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At least 1,117 records · Page 62Linked to original sources
PubMed1999

Quantitative measure of genetic differences in susceptibility to noise-induced hearing loss in two strains of mice.

The CBA/CaJ (CB) and C57BL/6J (B6) inbred strains of mice were exposed for 1 h to noise intensities between 98 and 119 dB SPL. Previous studies indicated that the B6 mice exhibited permanent threshold shifts (PTS) after 1h exposure to 110 dB, whereas the CB mice did not exhibit any PTS. These differences in susceptibility to noise-induced hearing loss (NIHL) appear to be due to a gene for age-related hearing loss (AHL). The current study was designed to determine dose-response curves for NIHL over the ranges of intensities of noise that would characterize the B6 and CB inbred strains of mice. Because of the considerable differences in sensitivity to NIHL, the noise exposures for the two strains overlapped only at 110 and 113 dB. Nevertheless, the two strains exhibited two different dose-response curves, offset and with different slopes. We postulate that the B6 strain of mice exhibits a more linear increase for PTS from 98-113 dB, consistent with incremental effects on some metabolic physiological mechanism(s); the abrupt transition in NIHL between 113 and 116 dB for the CB mice is consistent with an ototraumatic structural injury.

Animals↗
PubMed2002

An approach for the quantitative consideration of genetic polymorphism data in chemical risk assessment: examples with warfarin and parathion.

In recent years, a great deal of research has been conducted to identify genetic polymorphisms. One focus has been to characterize variability in metabolic enzyme systems that could impact internal doses of pharmaceuticals or environmental pollutants. Methods are needed for using this metabolic information to estimate the resulting variability in tissue doses associated with chemical exposure. We demonstrate here the use of physiologically based pharmacokinetic (PBPK) modeling in combination with Monte Carlo analysis to incorporate information on polymorphisms into the analysis of toxicokinetic variability. Warfarin and parathion were used as case studies to demonstrate this approach. Our results suggest that polymorphisms in the PON1 gene, that give rise to allelic variants of paraoxonase, which is involved in the metabolism of paraoxon (a metabolite of parathion), make only a minor contribution to the overall variability in paraoxon tissue dose, while polymorphisms in the CYP2C9 gene, which gives rise to allelic variants of the major metabolic enzyme for warfarin, account for a significant portion of the overall variability in (S)-warfarin tissue dose. These analyses were used to estimate chemical-specific adjustment factors (CSAFs) for the human variability in toxicokinetics for both parathion and warfarin. Implications of alternatives in the calculation of CSAFs are explored. Key decision points for applying the PBPK-Monte Carlo approach to evaluate toxicokinetic variability for other chemicals are also discussed.

Animals↗
PubMed2002

Genetic dissection of quantitative trait loci specifying sedative/hypnotic sensitivity to ethanol: mapping with interval-specific congenic recombinant lines.

BACKGROUND: Linkage studies alone do not produce sufficient resolution to narrow the location of a quantitative trait locus (QTL) to a small-enough chromosomal region for gene identification. One solution to this problem is to use interval-specific congenic recombinant (ISCR) lines to narrow the chromosomal interval known to contain the QTL. In previous work, we mapped four QTLs for differential ethanol sensitivity in the inbred long-sleep (ILS) and inbred short-sleep (ISS) strains and generated reciprocal congenic strains in which each full QTL interval from ILS was bred onto the ISS background and vice versa. METHODS: ISCR lines were derived by identifying mice carrying recombination events in the congenic interval during backcrossing of the ISS.ILS.Lore congenics to ISS. Recombinant mice were backcrossed to ISS, and progeny carrying the ISCR chromosome were identified and tested to determine whether the ISCR region carried the donor Lore QTL. RESULTS: We developed multiple ISCR lines for each Lore QTL, in which the QTL interval was broken into a number of smaller intervals. For all four QTLs, we reduced the size of the interval, in one case to 3.7 cM. CONCLUSIONS: Use of ISCR lines can narrow each Lore candidate region to a few centimorgans. Such an interval size is conducive to brute-force approaches to identify candidate genes, entailing bioinformatics, gene expression, and DNA sequencing strategies.

Alcohol Drinking↗
PubMed1975

Fowl Immunoglobulins: Quantitation in Birds Genetically Resistant and Susceptible to Marek's Disease.

The development of serum immunoglobulins was observed in chicks genetically resistant (N line) and susceptible (P line) to Marek's disease (MD), in conditions free from infection with MD. IgG was present at hatching at about 5.0 mg/ml and decreased to about 0.5 mg/ml by 12 to 15 days. Active production of IgG was apparent at about 20 days of age and reached levels of 2.0 to 3.0 mg/ml by 67 days. Low levels of IgM were present at hatching, and a gradual increase was seen to 1.0 to 2.0 mg/ml by 67 days. IgA was not detectable at hatching; it appeared in N-line birds at 5 days and in P-line birds at 13 days, and by 67 days was about 0.10 to 0.13 mg/ml. After 30 to 40 days, immunoglobulin levels were generally higher in N-line than in P-line birds. However, it was concluded that no primary immunoglobin deficiency existed sufficient to explain the susceptibility of the P-line birds to MD.

Journal Article↗
PubMed1985

Quantitative comparison of genetic effects of ethylating agents on the basis of DNA adduct formation. Use of O6-ethylguanine as molecular dosimeter for extrapolation from cells in culture to the mouse.

DNA-adduct formation and induction of gene mutations were determined simultaneously after treatment with the four ethylating agents, ethyl methanesulfonate (EMS), ethylnitrosourea (ENU), diethyl sulfate (DES), and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG). Both, in E. coli K-12 (NAL-resistance) and in V79 Chinese hamster cells in culture (HPRT-deficiency), the frequencies of mutation induction by all chemicals were the same when plotted against the amount of O6-ethylguanine formed in DNA, suggesting that this DNA adduct can be used as a common dosimeter for the comparisons of the frequencies of gene mutations induced by ethylating agents in various mutagenicity assay systems. Using ENU, such a comparison was performed between mutation induction in V79 cells in vitro and in the specific-locus assay in the mouse. The data indicate that at equal levels of O6-ethylguanine in the DNA of V79 cells and in testicular DNA from male mice treated with ENU, the frequencies of induced mutants in both assay systems were quite similar. These results support the concept that the determination of premutagenic DNA adducts in vivo can be used to monitor exposure to chemical mutagens and that genetic risk estimations may ultimately be performed on the basis of such measurements and of comparative mutagenesis in vitro and in vivo.

Alkylating Agents↗
PubMed2002

[Quantitative analysis of genetic parameters in populations of European (Capreolus capreolus L.) and Siberian (Capreolus pygargus Pall.) roe deer with RAPD markers].

A technique for obtaining unbiased estimates of genetic parameters (allelic frequencies of RAPD loci, heterozygosity (H), Wright's F statistic, and Nei's genetic distances) in populations of the European (Capreolus capreolus L.) and Siberian (Capreolus pygargus Pall.) roe deer is presented. The technique employs jackknifing and multiple comparative analysis based on a modified Holmes's procedure for Bonferroni's test. It was demonstrated that samples from local groups of roe deer in the Trans-Ural region did not differ significantly in allelic frequencies (0.8, 0.81, and 0.78; P > 0.447) or Nei's genetic distances (0.0056, 0.0273, and 0.0218; P = 0.26), but they could be differentiated based on Wright's F statistic (0.0346, 0.0519, and 0.0450; P = 10(-9)). The parameters of intrapopulation heterozygosity (from 0.18 to 0.042) formed a gradient from the east to the west. Calibration estimates of molecular evolution rate in the family Cervidae obtained based on published data and Jukes-Cantor genetic distances estimated in this study demonstrated that the Siberian roe deer has split into two subspecies, C. pygargus pygargus Pall. and C. pygargus tianschanicus Satunin in the interval between 229 and 462.3 thousand years ago. The species formation of the Siberian and European roe deer was dated between 1.375 and 2.75 Myr ago. Based on the results obtained we recommend the approaches used in the study for analysis of population genetic structure and phylogenetic relationships between populations, subspecies, species, and higher taxa.

Animals↗
PubMedDate not supplied

[Attempt at quantitative estimation of genetic effects of chemical pollution of atmospheric air in urban populations].

Epidemiological investigation of spontaneous abortions and congenital anomalies in three towns of Ukraine has shown that mutation rate in Mariupol, the most contaminated town, as compared with relatively clean town is essentially higher. Genetical consequences due to environmental chemical pollution in Mariupol proved to be equivalent to the chronic influence of ionizing radiation for 30 years in the dose of 230 REM.

Abortion, Spontaneous↗
PubMed1991

Quantitative analysis of genetic susceptibility to liver and lung carcinogenesis in mice.

One-week-old male and female mice of the A, BALB/c (C), and C3H/He (C3) strains and of the AC3 and CC3 F1 hybrids were treated with a single dose (300 mg/kg s.c.) of urethan and then kept without further treatment until 30 and 40 weeks (males) or 30 and 65 weeks (females). The degree of difference in susceptibility to hepatocarcinogenesis between the susceptible C3 and the resistant A and C mice, in the different age and sex groups, was 4-12-fold by the analysis of the number of nodules/cm3 (N/cm3), which represents an estimation of tumor frequency and was more than 400-fold as indicated by the percentage of liver volume occupied by nodules (V%), an estimation of tumor size. With regard to lung carcinogenesis, mice of the A strain proved 5-10- and 20-70-fold more susceptible than the C and the C3 mice, respectively, as indicated by the number of microscopically identified lung tumors/mouse (N), an estimation of tumor frequency. The lung tumor size, as estimated by the mean tumor volume (V), was similar in A and C mice but much higher in the A than in the C3 groups (13- approximately 1000-fold difference). The AC3 hybrid was highly susceptible to both liver and lung carcinogenesis. The CC3 hybrid was as susceptible to lung carcinogenesis as its C parent and had an intermediate susceptibility to hepatocarcinogenesis. Our results indicate that a major determinant in the genetic susceptibility to hepatocarcinogenesis, and perhaps to lung carcinogenesis too, is tumor growth, as evidenced by a much greater tumor size in genetically susceptible than resistant mice.

Age Factors↗