Differential spermatogenic response of mice to the induction of mutations by antineoplastic drugs

Ehling, U.H.

doi:10.1016/s0027-5107(74)80026-6

Cited by 121 publications

(18 citation statements)

References 31 publications

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“…Human single doses are typically between 10 and 20 mg/m 2 (23), with the equivalent mouse dose of 3 to 6 mg/kg. The results of previous studies have shown that exposure of male mice to >5 mg/kg of mitomycin C significantly increases the mutation rate in premeiotic spermatogonia (33,34). Our SM-PCR data further show the mutagenicity of this drug.…”

Section: Resultssupporting

confidence: 77%

Single-Molecule PCR Analysis of Germ Line Mutation Induction by Anticancer Drugs in Mice

2008

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Understanding and estimating the genetic hazards of exposure to chemical mutagens and anticancer drugs in humans requires the development of efficient systems for monitoring germ line mutation. The suitability of a single-molecule PCRbased approach for monitoring mutation induction at the mouse expanded simple tandem repeat (ESTR) locus Ms6-hm by chemical mutagens and anticancer drugs has been validated. The frequency of ESTR mutation was evaluated in the germ line of male mice exposed to the well-characterized alkylating agent and mutagen, ethylnitrosourea, and four widely used anticancer drugs, bleomycin, cyclophosphamide, mitomycin C, and procarbazine. The dose-response of ethylnitrosourea-induced mutation was found to be very close to that previously established using a pedigree-based approach for ESTR mutation detection. Paternal exposure to the clinically relevant doses of bleomycin (15-30 mg/kg), cyclophosphamide (40-80 mg/kg), and mitomycin C (2.5-5 mg/kg) led to statistically significant, dose-dependent increases in ESTR mutation frequencies in the germ line of treated male mice. Exposure to procarbazine led to a maximal increase in mutation frequency at 50 mg/kg, with a plateau at the higher concentrations. The results of this study show that the singlemolecule PCR technique provides a new and efficient experimental system for monitoring the genetic effects of anticancer drugs, capable of detecting increases in mutation rates at clinically relevant doses of exposure. In addition, this approach dramatically reduces the number of mice needed for the measurement of germ line mutation induction.

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Section: Resultssupporting

confidence: 77%

Single-Molecule PCR Analysis of Germ Line Mutation Induction by Anticancer Drugs in Mice

2008

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“…Certain basic patterns of efficacy become apparent as stage specificities of various mutagens are compared. Some, such as methyl methanesulfonate and ethylene oxide, are only active as mutagens in post-meiotic stages, as demonstrated by both specific locus and dominant lethal studies (Ehling, 1974;Generoso et al, 1986;Russell et al, 1990). Others, such as procarbazine hydrochloride and melphalan act as mutagens in both pre-and post-meiotic stages (Generoso et al, 1986;Russell et al, 1990Russell et al, , 1992.…”

Section: Resultsmentioning

confidence: 99%

Dominant lethal effects of nocodazole in germ cells of male mice

Attia

Ahmad

Okash³

et al. 2015

Food and Chemical Toxicology

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“…Change in genetic sensitivity of germline cells at different spermatogenesis stages depending on the structure (activity) of the substance and its concentration was established as early as in the 1960s [28][29][30][31][32][33][34][35].…”

Section: Resultsmentioning

confidence: 99%

Genetic Effects Induced by Nickel Sulfate in Germline and Somatic Cells of WR Mice

Domshlak¹,

Елаков²,

Osipov³

2005

Russ J Genet

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We examined the effects of nickel sulfate at doses 0.5 to 5.0 mg/kg (1/200-1/20 LD 50 ) on the frequency of dominant lethal mutations and double-strand DNA breaks (DSBs) in germline cells and on an increase in frequency in gene mutations W y in pigment cells of first-generation mice. The results indicated that spermatogenesis stages most sensitive to nickel sulfate (at a dose of 1.0 mg/kg) are spermatozoids, early spermatids, late spermatocytes, and stem spermatogonia. No statistically significant increase in the total TSB level was detected in spermatozoids 4 weeks after exposure. At the same time, a significant ( P < 0.05) increase in percentage of cells with an extremely high level of DNA fragmentation (supposedly apoptotic cells) was observed upon exposure at a dose of 0.5 mg/kg. Nickel sulfate at doses of 5.0 and 1.0 mg/kg induced a marked increase in the c-kit gene expression in pigment cells of heterozygous first-generation WR mice as compared to control ( P < 0.001). It was shown that the nonobservable adverse effect level (NOAEL) of nickel sulfate on the dominant lethal mutation frequency and gene mutations was 1/200 LD 50 , while the lowest observable adverse effect level (LOAEL) was

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Differential spermatogenic response of mice to the induction of mutations by antineoplastic drugs

Cited by 121 publications

References 31 publications

Single-Molecule PCR Analysis of Germ Line Mutation Induction by Anticancer Drugs in Mice

Single-Molecule PCR Analysis of Germ Line Mutation Induction by Anticancer Drugs in Mice

Dominant lethal effects of nocodazole in germ cells of male mice

Genetic Effects Induced by Nickel Sulfate in Germline and Somatic Cells of WR Mice

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