Potential role of α-2μ-globulin, protein droplet accumulation, and cell replication in the renal carcinogenicity of rats exposed to trichloroethylene, perchloroethylene, and pentachloroethane

Goldsworthy, Thomas L.; Lyght, Otis; Burnett, Vicki L.; Popp, James A.

doi:10.1016/0041-008x(88)90095-6

Cited by 84 publications

(36 citation statements)

References 10 publications

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“…Chemically induced renal cortical tumors have been observed in rats in several studies where the mechanism has been hypothesized to be related to accumulation of a-2p-globulin in the P2 segment of the proximal tubule and subsequent enhanced cell proliferation secondary to cytotoxicity (3)(4)(5)(6). This proposed mechanism is restricted to male rats that have androgen-dependent synthesis of a-2p-globulin in the liver.…”

Section: Discussionmentioning

confidence: 94%

“…The presence of an increase in protein droplets in renal tubular epithelial cells along with the occurrence of abnormally shaped cytoplasmic protein deposits is a hallmark of a-2p-globulin nephropathy (2,3). Since the proposed mechanism by which a-2p-globulin nephropathy leads to an increase in renal tumors supposedly involves cytotoxicity and secondary enhancement of cell proliferation (3)(4)(5)(6), we retrospectively examined kidney sections to determine if there was enhanced replicative DNA synthesis as indicated by the presence of S-phase nuclei.…”

Section: Introductionmentioning

confidence: 99%

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Retrospective study of possible alpha-2 mu-globulin nephropathy and associated cell proliferation in male Fischer 344 rats dosed with t-butyl alcohol.

Takahashi¹,

Lindamood²,

Maronpot³

1993

Environ Health Perspect

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Tert-butyl alcohol, an important commodity chemical, additive to unleaded gasoline, and contaminant of drinking water, was evaluated for toxicity and was found to enhance nephropathy in male Fischer 344 rats. Because male rats treated with t-butyl alcohol for 2 years had a low incidence of renal cortical tumors, additional renal sections for the 90-day toxicity study were examined for the presence of hyaline droplet accumulation, nephropathy, and evidence of replicative DNA synthesis (S-phase nuclei) to indirectly and retrospectively investigate a possible role of a-2p-globulin in the pathogenesis of the nephropathy. Dose levels for t-butyl alcohol were 0, 0.25, 0.5, 1, 2, and 4% (w/v) administered in drinking water. Significant body weight gain depressions were observed in all treated males, and there was an absolute weight loss in the 4% male group, none of which survived to the end of the study. Except for the 4% dose group, there was a treatment-related increase in hyaline droplet accumulation in the renal proximal tubules with crystalline, rectangular, and rhomboid forms of the protein evident. The severity of nephropathy was enhanced in treated rats, except for the 4% dose group. Replicative DNA synthesis, as measured by immunohistochemical staining for proliferating cell nuclear antigen, was increased in proximal tubules of rats dosed with 2% t-butyl alcohol. It is concluded that tbutyl alcohol exacerbated nephropathy in male Fischer 344 rats and increased renal accumulation of hyaline protein material consistent with a-2p-globulin deposition.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Retrospective study of possible alpha-2 mu-globulin nephropathy and associated cell proliferation in male Fischer 344 rats dosed with t-butyl alcohol.

Takahashi¹,

Lindamood²,

Maronpot³

1993

Environ Health Perspect

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“…Twenty-onemonth recovery studies after 3 months of exposure to decaline or JP-8 were not associated with a tumor response, suggesting that a longer exposure period may be required for tumor formation (17,33). Perchloroethylene causes aG nephropathy at high gavage or inhalation concentrations, but a 28-day inhalation exposure study of male rats to 400 ppm, a concentration associated with kidney tumors, did not cause aG nephropathy in these rats (14,34). Recently, the pharmaceutical agent, 1-(aminomethyl)cyclohexaneacetic acid, was shown to induce aG nephropathy but not renal tumors in a 2-year bioassay in rats (35).…”

Section: A2u-globulin Inducing Agentsmentioning

confidence: 99%

“…Increases in renal cell proliferation associated with aG nephropathy have been demonstrated in male rats after acute exposure to pentachloroethane and perchloroethylene (14) and 1,4-dichlorobenzene (23,28). Sustained increases in cell proliferation associated with aG nephropathy have been demonstrated in male rats after acute or Furthermore, the absence of aG nephropathy and P2 cell proliferation in female F344 rats exposed to UG or in aG-deficient male NBR rats exposed to dL demonstrated the requirement of this protein for protein droplet nephropathy and cell proliferation.…”

Section: A2u-globulin Inducing Agentsmentioning

confidence: 99%

Cell Proliferation and Renal Carcinogenesis

Short¹

1993

Environmental Health Perspectives

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Enhanced cell proliferation occurs at several stages of renal tumorigenesis. Initiation by genotoxic nephrocarcinogens such as dimethylnitrosamine (DMN) is likely a result of DNA damage coupled with an initial burst of DNA synthesis associated with the cytotoxic effects of the compound. The level of initiation by DMN can be further enhanced by unilateral nephrectomy or hydronephrosis, which induces a brief burst of cell proliferation followed by tumorigenesis in the contralateral kidney. The role of sustained cell proliferation in renal tumor development is less well understood. The most compelling evidence comes from studies with nongenotoxic renal carcinogens such as unleaded gasoline and d-limonene, which induce a2U-globulin (aG) nephropathy and renal epithelial tumors exclusively in male rats. Sustained increases in cell proliferation in these studies depend on the presence of a chemical-aG complex in phagolysosomes of P2 proximal tubule cells, which results in cytotoxicity and compensatory hyperplasia only in male F344 rats, but not female F344 rats or aG deficient male NBR rats. Furthermore, initiation-promotion experiments demonstrated a strong correlation between the dose-response of cell proliferation and the incidence of preneoplastic and neoplastic lesions. Clearly, similar correlative studies with a number of other renal carcinogens and noncarcinogens are warranted before general conclusions can be made. Cell proliferation is excessively elevated in tubules affected by chronic progressive nephropathy, but the significance of the lesion to renal carcinogenesis is unclear. Elucidating mechanisms of renal cell proliferation are necessary for our understanding of cause and effect relationships. An exciting recent finding is altered expression of transforming growth factor-a in hereditary rat renal cell carcinoma. This animal model may be useful for studying detailed histochemical relationships between altered growth factors and cell proliferation in various stages of renal carcinogenesis.

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“…In chemical toxicity and carcinogenesis studies, LIs obtained from solid organs such as liver (15) and kidney (8,23) are calculated as a percentage of labeled cells divided by the total (or a representative subtotal) cell population under study. In these studies, cells are usually counted in random fields, with total counts of one to three-thousand.…”

Section: Introductionmentioning

confidence: 99%

Unit Length as the Denominator for Quantitation of Cell Proliferation in Nasal Epithelia

1990

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Cell proliferation data, generally based on a labeling index (LI), provide a valuable endpoint for assessment of toxic and potentially carcinogenic responses in laboratory animals. Measurement of the LI is time consuming because of the large number of cells that need to be counted to determine the denominator. In respiratory mucosa, the total cell count of the surface epithelia may be altered in response to treatment, either through cell loss or increases in cell number (e.g., hyperplasia). As an alternative to the more conventional LI, the present studies were carried out to assess the value of expressing cell proliferation in nasal epithelia as a unit length labeling index (ULLI), defined as labeled cells per mm of basement membrane. Rats were exposed by inhalation to formaldehyde or methyl bromide, and changes in cell proliferation were determined in the respiratory and olfactory epithelia, respectively, using both total cell count and basement membrane length as denominators. Total cell counts were clearly influenced by treatment, while basement membrane length was not. Both methods revealed similar treatment-induced effects on cell proliferation, and in fact were highly correlated (R 2: 0.92, p < 0.001). It was concluded that the ULLI method provides an effectivealternative to total cell counts and the LI method. This approach is not influenced by alterations in the total cell population, and has the benefit of being less labor intensive than LI determinations.

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Potential role of α-2μ-globulin, protein droplet accumulation, and cell replication in the renal carcinogenicity of rats exposed to trichloroethylene, perchloroethylene, and pentachloroethane

Cited by 84 publications

References 10 publications

Retrospective study of possible alpha-2 mu-globulin nephropathy and associated cell proliferation in male Fischer 344 rats dosed with t-butyl alcohol.

Retrospective study of possible alpha-2 mu-globulin nephropathy and associated cell proliferation in male Fischer 344 rats dosed with t-butyl alcohol.

Cell Proliferation and Renal Carcinogenesis

Unit Length as the Denominator for Quantitation of Cell Proliferation in Nasal Epithelia

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