Rat adrenal pheochromocytoma

Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A 73 2424-2428... 

PC12h-AG8 (a clonal variant of PC12 rat adrenal pheochromocytoma nerve cell line ) was used as an example of the cell growth type III. 

No excess of cancer was reported in two follow-up smdies of affected individuals in Turkey about 20-30 years after consumption of contaminated grain had ceased. " In mice, liver tumors were observed after exposure to HCB at 12-24mg/kg/day in the diet, but not at 6mg/kg/day. Hepatomas, hepatocellular carcinomas, bile duct adenomas, and renal cell adenomas were observed in rats after dietary administration." Liver tumors were also observed in 100% of surviving females and 16% of males after dietary administration to rats for 90 weeks. In another study, increased incidence of parathyroid adenomas and adrenal pheochromocytomas were observed in male and female rats and liver neoplastic nodules in females of the Ei generation in a two-generation feeding study. 

A significant increase in hepatocellular carcinomas occurred in mice given 195 or 390mg/kg/day by gavage for 78 weeks. Adrenal pheochromocytomas were also increased for the high-dose female mice. No neoplasms were observed at statistically significant incidences in rats given up to 92 mg/kg/day. 

In a 2 year study by NTP, male and female rats and mice were administered corn oil 5 days week for 104 weeks. A nonsignificant increase in adrenal pheochromocytomas was observed in male rats. 

Another study has shown a significant association between the severity of pulmonary inflammation/fibrosis induced by IP, as well as other particulate compounds including nickel oxide, nickel subsulfide, cobalt sulfate, and talc, and increased incidences of adrenal pheochromocytoma in rats (Ozaki et al. 2002). The systemic hypoxemia and reduced gas exchange induced by chronic pulmonary lesions from IP exposures may result from stimulated catecholamine secretion from the adrenal medulla and this chronic endocrine hyperactivity may lead to hyperplasia and neoplasia of the adrenal gland. 

An increased incidence of pheochromocytomas in the adrenal gland was observed in male rats treated by gavage with hexachloroethane in com oil at 10 and 20 mg/kg/day 5 days/week for 2 years (NTP 1989). This effect is discussed further in Section 2.2.2.8, Cancer. 

Recent studies have shown that cyanide releases catecholamines from rat pheochromocytoma cells and brain slices (Kanthasamy et al. 1991b), from isolated bovine adrenal glands (Borowitz et al. 1988), and from the adrenals of mice following subcutaneous injection of high doses of potassium cyanide (Kanthasamy et al. 1991b). Thus, it was proposed that the cardiac and peripheral autonomic responses to cyanide are partially mediated by an elevation of plasma catecholamines (Kanthasamy et al. 1991b). 

The carcinogenicity of orally administered phenol was examined in rats and mice in a study reported by the National Cancer Institute (NCI 1980). Rats and mice received 0, 2,500, or 5,000 ppm in drinking water for 103 weeks. Calculated intakes for rats were 322 and 645 mg/kg/day for males and 360 and 721 mg/kg/day for females. Calculated intakes for mice were 590 and 1,180 mg/kg/day for males and 602 and 1,204 mg/kg/day for females. Statistically significant increased incidences of pheochromocytomas of the adrenal gland and leukemia or lymphomas were observed in male rats exposed to 322 mg/kg/day (2,500 ppm), but not in male rats exposed to 645 mg/kg/day (5,000 ppm). No significant effects were seen in female rats or mice of either sex exposed to either exposure level. Since cancer occurred only in males of one of the two species tested and a positive dose-response relationship could not be established, these results are inconclusive regarding the carcinogenic potential of orally administered phenol. 

Phaeochromocytoma (a tumor in the adrenal medulla) is not uncommon in rats, but rare in humans. Pheochromocytomas are induced in rats by a variety of non-genotoxic substances that may act indirectly by stimulating chromaffin cell proliferation. They are not known to be similarly inducible in other species. In the rat, a mechanism for the development may be hypercalcaemia (Tischler et al. 1999 Capen et ah, in Haschek et al. 2001). 

PC12 Rat pheochromocytoma (adrenal medullary tumor) Adrenergic neuron Tricresyl phosphate (organophosphate) Inhibition of neurofilament assembly and axonal growth... 

In the studies of long-term exposure of rats to both triphenyltin hydroxide and bis(tributyltin)oxide, most of the tumors were found in endocrine glands. In addition to the pituitary adenomas associated with bis(tributyltin)oxide and triphenyltin hydroxide, there was also an increased incidence of pheochromocytomas of the adrenal gland, parathyroid carcinomas and pancreatic adenocarcinomas in animals from at least one sex. Triphenyltin hydroxide was associated with an increased incidence of testicular Leydig cell tumors in male rats at the highest dose. Hepatic tumors were found in male and female mice following 80 weeks of triphenyltin hydroxide administration. 

Two-year rat chronic bioassay in rodents was performed Increased incidence of adrenal medullary hyperplasia and pheochromocytoma observed... 

Talc Adrenal gland neoplasms (pheochromocytomas) in rats Review of data indicates that tumors were not treatment-related [57]... 

Fig. 1. Pertussis toxin-mediated ADP ribosylation of membrane G proteins. Isolated cell membranes (50 ng of protein) from N1E 115 cells (mouse neuroblastoma cell line), N2A cells (mouse neuroblastoma cell line), S49-1 eye cells (S49(-) mutated mouse lymphoma cell line deficient in Ga ), 549 wt cells (wild-type mouse lymphoma cell line), RBL (RBL 2H3 rat basophilic leukemia cell line), GH3 cells (GH3 rat hypophyseal tumor cell line), PC-12 (rat pheochromocytoma cell line), HIT-T15 cells (hamster insulinoma cell line), Y-1 cells (mouse adrenal cortex tumor cell line), 108 cc 15 cells (mouse/rat neuroblastoma x glioma hybrid cell line), HL-60 cells (DMSO-differentiated human leukemia cell line), HL-60 (+PT) cells (HL-60 cells pretreated with 25 ng/ml of pertussis toxin for 24 h prior to preparation of membranes), RINm5F cells (rat insulinoma cell line), and C6-2 cells (rat glioma cell line) were subjected to P-ADP-ribosylation as described in section 4.3.3. Samples were precipitated as outlined in section 4.3.5 and subjected to SDS-PAGE with separating gels containing 8% acrylamide (w/v). An autoradiogram of the dried gel is shown. Molecular masses of marker proteins are indicated (kDa). Modified Ga proteins migrate at approximately 40 kDa. Radioactivity running in front of the 30 kDa marker protein comigrates with the dye front...

Ahnert-Hilger G, Bader MF, Bhakdi S, efal. (1988) Introduction of macromolecules into bovine adrenal medullary chromaffin cells and rat pheochromocytoma cells (PC 12) by permeabilization with streptolysin-O inhibitory effects of tetanus toxin on catecholamine secretion. In J Neurochem 52 1751-1758. 

Permeabilized secretory cells are widely used to study the final events during secretion by exocytosis. Convenient cellular models are bovine adrenal chromaffin cells in short term culture and the rat pheochromocytoma cell line PC 12. Both cell types take up labeled catecholamines and store them in secretory vesicles, from which they can be released upon stimulation. The released catecholamines can be detected in the supernatant. After permeabilization of the plasma membrane, release of catecholamines can be triggered by micromolar concentrations of Ca. ... 

Accutane is a potent rat and rabbit developmental toxin (teratogen). Testicular atrophy and evidence of lower spermatogenesis was noted in dogs given isotretinoin for 30 weeks at 20 or 60 mg kg day Fischer 344 rats dosed at 8 or 32 mg kg day for over 18 months had a dose-related raised incidence of pheochromocytoma, an adrenal gland tumor. The relevance in man is unknown since this animal develops spontaneous pheochromocytoma at a significant rate. 

A 2 year study indicated some evidence of carcinogenicity in male rats (pheochromocytomas of the adrenal gland and neoplasms of brain and lung) and equivocal results in female rats (neoplasms of brain and lung) and male mice (lung neoplasms). Female mice experienced an increase in uterine cancer. 

Other cell lines are available for in vitro studies, including the Y1 mouse adrenocortical cell line, with different advantages and disadvantages (for review, see [49]). PC-12 cells are from a rat pheochromocytoma, and they produce norepinephrine and dopamine [60], They have been used to study neuroendocrine signaling of the adrenal medulla and differentiate and stop proliferating following exposure to neural growth factor. Adrenal slices have also been used for short-term experiments, especially those that required the presence of both medulla and cortex, but this model has rarely if ever been used to study toxicity of endocrine disruptors. 

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