Julie A Skare - Academia.edu (original) (raw)

Papers by Julie A Skare

Springer eBooks, 1982

We presented evidence that primary cultures of rat pituitary cells respond to estradiol by increa... more We presented evidence that primary cultures of rat pituitary cells respond to estradiol by increased incorporation of precursors into prolactin. The response is specific for estrogenic hormones and is maximal at physiological concentrations of estradiol. The time course and magnitude of the response in cultured cells is in agreement with that observed under in vivo conditions, suggesting that estrogen exerts its effect mainly through a direct action on the pituitary gland. The data presented indicate that estrogen stimulates prolactin synthesis predominantly through increased prolactin mRNA accumulation, and to a lesser extent, through mammotroph cell proliferation. Chronic treatment with DES caused sustained proliferation of pituitary cells leading to prolactin producing pituitary tumors in the Fischer 344 rat, but not in the Holtzman rat. The genetic basis for these differences are currently under investigation.

Endocrinology, 1981

An 8-week period of continuous diethylstilbestrol (DES) treatment results in the development of p... more An 8-week period of continuous diethylstilbestrol (DES) treatment results in the development of pituitary tumors in 100% of male or female F344 rats. Similar treatment of Holtzman male or female rats results in a very low incidence of pituitary tumor development (2-6%). A series of crosses was performed between F344 and Holtzman rats to produce the F1 hybrid, the F2 generation, and the backcrosses of the F1 hybrid to either the F344 parent or the Holtzman parent. The incidence of DES-induced pituitary tumors was measured in these animals. The results indicate that pituitary tumor susceptibility does not result from the expression of genes that are simple dominant or recessive genes, since the tumor's incidence in the F1 hybrid is intermediate to that in the parental strains. However, the data are compatible with the involvement of a small number of genetic loci. We present a genetic model involving three independently segregating loci which agrees reasonably well with the experimental results. In the model, the Holtzman strain has normal alleles at these loci which prevent uncontrolled proliferation. The highly inbred F344 strain is homozygous mutant at these three loci and in unable to control DES-induced proliferation.

Veterinary and human toxicology, 1997

We studied accidental exposure to pediatric cough/cold medications in children under 6-y-of-age t... more We studied accidental exposure to pediatric cough/cold medications in children under 6-y-of-age to determine whether the presence of an antihistamine (chlorpheniramine) in the product increased the likelihood for adverse outcomes. General accidental exposure cases reported to the American Association of Poison Control Centers (AAPCC) during 1988-1992 were analyzed for specific over-the-counter cough/cold pediatric products containing identical concentrations of active ingredients except for the presence or absence of chlorpheniramine. These case reports were evaluated for differences in medical outcome, symptom assessment, management site and therapy, as coded by poison control centers participating in the AAPCC Toxic Exposure Surveillance System. A total of 10,289 cases of accidental exposures were evaluated for the specific products included in this analysis. While these cases represented a small percentage of total exposures to these products (approximately 3% of total cases in c...

Mutation Research/Genetic Toxicology, 1989

The genotoxicity of zinc was examined in 4 short-term mutagenicity assays. Zinc acetate produced ... more The genotoxicity of zinc was examined in 4 short-term mutagenicity assays. Zinc acetate produced dose-related positive responses in the L5178Y mouse lymphoma assay and an in vitro cytogenetic assay with Chinese hamster ovary cells, but was negative in the Salmonella mutation assay and did not induce unscheduled DNA synthesis in primary cultures of rat hepatocytes. Zinc-2,4-pentanedione produced frameshift mutations in Salmonella tester strains TA1538 and TA98, but did not induce unscheduled DNA synthesis in primary cultures of rat hepatocytes. The effect of ligand binding of zinc in the in vitro test systems is discussed.

Endocrinology, 1981

The pituitary response to chronic estrogen treatment was studied in two strains of rats, the Fisc... more The pituitary response to chronic estrogen treatment was studied in two strains of rats, the Fischer 344 (F344) and the Holtzman. Silastic tubing implants containing diethylstilbestrol (DES) were placed in weanling animals. Uterine and pituitary growth and protein synthesis were monitored over an 8-week period. The incorporation of [3H]leucine into PRL and GH was measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Both F344 and Holtzman strains respond to chronic DES with an increase in PRL synthesis. PRL synthesis is 7% of the total protein synthesis in ovariectomized female controls of both strains and increases to 40–50% in 8-week DEStreated F344 rats and to 35–45% in Holtzman rats. The uterine growth responses were similar in both strains and reached a plateau after approximately 2 weeks. Despite their similarity in PRL synthesis and uterine growth, these two strains differ dramatically in their pituitary growth response to DES. In the F344 strain, pituitaries from treated animals a...

Endocrinology, 1982

Anterior pituitary nuclei isolated from rats were used in an in vitro DNA synthesis assay. The ra... more Anterior pituitary nuclei isolated from rats were used in an in vitro DNA synthesis assay. The rate of in vitro synthesis was increased by prior in vivo estrogen treatment in a time-dependent and dose-dependent manner, and the observed increase was similar in magnitude to that measured by [3H] thymidine incorporation in whole tissue. In vitro DNA synthesis was sensitive to N-ethylmaleimide but resistant to dideoxythymidine triphosphate. Rates of pituitary DNA synthesis were compared in the Fischer 344 (F344) rat, a strain highly susceptible to diethylstilbestrol-induced pituitary tumors, and in the Holtzman rat, a strain resistant to rapid tumor induction by diethylstilbestrol. After chronic treatment (8 weeks) with estrogen, elevated DNA synthesis (2- to 3-fold) was observed in F344 pituitaries but not in Holtzman pituitaries. After short term (2-4 days) treatment with estrogen, however, DNA synthesis increased 2-fold in both Holtzman and F344 pituitary nuclei. The elevated DNA synthesis declined in the Holtzman strain after 5 or 6 days of additional estrogen treatment, but elevated DNA synthesis persisted in the F344 strain. These results suggest that the genetic difference is due to the lack of a proliferation control mechanism in the F344 strain that functions in the Holtzman strain to shut off estrogen-stimulated cell proliferation.

Food and Chemical Toxicology, 1990

Olestra, a mixture of hexa-, hepta- and octa-esters formed from the reaction of sucrose with long... more Olestra, a mixture of hexa-, hepta- and octa-esters formed from the reaction of sucrose with long-chain fatty acids, was evaluated for its genotoxic potential in the Salmonella/mammalian microsome test, the L5178Y thymidine kinase (TK+/-) mouse lymphoma assay, an unscheduled DNA synthesis assay in primary rat hepatocytes, and an in vitro cytogenetic assay in Chinese hamster ovary cells. The results indicated that olestra was non-genotoxic in these assays.

… medicine and biology, 1981

1. Adv Exp Med Biol. 1981;138:151-63. Regulation of pituitary growth and prolactin gene expressio... more 1. Adv Exp Med Biol. 1981;138:151-63. Regulation of pituitary growth and prolactin gene expression by estrogen. Lieberman ME, Maurer RA, Claude P, Wiklund J, Wertz N, Gorski J. We presented evidence that primary cultures ...

Journal of Pharmaceutical Sciences, 1996

Food Chem Toxicol, 2004

In the organism of mammals, important detoxification pathways of arylamines are catalysed by N-ac... more In the organism of mammals, important detoxification pathways of arylamines are catalysed by N-acetyltransferase 2 (NAT2). A recent case-control epidemiology study suggested that human NAT2 slow acetylators exposed to oxidative hair dyes may be at greater risk to develop bladder cancer. We therefore profiled urinary [14C]-metabolites and NAT2 genotype in eight human subjects following treatment with a dark-shade oxidative hair dye containing [14C]-para-phenylenediamine (PPD). Genotyping identified three subjects as slow, and five subjects as intermediate NAT2 acetylators. Within 24 h after treatment, the study subjects excreted a mean total of 0.43 ± 0.24% of the applied [14C] in the urine, where five different metabolites were found. The major urinary metabolites were concluded to be N-mono-acetylated and N,N′-diacetylated PPD. They were present in all urine samples and amounted to 80–95% of the total urinary [14C]. Another metabolite, possibly a glucuronic acid conjugate, was found in 6/8 urine samples at 5–13% of the total urinary [14C]. All metabolites appeared to be related to PPD, no evidence of the presence of high-molecular weight dye-intermediates or corresponding metabolites was found. The metabolite profile in the study subjects showed no significant differences between the NAT2 intermediate and NAT2 slow acetylator subgroups. Urine of NAT2 slow acetylators contained N-mono-acetylated-PPD at 42.2 ± 10.2% and N,N′-di-acetylated-PPD at 54.1 ± 7.6% of total urinary radioactivity, while the corresponding values of intermediate acetylators were 46.0 ± 8.9% and 45.7 ± 9.9%, respectively. Overall, our results suggest that the human acetylation rate of PPD after topical application is independent of the NAT2 genotype status, most likely due to metabolism by epidermal NAT1 prior to systemic absorption.

Mutation Research/Genetic Toxicology, 1986

Oral administration of up to 84 mg/kg of NaF to adult male rats did not induce DNA-strand breaks ... more Oral administration of up to 84 mg/kg of NaF to adult male rats did not induce DNA-strand breaks in testicular cells when measured by alkaline elution. Although plasma fluoride levels were as high as 12 ppm is rats given 84 mg/kg of NaF, testicular fluoride levels in most cases were only 10-20% of plasma levels. Fluoride did not accumulate in the testes after 5 daily treatments. Therefore, it is unlikely that NaF, even at high doses, poses a hazard with respect to heritable genetic effects.

Mutation research, 1984

The alkaline elution technique was used to measure DNA damage in the rat testis after intraperito... more The alkaline elution technique was used to measure DNA damage in the rat testis after intraperitoneal injection of 3 chemicals known to cause heritable mutations in rodents. These 3 chemicals are triethylenemelamine (TEM), mitomycin C, and cyclophosphamide. All three of these chemicals produced DNA damage which was readily detectable by alkaline elution. Both TEM and mitomycin C produced DNA interstrand cross-links, although TEM was a more potent cross-linker on an equimolar basis than mitomycin C. Cyclophosphamide produced both DNA cross-links and DNA strand breaks. Alkaline elution in the absence of proteinase K indicated that some of the strand breaks appeared to be closely associated with protein. These studied indicate that the alkaline elution technique is capable of detecting DNA damage in mammalian germ cells produced by chemical mutagens. This technique may prove useful as a screening tool for identifying chemicals which cause heritable mutations in mammals.

Regulatory Toxicology and Pharmacology, 2015

Mutation Research/Genetic Toxicology, 1986

Sodium fluoride (NaF) was assayed for the induction of DNA-repair synthesis in WI-38 human diploi... more Sodium fluoride (NaF) was assayed for the induction of DNA-repair synthesis in WI-38 human diploid fibroblasts and in primary cultures of rat hepatocytes. DNA-repair synthesis in non-replicating DNA was measured by ultracentrifugation of density-labeled DNA in CsCl gradients. When this method was used, NaF did not induce DNA-repair synthesis in either of these cell types. However, when NaF was assayed for induction of unscheduled DNA synthesis (UDS) in rat hepatocytes by autoradiography, an increased net nuclear grain count was observed. Because the autoradiographic results were not confirmed by density-gradient ultracentrifugation of hepatocyte DNA, which is a more definitive technique, it is doubtful whether the autoradiographic results actually represent DNA-repair synthesis. Modifications of the UDS/autoradiography protocol to include more extensive washing resulted in no UDS response. Published reports (Hellung-Larsen and Klenow, 1969; Srivastava et al., 1981) describe the formation of precipitable complexes of Mg2+, F-, and [3H]thymidine triphosphate which suggests that autoradiographic measurement of UDS may lead to artifacts when testing NaF unless extensive washing of the cultures is employed.