Current status of bioassays in genetic toxicology — The dominant lethal assay

Green, Sídney; Auletta, Angela E.; Fabricant, Jill D.; Kapp, Robert W.; Manandhar, Madhu; Sheu, C.W.; Springer, Janet A.; Whitfield, Brad

doi:10.1016/0165-1110(85)90009-0

Cited by 92 publications

(12 citation statements)

References 119 publications

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“…Results were analyzed according to recently published recommendations for statistical analysis of dominant-lethal data (16); to achieve desirable distributional properties prior to conduct of parametric testing procedures, a data-clustering scheme was employed which has been extensively evaluated for its applicability to dominant-lethal data (31).…”

Section: Methodsmentioning

confidence: 99%

“…Dominant lethal mutations result from DNA damage in male germ cells sufficient to cause pre-and/or postimplantation embryonic deaths in females bred to genotoxicant-exposed males (15). Postimplantation loss is the more reliable index of genotoxicity, since preimplantation loss can result not only from genotoxicity but also from cytotoxic events that lead to failure of fertilization (16).…”

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confidence: 99%

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Role of epididymal inflammation in the induction of dominant lethal mutations in Fischer 344 rat sperm by methyl chloride.

Chellman¹,

Bus²,

Working³

1986

Proc. Natl. Acad. Sci. U.S.A.

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This study assessed the possible relationship between methyl chloride (MeCl)-induced epididymal inflammation and the formation of dominant lethal mutations in sperm of Fischer 344 rats. Groups of 40 males were exposed to MeCl (3000 ppm 6 hr/day for 5 days), with or without concurrent treatment with the anti-inflammatory agent 3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW 755C; 10 mg/kg, i.p. 1 hr pre-and postexposure); BW 755C was shown previously to inhibit MeCl-induced epididymal inflammation. Control groups (n = 20) were either untreated, injected as described above with BW 755C, or injected on the afternoon of day 5 with triethylenemelamine (0.2 mg/kg), a known dominant lethal mutagen. Each male was caged with one female weekly for 3 weeks; 12-18 days after mating, females were killed to assess dominant lethal parameters. In females bred to MeCl-exposed males, significant increases were observed in postimplantation loss at postexposure week 1 (0.84 dead implants per female vs. 0.29 in untreated controls) and in dead implants/total implants at both week 1 (0.10 vs. 0.04 control) and week 2 (0.24 vs. 0.06 control). These increases were not observed in females bred to males treated with BW 755C during MeCl exposure. Coadministration of BW 755C to males along with MeCl also reduced the percentage of mated females with two or more postimplantation losses from 31% to 8% (week 1) and 30% to 12% (week 2). Therefore, the dominant lethal mutations induced by MeCl appear to be a consequence of its induction of inflammation in the epididymis. These data demonstrate the potential genotoxicity of inflammatory processes in vivo.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Role of epididymal inflammation in the induction of dominant lethal mutations in Fischer 344 rat sperm by methyl chloride.

Chellman¹,

Bus²,

Working³

1986

Proc. Natl. Acad. Sci. U.S.A.

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“…The dominant lethal assay was performed according to the standard protocol (Ehling et al 1978;Green et al 1985). Because there was no data on the reproductive genotoxicity of Ascaris chymotrypsin inhibitor in mice, the current study was designed to prescreen the effects on the main periods of spermatogenesis in a pilot experiment using a minimal number of females.…”

Section: Dominant Lethal Assay In Micementioning

confidence: 99%

“…Results were analyzed according to published recommendations for statistical analysis of dominant-lethal data (Green et al 1985;Adler et al 1998). The data were taken only from fertile mating as indicated by the presence of at least one implant in the uterus.…”

Section: Dominant Lethal Assay In Micementioning

confidence: 99%

Mutagenicity of Ascaris chymotrypsin inhibitor in germ cells of mice

Błaszkowska

2007

Cell Biol Toxicol

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Chymotrypsin inhibitor isolated from Ascaris suum (ACHI) was tested for the induction of dominant lethal mutations in male mice. Dominant lethal effects of ACHI for the main stages of germ cell development were analyzed by mating at specific time points after dosing. Two groups of adult BALB/c males received 24 or 40 mg per kilogram body weight (BW) per day intraperitoneal (IP) injection of ACHI in sterile phosphate-buffered saline (PBS) for five consecutive days (subacute exposure). Males from a third group were administered single IP injections of ACHI-60 mg/kg BW (acute exposure). The control group received concurrent injections of PBS for five successive days. After the last dose, each male was mated with two untreated females. For fractionated examination with regard to successive germ cell stages (spermatozoa, spermatids, spermatocytes, spermatogonia), every second week, two other untreated virgin females were placed with each male for mating. The uteri of the females were inspected on the 15th day of gestation, and preimplantation loss and postimplantation loss determined from dominant lethal parameters. Exposure of mice germ cells to ACHI did not impair mating activity of males. Fertility index was reduced (P < 0.05) only for females mated at the third week with males exposed to the highest dose of ACHI. In the females bred to ACHI-treated males, significant (P < 0.05) increase in preimplantation loss was observed at postinjection weeks 1 (reflecting exposure to spermatozoa after single treatment and to spermatozoa or late spermatids after subacute dosing) and 3 (reflecting exposure to mid and early spermatids for acute dosing and to mid and early spermatids or late spermatocytes following acute treatment), regardless of dose and length of exposure to the inhibitor. At the 60-mg/kg-BW group, a significant increase of this parameter was also noted at week 5 (reflecting exposure to early spermatocytes). During mating days 15-21, a significant (P < 0.05) increase in postimplantation loss and dominant lethal effects were observed for all doses of ACHI. Acute ACHI exposure 5 weeks prior to mating resulted in dominant lethal effects in early spermatocytes. These preliminary data suggest that ACHI induces dominant lethal mutations at postmeiotic and meiotic stages of spermatogenesis, but spermatids are the most sensitive cell stage to the effect of ACHI. These results show that ACHI may be one of the factors causing disturbances in spermatogenesis leading to a reduction of host reproductive success.

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“…The control group received 1 mL of distilled water following the same protocol as the treatment group. Each animal of groups T1 and C1 was mated with 2 untreated virgin females in estrus from the second to the eighth week of treatment (Green et al, 1985;Zenick et al, 1994) whereas each animal of groups T2 and C2 was mated with 2 untreated virgin females in estrus one week before the beginning of treatment and on the week following the end of treatment. The presence of spermatozoa in the vaginal smear indicated successful mating and was considered as day one of gestation (Gleich and Frohberg, 1977;Kato et al, 1979).…”

Section: Treatment and Mating Proceduresmentioning

confidence: 99%

Absence of mutagenic effect of Mikania glomerata hydroalcoholic extract on adult wistar rats in vivo

Sá

Leite

Peters

et al. 2006

Braz. arch. biol. technol.

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This work makes an assessment of the dominant lethality of Mikania glomerata in male Wistar rats. Adult male received 1 mL of M. glomerata hydroalcoholic extract at a dose level of 3.3 g/kg body weight for 52 days and were mated with untreated females for seven weeks (group 1) or one week prior to the beginning of treatment and on the week following the end of treatment (group 2). The parameters analyzed were: number of implanted embryos, resorptions and corpora lutea; mating, gestation, preimplantation loss, implantation and resorption indexes (group 1); number of offspring and weaning animals (group 2). The administration of M. glomerata did not show any impairment of fertility and no significant difference in the parameters analyzed, suggesting an absence of mutagenic effect on Wistar rats.

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Current status of bioassays in genetic toxicology — The dominant lethal assay

Cited by 92 publications

References 119 publications

Role of epididymal inflammation in the induction of dominant lethal mutations in Fischer 344 rat sperm by methyl chloride.

Role of epididymal inflammation in the induction of dominant lethal mutations in Fischer 344 rat sperm by methyl chloride.

Mutagenicity of Ascaris chymotrypsin inhibitor in germ cells of mice

Absence of mutagenic effect of Mikania glomerata hydroalcoholic extract on adult wistar rats in vivo

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