufficiently long periods, can result in the observation of a non-carcinogenic response. The exact dose/time requirements for carcinogenicity have not been defined and may be species/strain/sex-specific. Some chemicals induce liver enlargement and mitogenesis in the absence of overt hepatotoxic effects. The early phases of hepatomegaly are associated with mitogenic effects that can be measured as cells in S-phase within the first few days of administration. The later stages of hepatomegaly appear to be associated more with cellular hypertrophy. Both effects appear to be threshold-related. Further, sustained hepatomegaly is associated with proliferation of SER and the induction of a range of liver enzymes. These changes (mitogenesis, hepatomegaly, enzyme induction), in isolation, are less definitive indicators of carcinogenicity, but they occur for a sufficient number of liver-specific carcinogens that their role as early indicators is worthy of confirmed study. The major area of study required for all possible early markers of hepatocarcinogenicity is to establish the dose and time dependence of these changes in relation to the eventual appearance of tumours. Finally, the specificity of all these markers require evaluation by the study of appropriate non-carcinogens.

Animals↗
PubMed1991

Evidence for and possible mechanisms of non-genotoxic carcinogenesis in mouse skin.

Most chemicals that produce skin cancer are genotoxic by in vitro and in vivo short-term assays and produce a high incidence of skin cancer within a year if optimal doses are applied. If in long-term skin painting studies one or two tumours in 50 mice are observed there is a general consensus that no carcinogenic activity can be claimed and it has been suggested that if up to 10% tumours are induced by irritant substances this could be due to an enhancement of spontaneous tumour incidence. Observations of skin tumour incidences higher than 10% with non-genotoxic substances, usually after a long latent period, is considered to represent evidence for a non-genotoxic mechanism. Examples of such substances include croton oil, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), sodium hydroxide, potassium hydroxide, phenol, dodecylbenzene and petroleum-derived middle distillates. Two distinct mechanisms appear to be involved in the production of tumours by a non-genotoxic substance. The first of these is that seen with the strong promoting agents. These, by binding to and activating protein kinase C, appear to directly stimulate sustained epidermal hyperplasia without severe skin damage. The other appears to involve substances producing severe skin damage either by a direct caustic effect or by cumulative irritancy. These changes give rise to marked epidermal hyperplasia with repeated episodes of regeneration and damage. The tumour induction by both mechanisms probably results from oncogene activation and it is possible that oxidative enzymes from inflammatory cells may be involved in the activation process. Various reasons are given why non-genotoxic carcinogenesis in the skin is considered not to be relevant to man and ways of recognising and avoiding its occurrence in animals studies are recommended.

Animals↗
PubMed1991

Structure--function relationships of the glycoprotein hormones and their receptors.

The primary structures of the glycoprotein hormones follitropin (FSH), lutropin (LH), human choriogonadotropin (hCG) and thyrotropin (TSH) have been determined, hCG has been crystallized and initial diffraction data obtained. Studies with synthetic peptides have provided information on regions involved in receptor interaction and signal transduction. The receptors for the glycoprotein hormones have been prepared by gene cloning methods and their primary structures deduced. As Leo Reichert and colleagues discuss here, although cAMP is involved in glycoprotein hormone signal transduction, recent evidence also implicates other second messengers, especially Ca2+ and may include both the phosphatidylinositol pathway and activation of Ca2+ channels.

Animals↗
PubMed1991

Early changes in the forestomach of rats, mice and hamsters exposed to dietary propionic and butyric acid.

Groups of five male and five female rats, mice and hamsters were fed diet containing 4% propionic or butyric acid for 7 days. Evidence of damage and cellular proliferation in the epithelium of the forestomach and limiting ridge was detected in all three species. Changes were particularly marked in animals fed butyric acid diet and rats appeared to be the most sensitive species. It is postulated that tumours of the forestomach reported in rats after long-term feeding of propionic acid diet may be a consequence of continued damage and repair, and that butyric acid, which occurs naturally in foods at concentrations up to 5%, would be at least as potent as propionic acid if similarly tested.

Administration, Oral↗
PubMed1991

A synthetic peptide corresponding to hFSH-beta-(81-95) has thioredoxin-like activity.

The thioredoxin-like activity of human follicle stimulating hormone (hFSH), hFSH-beta-(83-88) peptide amide (hFSH-beta-(83-88) which has a sequence similar to the thioredoxin active center (-His-Cys-Gly-Lys-Cys-Asp-)) and thioredoxin-(31-36)-peptide amide (TD-(31-36) which contains the redox-active dithiol of thioredoxin (-Trp-Cys-Gly-Pro-Cys-Lys-)) was characterized by their ability to reactivate reduced and denatured bovine pancreatic ribonuclease (RNase). This assay reflects the recently recognized ability of thioredoxin to catalyze disulfide bond formation in proteins. Compared to uncatalyzed refolding of reduced, denatured substrate, hFSH was approximately 10-fold more active than thioredoxin on a molar basis. The catalytic activity of hFSH-beta-(83-88) and TD-(31-36) was equivalent to that of an equimolar concentration of thioredoxin. Screening of 11 overlapping peptide amides representing the entire primary structure of hFSH-beta-subunit indicated that hFSH-beta-(81-95), which contains the sequence similar to the thioredoxin active center within a receptor-binding region of the hFSH-beta-subunit, possesses strong thioredoxin-like activity and was more active than an equimolar concentration of thioredoxin. In contrast, hFSH-beta-(33-53), a thiol-containing peptide which corresponds to a second FSH receptor-binding domain but lacks the sequence similar to the thioredoxin active center, was inactive. Synthetic peptide amides corresponding to other regions of hFSH-beta-subunit were less effective than hFSH-beta-(81-95) in reactivating reduced and denatured RNase. Our data provide evidence that the recently reported thioredoxin-like catalytic activity of FSH may be due, at least in part, to the redox-active dithiol present within a receptor-binding domain of its beta-subunit, and thus may have a physiological role in receptor binding or signal transduction.

Amino Acid Sequence↗
PubMed1991

Role of persistent, non-genotoxic tissue damage in rodent cancer and relevance to humans.

This review has focused on the importance of cellular proliferation in neoplasia induced by nongenotoxic carcinogens and has not attempted to address the mechanisms involved in the progression from the hyperplastic to the neoplastic state. Major advances in this area are likely in the next decade and should explain how cells in an abnormally high proliferative state are rendered more vulnerable either to the action of endogenous or environmental mutagens or to defects in cell reproduction, thus providing the stimulus for progression to neoplasia (165). In this review evidence has been presented to support the hypothesis that sustained tissue damage induced by nongenotoxic compounds in rodents predisposes to tumor development. The evidence has been obtained by drawing from the published findings of experimental rodent studies conducted over the past 50 years. The experience gained at various sites in the rodent including the connective tissue, liver, bladder, and forestomach shows the existence of a threshold dose for various test materials/agents, below which neither sustained tissue damage nor tumor induction occurs but above which level both effects are manifest. Taken collectively, an overall picture emerges that sustained cell proliferation renders various sites in the rodent vulnerable to tumor development. The validity of this hypothesis is of importance to the evaluation of carcinogenic risk of chemicals to humans. For those nongenotoxic carcinogens known to cause characteristically defined and sustainable tissue damage as a precursor of tumor development in rodents, it should be possible to establish a threshold dose below which both effects disappear and upon which a safety margin in humans can be based. Some limited evidence supports an association between chronic tissue injury and neoplastic development in humans. Note, however, that certain types of induced tissue damage may be rodent-specific and therefore have no relevance for humans. We conclude that the appearance of persistent tissue damage predisposes to tumor development in rodents exposed to nongenotoxic carcinogens and that systematic studies in rodents should provide a rational basis for arriving at a safety margin in humans exposed to such agents.

Animals↗