Metabolic requirements for the hepatocellular proliferation induced by peroxisome proliferators. Role of coenzyme A.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
M L Cunningham
Publications and source records attributed to M L Cunningham.
Glycoprotein IV-independent adhesion of sickle red blood cells to immobilized thrombospondin under flow conditions.
The abnormal adherence of red blood cells (RBC to the blood vessel wall is believed to contribute to the vascular occlusion observed in patients with sickle call anemia. The cell adhesion receptors GPIV (CD36) and integrin alpha 4 beta 1 (CD49d/CD29) were previously identified on circulating sickle reticulocytes, and shown to mediate sickle RBC adhesion to the endothelium. The presence of damaged endothelium in these patients suggests that exposed extracellular matrix proteins could provide a potential substrate for sickle RBC adhesion. To determine whether RBC adhesion receptors could mediate adhesion to extracellular matrix proteins, we tested their ability to adhere to a variety of immobilized, purified proteins under flow conditions. Neither sickle nor normal RBC adhered to fibronectin, vitronectin, fibrinogen, or collagen. In contrast, we observed substantial adhesion of sickle but not normal RBC to thrombospondin (TSP). The adhesion was not inhibited with known antagonists of the GPIV-TSP interaction, nor by inhibitors of several other known binding domains in TSP. Moreover, the adhesion was resistant to inhibition by soluble TSP, suggesting that immobilization of TSP exposes an adhesive site that is cryptic on TSP in solution. However, the glycosaminoglycans, chondroitin sulfate A, and dextran sulfate were potent inhibitors of this adhesion. These results suggest that a mechanism distinct from GPIV is responsible for sickle RBC adhesion to immobilized TSP under flow conditions.
Aggrecans↗
The crystal structure of trypanothione reductase from the human pathogen Trypanosoma cruzi at 2.3 A resolution.
Trypanothione reductase (TR) is an NADPH-dependent flavoprotein unique to protozoan parasites from the genera Trypanosoma and Leishmania and is an important target for the design of improved trypanocidal drugs. We present details of the structure of TR from the human pathogen Trypanosoma cruzi, the agent responsible for Chagas' disease or South American trypanosomiasis. The structure has been solved by molecular replacement, using as the starting model the structure of the enzyme from the nonpathogenic Crithidia fasciculata, and refined to an R-factor of 18.9% for 53,868 reflections with F > or = sigma F between 8.0 and 2.3 A resolution. The model comprises two subunits (968 residues), two FAD prosthetic groups, two maleate ions, and 419 water molecules. The accuracy and geometry of the enzyme model is improved with respect to the C. fasciculata enzyme model. The new structure is described and specific features of the enzyme involved in substrate interactions are compared with previous models of TR and related glutathione reductases from human and Escherichia coli. Structural differences at the edge of the active sites suggest an explanation for the differing specificities toward glutathionylspermidine disulfide.
Amino Acid Sequence↗
Biochemical effects of the mouse hepatocarcinogen oxazepam: similarities to phenobarbital.
The National Toxicology Program (NTP) recently determined that the commonly prescribed sedative hypnotic agent oxazepam is a mouse liver carcinogen. Many other benzodiazepines are metabolized to oxazepam resulting in further human exposure to this drug. This has resulted in considerable interest in the mechanism of oxazepam-mediated mouse liver carcinogenesis for use in human risk assessment. Several directions for mechanistic research were examined in this study. B6C3F1 mice were treated with oxazepam-dosed feed at 125 (noncarcinogenic) and 2500 ppm (carcinogenic) for 3, 7, 10, and 21 days. Cell proliferation in liver, cytochrome P450 induction, free radical formation, GSH depletion, and levels of circulating thyroid-stimulating hormone (TSH) were analyzed at these time points. Increased levels of hepatic cell proliferation were observed by 7 days at 125 ppm and by 10 days at 2500 ppm. Microsomal enzyme induction also occurred and was associated with elevated plasma TSH levels. Hepatic GSH levels were slightly depressed but there was no evidence of increased oxidative stress. A similar pattern of biochemical events has been observed to occur during dosed feed treatment with phenobarbital. These results suggest that oxazepam and phenobarbital may induce carcinogenesis by similar mechanisms in mice.
Animals↗
Role of increased DNA replication in the carcinogenic risk of nonmutagenic chemical carcinogens.
DNA replication is not an error-free process; therefore induction of cell proliferation with the requisite increase in DNA replication may be an important mechanism by which carcinogenesis can be induced by chemicals. Data presented in this overview indicate a positive association between increased cell proliferation and carcinogenesis, and illustrate the value of performing mechanistic studies such as cell proliferation assays in conjunction with short-term tests to further investigate the results of cancer bioassays. Whereas chemically-induced cell proliferation per se may not be sufficient to induce carcinogenesis, it creates a favorable environment for tumor development. There are two types of chemically-induced cell proliferation, mitogenic and cytotoxic, and they have different consequences regarding the mechanism of carcinogenesis of a chemical. Mitogenic chemical such as phenobarbital, oxazepam, and the peroxisome proliferating agents exert a short-term cell proliferative response that may exert its primary effect in carcinogenesis at the promotion stages. It is not clear at what stage(s) cytotoxic agents such as methapyrilene, alpha 2u-globulin inducers or saccharin exert their effects in carcinogenesis. A confounding factor in evaluation of cell proliferation in risk assessments is the production of chemical specific pleiotropic effects that may contribute to the carcinogenicity of a chemical. It is clear that mechanistic studies performed to understand the relationship of sex, species and dose in rodent carcinogenicity assays of chemicals is critical for the extrapolation of such data for human health assessments.
Carcinogens↗
The differential diagnosis of posterior plagiocephaly: true lambdoid synostosis versus positional molding.
The diagnosis and treatment of posterior plagiocephaly is one of the most controversial aspects of craniofacial surgery. The features of true lambdoid synostosis versus those of deformational plagiocephaly secondary to positional molding are inadequately described in the literature and poorly understood. This has resulted in many infants in several craniofacial centers across the United States undergoing major intracranial procedures for non-synostotic plagiocephaly. The purpose of this study was to describe the detailed clinical, imaging, and operative features of true lambdoid synostosis and contrast them with the features of positional plagiocephaly. During a 4-year period from 1991 to 1994, 102 patients with posterior plagiocephaly were assessed in a large multidisciplinary craniofacial program. During the same period, 130 patients with craniosynostosis received surgical treatment. All patients were examined by a pediatric dysmorphologist, craniofacial surgeon, and pediatric neurosurgeon. Diagnostic imaging was performed where indicated. Patients diagnosed with lambdoid synostosis and severe and progressive positional molding underwent surgical correction using standard craniofacial techniques. Only 4 patients manifested the clinical, imaging, and operative features of unilambdoid synostosis, giving an incidence among all cases of craniosynostosis of 3.1 percent. Only 3 among the 98 patients with positional molding required surgical intervention. All the patients with unilambdoid synostosis had a thick ridge over the fused suture, identical to that found in other forms of craniosynostosis, with compensatory contralateral parietal and frontal bossing and an ipsilateral occipitomastoid bulge. The skull base had an ipsilateral inferior tilt, with a corresponding inferior and posterior displacement of the ipsilateral ear. These characteristics were completely opposite to the findings in the 98 patients who had positional molding with open lambdoid sutures and prove conclusively that true unilambdoid synostosis exists as a specific but rare entity. Awareness of the features of unilambdoid synostosis will allow more accurate diagnosis and appropriate treatment of posterior plagiocephaly in general and in particular will avoid unnecessary surgical intervention in patients with positional molding.
Cranial Sutures↗
Distinction of mutagenic carcinogens from a mutagenic noncarcinogen in the big blue transgenic mouse.
The aromatic amines 2,4-diaminotoluene (2,4-DAT) and 2,6-diaminotoluene (2,6-DAT) are structural isomers that have been extensively studied for their mutagenic and carcinogenic characteristics. Both compounds are rapidly absorbed after oral administration and are equally mutagenic in the Ames test; however, 2,4-DAT is a potent hepatocarcinogen, whereas 2,6-DAT does not produce an increased incidence of tumors in rats or mice at similar doses. The Big Blue transgenic B6C3F1 mouse carries multiple copies of the lacl mutational target gene. Our studies were designed to determine whether the Big Blue system could be used to detect differences in the vivo mutagenic activity between the carcinogen-noncarcinogen pair 2,4-DAT and 2,6-DAT and to determine whether the in vivo mutagenesis assay results correspond to the rodent carcinogen bioassay results. Male B6C3F1 transgenic mice were exposed to 2,4-DAT or 2,6-DAT at 0 or 1,000 ppm in the diet for 30 and 90 days or to dimethylnitrosamine as a positive control. Mutant frequencies were nearly identical for all three groups at 30 days, while at 90 days the mutant frequency for the hepatocarcinogen 2,4-DAT (12.1 +/- 1.4 x 10(-5)) was significantly higher (p < 0.01) as compared to both age-matched (spontaneous) controls (5.7 +/- 2.9 x 10(-5)) and the 2,6-DAT-exposed group (5.7 +/- 2.4 x 10(-5)). Results from this study demonstrate that the Big Blue transgenic mutation assay can distinguish differences in vivo between the mutagenic responses of hepatic carcinogens ad a noncarcinogen; is sensitive to mutagens through subchronic dietary exposure; and yields a differential response depending upon the length of time mice are exposed to a mutagen.
Animals↗
Dorsal laminectomy in the adult mouse: a model for nervous system research.
Animal strains with specific genetic mutations can serve as powerful tools to study normal and pathologic cellular and molecular processes. The mammalian species with the largest number of known genetic mutations is the mouse. In spinal cord research, mice have not been used as extensively as other species because of the difficulty in accessing and manipulating their spinal cord. We describe the technique of exposing and manipulating the spinal cord of normal mice and of mice with the severe combined immunodeficiency (scid) mutation. Surgical outcome and complications are discussed. We conclude that dorsal laminectomy with subsequent access and manipulation of the spinal cord and its roots can be accomplished consistently with practice.
Animals↗
Rotenone, an anticarcinogen, inhibits cellular proliferation but not peroxisome proliferation in mouse liver.
In previous National Toxicology Program (NTP) studies, rotenone reduced the background incidence of hepatocellular carcinoma in male B6C3F1 mice. In the present studies, rotenone reduced the basal hepatic labeling index of male B6C3F1 mice in a dose-dependent fashion and inhibited hepatocellular proliferation, but not peroxisome proliferation, induced by the peroxisome proliferator Wy-14,643. These results indicate that reduction of hepatic tumors by rotenone may have been due to decreased liver cell replication, that peroxisome proliferation can be induced in the absence of hepatocellular proliferation and suggest rotenone as a potential tool in studies of relationships of cell proliferation, peroxisomal proliferation and hepatocarcinogenesis.
Animals↗
Trypanothione reductase from Leishmania donovani. Purification, characterisation and inhibition by trivalent antimonials.
Trypanothione reductase was purified to homogeneity from Leishmania donovani promastigotes transfected with the expression plasmid pTEX-LdTR. The physical, spectral and kinetic properties were found to be similar to those obtained from other pathogenic trypanosomatids. The substrates trypanothione disulfide and NADPH exhibit Michaelis-Menten saturation kinetics with Km values of 36 microM and 9 microM, respectively, the former yielding a kcat/Km of 5.0 x 10(6) M-1 s-1. Like other trypanothione reductases, the leishmania enzyme is unable to use glutathione disulfide as substrate. Both trypanothione reductase and the analogous mammalian enzyme, glutathione reductase, are inhibited by trivalent but not pentavalent anti-leishmanial antimonials. Inhibition by trivalent sodium antimonyl gluconate (Triostam) occurs in a time-dependent manner, with the pseudo-first-order rate constants of inhibition being linearly related to drug concentration. Inhibition proceeds until an apparent equilibrium between active enzyme/free drug and inactive enzyme-drug complex is reached. MelT, an adduct of melarsen oxide and dihydrotrypanothione which is a competitive inhibitor of the disulfide binding site of trypanothione reductase, confers protection against Triostam. Prior reduction of the catalytically active disulfide bridge by NADPH is essential for inhibition. Spectral analysis shows that the broad absorbance band centred on 530 nm, characteristic of the charge-transfer complex in the two-electron-reduced EH2 enzyme, is lost upon addition of Triostam. Further spectral changes resemble those associated with reduction of the FAD prosthetic group to FADH2. Inhibition by Triostam is readily reversed by dilution or addition of the dithiols 2,3-dimercaptopropanol, 2,3-dimercaptosuccinate or dithiothreitol, but not dihydrotrypanothione, suggesting that this trypanosomatid-unique metabolite is unlikely to protect the enzyme from inhibition in whole cells. A mechanism consistent with these observations is proposed.
Animals↗
Site-directed mutagenesis of the redox-active cysteines of Trypanosoma cruzi trypanothione reductase.
The gene for trypanothione reductase from the Silvio strain of Trypanosoma cruzi has been cloned, sequenced and overexpressed in Escherichia coli using the constitutive lpp promoter on the expression plasmid pBSTNAV. Up to 13% of the total soluble protein is enzymically active trypanothione reductase with kinetic properties similar to the enzyme purified from T. cruzi. In order to assess the catalytic role of the putative active-site cysteine residues (C53 and C58), three mutant proteins have been constructed by site-directed mutagenesis substituting alanine or serine residues for cysteine; [C53A]trypanothione reductase, [C53S]trypanothione reductase and [C58S]trypanothione reductase. Although the purified, recombinant mutant proteins were catalytically inactive with NADPH and trypanothione disulphide as substrates, all showed comparable levels of transhydrogenase activity between NADPH and thio-NADP+, suggesting that the mutant proteins had correctly folded in vivo. All three mutants showed substantially different catalytic parameters for thio-NADP+ than the wild-type enzyme, presumably as a consequence of modifying the environment of the enzyme-bound flavin, thereby altering its chemical reactivity. The purified [C58S]trypanothione reductase showed spectral properties similar to the oxidised wild-type enzyme but, unlike the wild-type enzyme, did not acquire the characteristic charge-transfer complex of the EH2 form on addition of NADPH. In contrast, in the absence of NADPH both [C53A]trypanothione reductase and [C53S]trypanothione reductase showed spectral properties similar to the EH2 form of the wild-type enzyme. These data indicate that both C53 and C58 are essential for overall catalysis, with the thiolate anion of C58 interacting with the enzyme-bound FAD and C53 interacting with the disulphide substrate. These mutants should be useful in crystallographic studies of reaction intermediates which cannot be obtained with the catalytically active native enzyme.
Animals↗
The hepatocarcinogen methapyrilene but not the analog pyrilamine induces sustained hepatocellular replication and protein alterations in F344 rats in a 13-week feed study.
Methapyrilene (MPH) was a widely used antihistamine until it was found to produce hepatocellular carcinoma and cholangiocarcinoma in Fischer 344 rats. The structurally similar antihistamine pyrilamine (PYR) was marginally or noncarcinogenic in a similar study. The peroxisome proliferator Wy-14,643 was included in this study as a positive control. As part of a program to investigate the mechanisms whereby structurally similar chemicals produce different toxicities, we studied these three chemicals for the induction of cell proliferation in the liver of F344 rats. Male rats were treated for up to 13 weeks with feed dosed with MPH (HCl salt) at 0, 50, 100, 250, or 1000 ppm or PYR (maleate salt) at 1000 ppm to duplicate the route of administration and high-dose groups used in the carcinogenesis assay. In addition, the nongenotoxic hepatocarcinogen peroxisome proliferator Wy-14,643 was included as a positive cell-proliferating chemical. Cell proliferation was quantitated by measuring the incorporation of bromodeoxyuridine (BrDU) administered by osmotic minipump for 7 days and the appearance of proliferating cell nuclear antigen (PCNA) immunohistochemically. The BrDU-labeling index showed a large and sustained increase in rats treated with MPH at 250 and 1000 ppm, sustaining greater than 50% labeling in the higher dose group of 4-, 6-, and 13-week treatment groups. PYR at 1000 ppm demonstrated no significant increase in labeling above control levels at any time point. PCNA-labeling indexes showed similar but reduced increases for MPH and were comparable to control for the PYR dose groups. Two-dimensional gel electrophoresis was used for the detection of quantitative changes in gene expression and qualitative changes in the charges of specific mitochondrial and cytosolic proteins. Quantitative changes in 32 proteins induced by MPH and 39 changes induced by Wy-14,643 were detected throughout the 13-week study. Specific mitochondrial protein charge shifts were associated with high-dose MPH treatment that were not observed in animals treated with Wy-14,643. PYR induced no significant qualitative or quantitative protein alterations. Hepatocellular proliferation of the large magnitude observed following dietary administration of MPH, and not PYR may contribute to the mechanism of carcinogenesis of MPH.
Administration, Oral↗
Cell proliferation as a determining factor for the carcinogenicity of chemicals: studies with mutagenic carcinogens and mutagenic noncarcinogens.
Recent work in our laboratory has examined mechanisms whereby chemicals produce mutagenicity in short-term in vitro assays yet fail to produce carcinogenesis in 2-year rodent bioassays. These studies have used mutagenic structural analogs of carcinogenic and noncarcinogenic chemicals for comparison. Our previous studies have determined that differences in the metabolism and disposition of these chemicals were not responsible for their observed carcinogenic differences, but that carcinogenicity correlated with the ability of the respective isomer to induce cell proliferation in the target organ. Mutagenic noncarcinogens such as 2,6-diaminotoluene (DAT), 1-nitropropane (NP), dimethoate, dioxathion, and dichlorvos failed to induce an increase in cell turnover in the target organs. An increase in cell proliferation was observed following exposure to the mutagenic carcinogen analogs 2,4-DAT (liver), 2-NP (liver), and tris(2,3-dibromopropyl)phosphate (kidney). Our recent studies have used transgenic (Big Blue) mice to detect in vivo mutagenesis induced by DAT isomers. Results of these studies demonstrate that administration of the carcinogenic isomer, 2,4-DAT, resulted in an increase in in vivo mutation frequency, whereas administration of the noncarcinogenic isomer, 2,6-DAT, failed to do so. These results indicate that cell proliferation may be requisite for expression of chemical-induced mutagenicity in vivo and thereby accommodate expression of carcinogenicity.
Animals↗
Activity of hepatic drug metabolizing enzymes following oxazepam-dosed feed treatment in B6C3F1 mice.
Oxazepam has been determined to be a potent hepatocarcinogen in mice. Evidence in the literature indicates that oxazepam is capable of inducing drug metabolizing enzymes in rodents and an association between enzyme induction and carcinogenesis has been proposed for other compounds such as phenobarbital. We examined the pattern of enzyme induction that occurs under bioassay conditions in male B6C3F1 mice. The results indicate that oxazepam is capable of inducing multiple drug metabolizing enzymes under bioassay conditions. Closer examination of the most induced samples suggests that oxazepam is a phenobarbital-type enzyme inducer.
Aminopyrine N-Demethylase↗
Differential in vivo mutagenicity of the carcinogen/non-carcinogen pair 2,4- and 2,6-diaminotoluene.
The aromatic amines 2,4-diaminotoluene (2,4-DAT) and 2,6-diaminotoluene (2,6-DAT) are structural isomers that have been extensively studied for their mutagenic and carcinogenic characteristics. Both compounds are equally mutagenic in the Ames/Salmonella assay in the presence of S9. However, the differences in the results of chronic rodent carcinogen bioassays using these two compounds are significant, in that 2,4-DAT is a potent hepatocarcinogen, whereas 2,6-DAT does not produce an increased incidence of tumors in rats or mice at similar doses. The Big Blue transgenic B6C3F1 mouse carries multiple copies of bacteriophage lambda, each with a lacI mutational target gene, integrated into mouse chromosome 4. Our studies were designed to determine whether the Big Blue system could be used to detect differences in the in vivo mutagenic activity between the carcinogen/non-carcinogen pair 2,4- and 2,6-DAT and to determine whether the in vivo mutagenesis assay results correspond to the rodent carcinogen bioassay results. Male B6C3F1 transgenic mice were exposed to 2,4- or 2,6-DAT at 0 or 1000 p.p.m. in the diet for 30 and 90 days. Mice serving as positive controls were administered five daily i.p. injections of 6 mg/kg dimethylnitrosamine (DMN) in saline and were sacrificed 15 days following the last injection. Mutant frequencies at lacI were determined by recovering the genomically integrated lambda phage using an in vitro packaging reaction followed by infection of an appropriate Escherichia coli host. Complete non-sectored blue mutant plaques were scored against a background of clear non-mutant plaques. Mutant frequencies were nearly identical for all three groups at 30 days, while at 90 days the mutant frequency for the hepatocarcinogen 2,4-DAT (12.1 +/- 1.4 x 10(-5)) was significantly higher (P < 0.01) as compared with both age-matched (spontaneous) controls (5.7 +/- 2.9 x 10(-5)) and the 2,6-DAT-exposed group (5.7 +/- 2.4 x 10(-5)). Mutations at lacI arising ex vivo during replication in E. coli are observed in this system as sectored blue plaques. The sectored plaque frequency in this study was constant across all groups at approximately 9.0 x 10(-5). Results from this study demonstrate that the Big Blue transgenic mutation assay: (i) can distinguish differences in vivo between the mutagenic responses of a carcinogen and a non-carcinogen which elicited comparable mutagenic activity in S.typhimurium; (ii) is sensitive to mutagens through subchronic dietary exposure; and (iii) yields a differential response depending upon the length of time mice are exposed to a mutagen.
Animals↗
Mechanism of inhibition of trypanothione reductase and glutathione reductase by trivalent organic arsenicals.
The dithiol trypanothione, novel to trypanosomatids and analogous to glutathione in mammalian systems, has been shown to interact with anti-trypanocidal trivalent arsenical drugs forming a stable adduct, MelT. This adduct is a competitive inhibitor of the flavoprotein trypanothione reductase, responsible for maintaining intracellular trypanothione in the reduced form. Since trypanothione reductase and the analogous glutathione reductase both contain catalytically active sulphydryl groups we have examined the ability of several arsenicals to differentially inhibit these enzymes. Melarsen oxide [p-(4,6-diamino-s-triazin-2-yl)aminophenylarsenoxide] potently inhibits both enzymes in two stages, the first being essentially complete within 1 min, the second being time dependent, exhibiting saturable pseudo-first-order kinetics with kinact of 14.3 x 10(-4) s-1 and 1.06 x 10(-4) s-1 and Ki of 17.2 microM and 9.6 microM for trypanothione reductase and glutathione reductase, respectively. Inhibition requires prior reduction of the enzyme by NADPH and can be reversed by excess dithiols or prevented by MelT in the case of trypanothione reductase. In both cases a time-dependent loss of the characteristic charge-transfer absorbance band at 530 nm is observed upon addition of arsenical to pre-reduced enzyme, which with excess NADPH leads to a spectrum resembling the EH4 form and is accompanied by an increased ability to reduce molecular oxygen. A model for inhibition is proposed where, first, free arsenical and previously reduced enzyme immediately establish an equilibrium with an inactive monothioarsane enzyme-inhibitor complex involving the interchange cysteine distal to the FAD; second, a subsequent rearrangement about the sulphur-arsenic bond leads to the binding of the arsenical to the charge-transfer cysteine, proximal to the FAD, forming a more stable dithioarsane complex. Molecular modelling suggests that the differences in kinetic behaviour of the two enzymes can be attributed to structural features of their respective disulphide-binding sites. Incubation of reduced trypanothione reductase with excess dihydrotrypanothione and melarsen oxide prevents direct inhibition of the enzyme, suggesting that dihydrotrypanothione acts as a protectant in vivo, preventing the direct modification of trypanothione reductase by sequestering the arsenical as MelT.
Animals↗
From gastrulation to neurulation: transition in retinoic acid sensitivity identifies distinct stages of neural patterning in the rat.
Early neural development is a multistep process with morphologically distinct stages; however, the molecular events that underlie morphologic development are poorly understood. Retinoic acid (RA) was chosen as a teratogen to perturb development because this endogenous molecule is thought to play an integral role in normal neuraxis formation in many vertebrate species. We have examined the effects of RA on early neural patterning in the rat at three morphologically distinct stages: late streak, foregut pocket, and early somite. In this model exogenous RA exposure during mid-gastrulation (late streak stage) leads to severe disruption of anterior neural development as determined by morphologic and molecular (Engrailed [En] gene expression) markers. This disruption in anterior neural development is associated with excessive cell death in the hindbrain posterior to the En expression domain. In contrast, at the time the neural folds begin to elevate (foregut pocket stage) there is a dramatic reduction in the sensitivity of anterior neural development to exogenous RA as reflected by En expression and cell death patterns. These results suggest that we have identified a major transition in the development of the anterior neuraxis that is reflected in a transition in sensitivity to RA. This transition in sensitivity demonstrates that the fundamental patterning mechanisms that separate fore- and midbrain from hindbrain occurs very early in neurogenesis.
Animals↗
Relationship of carcinogenicity and cellular proliferation induced by mutagenic noncarcinogens vs carcinogens. III. Organophosphate pesticides vs tris(2,3-dibromopropyl)phosphate.
Our laboratory has been examining the mechanisms whereby chemicals produce mutagenicity in short-term in vitro assays yet fail to produce carcinogenesis in 2-year rodent bioassays. Previous studies indicated that some mutagenic hepatocarcinogens increased cell proliferation in the target organ, the liver, while other structurally related mutagens that were noncarcinogenic failed to do so. We demonstrate in this report that another mutagenic carcinogen, tris(2,3-dibromopropyl phosphate), increased cell proliferation that was localized in the outer medulla of the kidney. This was also the target site for carcinogenesis in a 2-year bioassay and is another example of the association between chemically induced cell proliferation and carcinogenesis. This study also reports the absence of increased cell proliferation in the liver or kidney after exposure in the diet to the mutagenic organophosphate insecticides dimethoate, dioxathion, and dichlorvos following dietary exposure for 2 weeks at the same dose levels and routes of exposure that did not increase the tumor incidence in either organ in 2-year carcinogenesis assays. The present studies support the tenet that chemically induced cell proliferation may be a necessary prerequisite for chemical carcinogenesis, since in rat liver and kidney there was neither cell proliferation after 2 weeks nor tumor development after 2 years dietary exposure to the mutagenic organophosphate insecticides dimethoate, dioxathion, and dichlorvos.
Animals↗