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Biomedical subjects

A Poland

Publications and source records attributed to A Poland.

At least 55 records · Page 3Linked to original sources
PubMed1984

Histologic changes produced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the skin of mice carrying mutations that affect the integument.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) produces epidermal hyperplasia and hyperkeratosis, squamous metaplasia of the sebaceous gland, and keratinized cyst formation in 8 strains of mice with the recessive mutation, hairless (hr/hr). The extent of these histologic changes is dependent on the genetic background. No cutaneous lesions are produced in haired (hr/+) mice. In examination of mice with 7 other mutations affecting the integument, TCDD produced similar histologic skin changes in cryptothrix, nude, plucked, and atrichosis; a marginal squamous metaplasia of sebaceous glands in Repeated epilation, and had no effect in fur deficient and Naked mutants. These genetically determined epidermal responses are discussed in light of the mechanism of action of TCDD.

Alleles↗
PubMed1983

Effect of the brachymorphic trait in mice on xenobiotic sulfate ester formation.

Mice carrying the recessive mutation brachymorphic have been shown previously to have a reduced capacity to synthesize 3'-phosphoadenosine-5'-phosphosulfate (PAPS), the required coenzyme in sulfation reactions [K. Sugahara and N. Schwartz, Proc. natn. Acad. Sci. U.S.A. 76, 6615 (1979)]. The capacity of the liver cytosol fractions from brachymorphic (bm/bm) mice or their phenotypically normal littermates (+/+ or +/bm) to catalyze the formation of sulfate esters of [3H]estrone and [14C]p-nitrophenol in vitro was determined. When PAPS was added to the reaction, the rates of sulfate ester formation catalyzed by the two cytosol fractions were similar. In contrast, when PAPS was generated in situ from ATP and SO(4)2-, the rates of sulfate ester formation catalyzed by the brachymorphic cytosol were only 4-22% of the rates catalyzed by the cytosol fraction from normal mice. The hepatic cytosol fraction from brachymorphic mice incorporated less 35SO(4)2- into PAPS than that catalyzed by cytosol of normal mice. [14C]p-Nitrophenol (1.5 mumoles/kg) was eliminated from brachymorphic and normal mice as urinary conjugates; in normal mice, 73% of the urinary radioactivity was p-nitrophenyl sulfate, while in the brachymorphic mice only 33% of the urinary excretion was the sulfate ester. Brachymorphic mice have a reduced capacity for synthesizing sulfate esters of xenobiotics in vitro and in vivo, which is attributable to their reduced synthesis of PAPS.

Adenine Nucleotides↗
PubMed1983

Strong evidence from studies with brachymorphic mice and pentachlorophenol that 1'-sulfoöxysafrole is the major ultimate electrophilic and carcinogenic metabolite of 1'-hydroxysafrole in mouse liver.

The role of sulfation of 1'-hydroxysafrole in the formation of hepatic macromolecular adducts and in hepatic tumor formation in mice given 1'-hydroxysafrole was investigated by the use of: (a) mice treated with the specific sulfotransferase inhibitor pentachlorophenol; and (b) brachymorphic mice, which are characterized by a deficiency in the hepatic synthesis of 3'-phosphoadenosine 5'-phosphosulfate. Cytosolic sulfotransferase activity for 1'-hydroxysafrole in both mouse and rat liver was significantly inhibited by 10 microM pentachlorophenol, usually by greater than 90%. Prior administration of nontoxic amounts of pentachlorophenol, either in the diet of adult female CD-1 mice or by i.p. injection of 12-day-old male C57BL/6 X C3H F1 (hereafter called B6C3F1) mice, resulted in an 85% decrease in the level of adducts formed from 1'-hydroxysafrole in hepatic DNA and RNA as compared to those of non-pentachlorophenol-treated animals. Likewise, the chronic administration of a nontoxic level of pentachlorophenol in the diet of adult female CD-1 mice strongly inhibited hepatic tumor induction by long-term dietary administration of either safrole or 1'-hydroxysafrole. Initiation of hepatic tumors by a single i.p. injection of 1'-hydroxysafrole to 12-day-old male B6C3F1 mice was strongly inhibited by prior treatment with pentachlorophenol. Under these conditions, the hepatocarcinogenicity of diethylnitrosamine was not inhibited by pentachlorophenol. Supplementation with adenosine triphosphate and sulfate of hepatic cytosols from adult female or 12-day-old brachymorphic progeny of a B6C3 background outbred to B6C3F1 mice (B6C3F2), of either sex, resulted in 5- to 10-fold less binding of 1'-hydroxysafrole to added RNA than when cytosols from phenotypically normal B6C3F2 mice were used. On administration of [3H]-1'-hydroxysafrole to adult female or 12-day-old brachymorphic B6C3F2 mice of either sex, the levels of hepatic DNA and RNA adducts were 7- to 12-fold lower than those obtained in phenotypically normal B6C3F2 mice of the same age and sex. Brachymorphic mice were also much less responsive than their phenotypically normal littermates to the induction of liver tumors by 1'-hydroxysafrole; lower incidences were observed both when the carcinogen was fed chronically to adult females and when it was administered to males only prior to weaning. Thus, all of these data strongly support the conclusion that 1'-sulfoöxysafrole is the major ultimate electrophilic and tumor-initiating metabolite of 1'-hydroxysafrole.

Animals↗
PubMed1982

Response of murine epidermis to 2,3,7,8-tetrachlorodibenzo-p-dioxin: interaction of the ah and hr loci.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons produce epidermal hyperplasia, hyperkeratosis and sebaceous gland metaplasia in the skin of mice bearing the recessive mutation (hr/hr) hairless. This response is mediated through the cytosol receptor protein: the structure-activity relationship for receptor binding corresponds to that for production of the skin lesion, and these histopathological changes segregate with the genetic polymorphism at the Ah locus, the locus determining the cytosol receptor. In HRS/J mice, an inbred strain segregating for the hr locus, both hairless (hr/hr) and haired (hr/+) mice possess the high-affinity cytosol receptor and respond to TCDD with the induction of epidermal aryl hydrocarbon hydroxylase activity, a receptor-mediated biochemical response; however, only hr/hr mice develop the proliferative/metaplastic skin response. We propose a genetic model for the interaction of the Ah and hr loci, to account for the differential response to TCDD observed in the skin of HRS/J hr/hr and hr/+ mice.

Animals↗
PubMed1982

2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity.

In this review, we have examined the biochemical and toxic responses produced by halogenated aromatic hydrocarbons and have tried to develop a model for their mechanism of action. These compounds bind to a cellular receptor and evoke a sustained pleiotropic response. In many tissues this response consists of the expression of a battery of enzymes which are, for the most part, involved in drug metabolism, but in other tissues, those which develop toxicity, an additional set of genes is expressed which effects cellular involution, division, and/or differentiation. The toxicity of these compounds appears to be due to the sustained expression of a normal cellular regulatory system, of which we were previously unaware. In future investigations it is hoped that we will learn the nature and physiologic role of this regulatory system. Only then can we hope to understand the mechanism of toxicity of these compounds.

Animals↗
PubMed1980

Genetic polymorphism of microsomal epoxide hydrolase activity in the mouse.

Hepatic microsomal epoxide hydrolase activity (EC 3.3.2.3), assayed using styrene oxide as the substrate, has a pH optimum of 9.5 from C57BL/6J mice and a pH optimum of 8.7 from DBA/2J mice. In cross and back-cross matings between C57BL/6J and DBA/2J mice, this phenotypic difference in epoxide hydrolase activity is inherited as a single autosomal trait, with co-dominant expression in heterozygotes. Heating liver microsomes from C57Bl/6J mice at 62 degrees C for 30 min produced a slight decrease in enzyme activity, whereas the same treatment of DBA/2J microsomes reduced enzyme activity to less than 3% of its initial value. Twenty-six inbred strains of mice were examined and separated into two phenotypic classes on the basis of differences in pH optima and heat sensitivity of microsomal epoxide hyrolase activity. Eph-1 is proposed as the locus symbol of the structural gene for microsomal epoxide hydrolase, with superscripts b and d designating the alleles carried by C57BL/6J and DBA/2J mice, respectively. Using 24 recombinant inbred strains derived from C57BL/6J and DBA/2J mice, Eph-1 was found to be linked to two loci on Chromosome 1.

Animals↗
PubMed1980

Quantitative evaluation of the promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxin of hepatocarcinogenesis from diethylnitrosamine.

In order to test the potential of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a promoter of hepatocarcinogenesis, rats which had received a single 10-mg/kg dose of diethylnitrosamine (DEN) following partial hepatectomy were given TCDD (0.14 and 1.4 micrograms/kg s.c. once every 2 weeks) for 7 months. Animals which received (a) only a single initiating dose of DEN after partial hepatectomy and no further treatment of (b) TCDD alone with no initiating dose of DEN exhibited relatively few enzyme-altered foci and no hepatocellular carcinomas. However, animals initiated with DEN and then given TCDD had a marked increase in enzyme-altered foci. At the higher dose of TCDD, hepatocellular carcinomas were present in five of seven rats. By means of three different enzyme markers used to evaluate the phenotypes of the enzyme-altered foci, a distinct phenotype heterogeneity of the foci was noted with a shift towards phenotypes exhibiting a greater deviation from normal liver when TCDD was given following DEN-partial hepatectomy. Quantitation of the numbers of enzyme-altered foci was performed by relating measurements made from two-dimensional tissue sections to the numbers of foci per unit volume of liver using relationships established in the field of stereology. The total volume of the liver occupied by the enzyme-altered foci, but not their number, increased with the dose of TCDD administered following DEN-partial hepatectomy. These studies demonstrate that TCDD is a potent promoting agent for hepatocarcinogenesis.

Adenosine Triphosphatases↗
PubMed1979

An estimate of the maximum in vivo covalent binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin to rat liver protein, ribosomal RNA, and DNA.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an extraordinarily potent toxin, has recently been found to be a potent carcinogen producing mucosal, lung, and liver tumors in female rats. In light of this carcinogenicity, we reexamined the in vivo covalent binding of [3H]TCDD to rat liver macromolecules. Immature Sprague-Dawley rats, receiving [3H]TCDD (0.87 mCi/kg; specific activity, 39 Ci/mmol) concentrated 18 to 64% of the total administered dose in their livers, but virtually all of this radioactivity (greater than 99.9%) was extractable. The maximum unextractable radioactivity was: protein, 60 pmol TCDD per mol of amino acid residue; rRNA, 12 pmol TCDD per mol of nucleotide residue; and DNA, 6 pmol TCDD per mol of nucleotide residue. If one assumes that this small residual amount of radioactivity represents covalent binding, this binding is 4 to 6 orders of magnitude lower than that of most chemical carcinogens, and the binding to DNA is equivalent to one molecule of TCDD per DNA, equivalent to 35 cells. The results suggest it is unlikely that TCDD-induced oncogenesis is through a mechanism of covalent binding to DNA and somatic mutation.

Animals↗
PubMed1978

An improved assay of 7-ethoxycoumarin O-deethylase activity: induction of hepatic enzyme activity in C57BL/6J and DBA/2J mice by phenobarbital, 3-methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin.

An improved in vitro fluorometric assay of the O-deethylation of 7-ethoxycoumarin which is at least 10 times more sensitive than existing methods is described. Nearly quantitative recovery of the product which is essentially free of fluorescent impurities is obtained by a simple two-step extraction procedure. In C57BL/6J mice O-deethylating activity was induced 3-fold by 3-methylcholanthrene and 7-fold by phenobarbital. Administration of phenobarbital resulted in a 10-fold stimulation of enzyme activity in DBA/2J mice. Kinetic analysis indicated that at least two and possibly more components are involved in the metabolism of 7-ethoxycoumarin. Differential stimulation of the maximal activities associated with these components was observed after the administration of phenobarbital, 3-methylcholanthrene, or 2,3,7,8-tetrachlorodibenzo-p-dioxin. The ED50 values for the induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin of 7-ethoxycoumarin O-deethylase and aryl hydrocarbon hydroxylase activities in C57BL/6J mice were almost identical and approximately 10-fold less than in DBA/2J mice similarly treated.

Animals↗