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Considerations in the Design and Conduct of Subchronic and Chronic Dermal Exposure Studies with Chemicals
Published in David W. Hobson, Dermal and Ocular Toxicology, 2020
The nature and severity of a toxic response is not only a function of the sensitivity of the animal species used in the study, but also may be related to the strain used within a given species. In selecting an appropriate animal strain, genetics (i.e., whether the animals are inbred, hybrid, or outbred) is usually an important consideration. Many laboratories have experience with outbred strains because they are more readily available and these strains are commonly more disease resistant than inbred animals. However, randomly bred strains are subject to genetic drift and this can produce considerable variation in response. On the other hand, inbred strains are single genotypes and may not be representative of the species. F1 hybrids are a uniform genotype, but they have a level of heterozygosity more closely resembling the outbred animals.1,3
Chromosome Pairing and Fertility in Plant Hybrids
Published in Christopher B. Gillies, Fertility and Chromosome Pairing: Recent Studies in Plants and Animals, 2020
L. temulentum and L. perenne differ in nuclear DNA amount by about the same degree as the parents of the fescue hybrid,51 and the “extra” DNA of L. temulentum is apportioned roughly equally among the chromosomes of its complement,11 again like the fescue hybrid. However, this hybrid has a chiasma frequency at metaphase I similar to one of its parents, with less than 20% of pollen mother cells containing univalents. Nevertheless, the F1 hybrid is male-sterile, but will produce progeny when backcrossed as female to L. perenne.51 As expected, pairing at pachytene is regular and complete, with structural differences appearing as loops under the light microscope,13,23,24 as in the hybrids of Allium and Festuca. Since all the chromosomes are paired, unlike in the Festuca hybrid, it was hoped to locate the sites of amplified DNA within the entire complement simply by mapping the intrachro-mosomal positions of loops. Unfortunately, this proved not to be possible under the light microscope because the chromosomes were too long and intertwined to allow a detailed comprehensive analysis.11 It was necessary to employ a more sensitive technique, that of three-dimensional reconstruction of SCs, which would not only reveal the distribution of loops both within and between the chromosomes of the complement, but also the ultrastructure of the loops themselves.
Genetic and Developmental Implications for Trace Metal metabolism from Mutant and Inbred Strains of Animals
Published in Owen M. Rennert, Wai-Yee Chan, Metabolism of Trace Metals in Man, 2017
The possibility also exists for interactions between the maternal and fetal genotypes. Such possibilities must be considered by examining the results from reciprocal crosses, including the outcrosses to produce the F1 progeny and the backcrosses of the F1 hybrids to the parental inbreds. Wolkowski made such crosses, and her results demonstrate that there was an effect of the BIO maternal genotype. The F1 progeny exhibited a 7% higher incidence (than saline controls) of embryotoxicity when the dam was BIO but not when the dam was NAW. This 7% divided by the maximally observed 46% embryotoxicity amounts to a maternal effect of approximately 15%. A similar maternal effect was observed among backcross progenies of the BIO dams.
Dose-dependent long-term effects of a single radiation event on behaviour and glial cells
Published in International Journal of Radiation Biology, 2021
Marie-Claire Ung, Lillian Garrett, Claudia Dalke, Valentin Leitner, Daniel Dragosa, Daniela Hladik, Frauke Neff, Florian Wagner, Horst Zitzelsberger, Gregor Miller, Martin Hrabĕ de Angelis, Ute Rößler, Daniela Vogt Weisenhorn, Wolfgang Wurst, Jochen Graw, Sabine M. Hölter
This study is part of the INSTRA project, first presented in 2018 (Dalke et al. 2018). F1 hybrids of a C57BL/6J female and a C3HeB/FeJ male were used as wt; as heterozygous mutants F1 hybrids of a wild-type C57BL/6JG mother and a homozygous Ercc2S737P father on C3HeB/FeJ background (Kunze et al. 2015) were used as het. This breeding schedule was chosen, because the recessive Ercc2S737P mutation was bred on the C3H strain background suffering from a recessive retinal degeneration caused by a mutation in the Pde6b gene (Pittler and Baehr 1991). To overcome this situation, we crossed homozygous male mutants (homozygous female mutants are sterile) with female C57BL/6JG mice resulting in healthy het Ercc2S737P mutants. Importantly, these mice are also het for the two parental strains (F1 hybrids), thus keeping the genetic background comparable.
Therapeutic implications of NK cell regulation of allogeneic CD8 T cell-mediated immune responses stimulated through the direct pathway of antigen presentation in transplantation
Published in mAbs, 2018
J.I. Rodriguez-Barbosa, M.C. Ferreras, L. Buhler, N.D. Jones, P. Schneider, J.A. Perez-Simon, M.L. del Rio
NK cells are also very sensitive to changes on MHC class I expression. Thus, cells expressing MHC class I mismatched molecules or autologous cells lacking self-MHC class I molecules or cells in which self-MHC class I molecules are down-regulated (missing self-theory) become targets for NK cell-mediated cytolysis.5–7 Moreover, lethally irradiated F1 hybrid mice spontaneously reject parental bone marrow cells (BMCs) or hematopoietic cells, a phenomenon against the laws of transplantation named “hybrid resistance”, first described by Snell et al., and then confirmed by others.8–11
Posterior subcapsular cataracts are a late effect after acute exposure to 0.5 Gy ionizing radiation in mice
Published in International Journal of Radiation Biology, 2021
Sarah Kunze, Alexander Cecil, Cornelia Prehn, Gabriele Möller, Andreas Ohlmann, Gerhild Wildner, Stephan Thurau, Kristian Unger, Ute Rößler, Sabine M. Hölter, Soile Tapio, Florian Wagner, Andreas Beyerlein, Fabian Theis, Horst Zitzelsberger, Ulrike Kulka, Jerzy Adamski, Jochen Graw, Claudia Dalke
Taking together, using histological analysis we observed a significant increase in PSCs at the highest dose of 0.5 Gy (14 PSCs), when compared to the nonirradiated controls (2 PSCs) at 12 to 24 months after irradiation. This finding is in line with previous reports, which found stage I cataracts in mice following an irradiation of 0.5 Gy (based upon the classification of Merriam and Focht 1962). However, we did not observe any severe forms of cataract such as nuclear cataracts, neither by Scheimpflug imaging nor by histology. In addition to the PSCs, just two ASCs were found, both in the 0.5 Gy group, at 18 and 24 months after irradiation. Therefore, the question remains open whether the difference between the observations demonstrated here and in our previous paper (Dalke et al. 2018) and those previously published by others (Hall et al. 2006; Merriam and Focht 1962; Worgul et al. 2002; Worgul et al. 2005) is due to the use of different mouse strains with perhaps different radiation sensitivity. It is known since decades that mice strains show different sensitivity to radiation exposure (Roderick 1963) and this fact has potential impact on the outcome of a study, depending on the mouse strain used. In this study, we used a F1 hybrid strain of a cross between C57BL/6J and C3H (B6C3F1) mice. While the C57BL/6J strain shows medium radiation sensitivity and C3HeB/FeJ mice are one of the highly radiation sensitive strains (Roderick 1963) the F1 hybrids in this study seem to have a higher radioresistance compared to the pure strains. Different strain-related radiosensitivity was also found in lens epithelial cells from various mouse strains, tested by DNA damage response after irradiation (Barnard et al. 2018). Also the heterozygous Ercc2 mutation (Ercc2+/S737P) caused an increased radiation sensitivity in lymphocytes compared to wild type (Kunze et al. 2015). On the other hand, in this study the Ercc2+/S737P mutation has no measurable impact upon the incidence of PSC and obviously does not enhance the radiation sensitivity of Ercc2+/S737P mice. It should be noted that our analyses were not corrected for multiple testing, because this was mainly an explorative study with small sample sizes. Hence, some of our findings may be false positive, which might possibly explain why we observed seemingly inconsistent age effects for several outcomes. Therefore, all findings basically require confirmation from validation studies.