Radiation-induced malformations after exposure of murine germ cells in various stages of spermatogenesis

Müller, Wolfgang‐Ulrich; Streffer, C.; Wójcik, Andrzej; Niedereichholz, F.

doi:10.1016/s0027-5107(99)00028-7

Cited by 21 publications

(10 citation statements)

References 22 publications

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“…11 There are some interesting findings from experimental research about the male mediated teratogenetic and mutagenetic effects on germ cells covering various stages of spermatogenesis. [2][3][4][5][6] Multiple mechanisms seem to be involved, including cytogenetic damage, proliferation arrest or delay, and fertilisation failure. 2 Extrapolations from results of experimental studies to humans are complicated because there are structural and functional differences between species, and the mechanisms of harmful effects are seldom known.…”

Section: Resultsmentioning

confidence: 99%

“…The role of paternal exposure received less attention despite animal evidence showing that exposures of males to toxic agents may result in congenital malformations in offspring. [2][3][4][5][6][7][8][9] With increasing concern about male reproductive function in the past decade, epidemiological studies are being published considering the role of paternal exposures by evaluating paternal occupations and risk of birth defects.…”

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confidence: 99%

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Review of recent epidemiological studies on paternal occupations and birth defects

Chia

Lm²

2002

Occup Environ Med

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The main findings reported by recent epidemiological studies on paternal occupations and birth defects are reviewed, and the main limitations associated with these studies discussed. Epidemiological studies on paternal occupations and birth defects were reviewed for the period 1989 to 1999 inclusive. Systematic searches were made with search engines with related keywords. There were several common paternal occupations that were repeatedly reported to be associated with birth defects. These paternal occupations were janitors, painters, printers, and occupations exposed to solvents; fire fighters or firemen; and occupations related to agriculture. The common weaknesses in most of these studies include inaccurate assessment of exposures, different classification systems, different inclusion criteria of birth defects, and low statistical power. It is concluded that epidemiological studies, reported in the past decade, suggest that several common paternal occupations are associated with birth defects. Future studies could be focused on these specific, rather than general, occupational groups so that causative agents may be confirmed and thus enable appropriate preventive measures to be taken.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Review of recent epidemiological studies on paternal occupations and birth defects

Chia

Lm²

2002

Occup Environ Med

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“…The lower mutant frequency was maintained throughout the remainder of spermatogenesis. These observations suggest that mechanisms operate to provide spermatozoa with a low mutant frequency.The specific-locus test and analysis of embryonic malformations have been used to indirectly study germ line mutagenesis in mice (19,44,47,52). These studies revealed a differential susceptibility to induced mutagenesis.…”

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confidence: 99%

“…The specific-locus test and analysis of embryonic malformations have been used to indirectly study germ line mutagenesis in mice (19,44,47,52). These studies revealed a differential susceptibility to induced mutagenesis.…”

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confidence: 99%

Base Excision Repair Is Limited by Different Proteins in Male Germ Cell Nuclear Extracts Prepared from Young and Old Mice

Intano

McMahan

McCarrey

et al. 2002

Molecular and Cellular Biology

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The combined observations of elevated DNA repair gene expression, high uracil-DNA glycosylase-initiated base excision repair, and a low spontaneous mutant frequency for a lacI transgene in spermatogenic cells from young mice suggest that base excision repair activity is high in spermatogenic cell types. Notably, the spontaneous mutant frequency of the lacI transgene is greater in spermatogenic cells obtained from old mice, suggesting that germ line DNA repair activity may decline with age. A paternal age effect in spermatogenic cells is recognized for the human population as well. To determine if male germ cell base excision repair activity changes with age, uracil-DNA glycosylase-initiated base excision repair activity was measured in mixed germ cell (i.e., all spermatogenic cell types in adult testis) nuclear extracts prepared from young, middle-aged, and old mice. Base excision repair activity was also assessed in nuclear extracts from premeiotic, meiotic, and postmeiotic spermatogenic cell types obtained from young mice. Mixed germ cell nuclear extracts exhibited an age-related decrease in base excision repair activity that was restored by addition of apurinic/apyrimidinic (AP) endonuclease. Uracil-DNA glycosylase and DNA ligase were determined to be limiting in mixed germ cell nuclear extracts prepared from young animals. Base excision repair activity was only modestly elevated in pachytene spermatocytes and round spermatids relative to other spermatogenic cells. Thus, germ line shortpatch base excision repair activity appears to be relatively constant throughout spermatogenesis in young animals, limited by uracil-DNA glycosylase and DNA ligase in young animals, and limited by AP endonuclease in old animals.Germ line genomic stability is an important factor in reproductive health, with approximately 20% of genetic diseases attributed to new germ line mutations (12,13,46). Several autosomal dominant genetic diseases due to de novo male germ line mutations are associated with increased paternal age (18,21,45,49), suggesting that male germ line genomic stability is compromised with age. Analysis of chromosomes in spermatozoa revealed an increased frequency of aberrations with age (24, 34, 41, 54), providing additional evidence that male germ line genomic stability decreases with age. Similarly in mice, the spontaneous mutant frequency in a lacI transgene recovered from pachytene spermatocytes, round spermatids, and epididymal spermatozoa obtained from old animals was approximately 10-fold higher than the mutant frequency observed for young mice (60).In contrast to the decline in germ line genetic integrity with old age, the germ line DNA of young mice appears to be well maintained. Compared to somatic tissues, a lower spontaneous mutant frequency in the male germ line for a lacI transgene has been reported for fish (65), mice (32, 60), and rats (16). The murine mitotically proliferating male germ cell pool is comprised of primitive type A spermatogonia, which sequentially give rise to mitotically active, type ...

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“…Among the malformed fetuses, however, between 30 and 50 % were growth retarded. Müller et al (1999) showed that in the mouse strain "Heiligenberger Stamm" there was an increase in the frequency (4.5 vs 2.3 % in control) of one particular malformation, namely gastroschisis in 19-day-old fetuses after 137 Cs Á-irradiation of meiotic stages of parental males. However, in this strain, the above malformation occurs at a comparatively high frequency in controls (around 2 % in some up to 4 %).…”

Section: Discussionmentioning

confidence: 99%

Transgenerational transmission of radiation- and chemically induced tumors and congenital anomalies in mice: studies of their possible relationship to induced chromosomal and molecular changes

Nomura

Nakajima²,

Ryo³

et al. 2004

Cytogenet Genome Res

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This article provides a broad overview of our earlier studies on the induction of tumors and congenital anomalies in the progeny of X-irradiated or chemically treated mice and our subsequent (published, hitherto unpublished and on-going) investigations aimed at identifying potential relationships between genetic changes induced in germ cells and the adverse effects manifest as tumors and congenital anomalies using cytogenetic and molecular approaches. The earlier studies document the fact that tumors and congenital anomalies can be induced by irradiation or treatment with certain chemicals such as urethane and that these phenotypes are heritable i.e., transmitted to generations beyond the first generation. These findings support the view that transmissible induced genetic changes are involved. The induced rates of congenital abnormalities and tumors are about two orders of magnitude higher than those recorded in the literature from classical mutation studies with specific locus mutations. The cytogenetic studies addressed the question of whether there were any relationships between induced translocations and induced tumors. The available data permit the inference that gross chromosomal changes may not be involved but do not exclude smaller induced genetic changes that are beyond the resolution of the techniques used in these studies. Other work on possible relationship between visible chromosomal anomalies (in bone marrow preparations) and tumors were likewise negative. However, there were indications that some induced cytogenetic changes might underlie induced congenital anomalies, i.e., trisomies, deletions and inversions were observed in induced and transmissible congenital anomalies (such as dwarfs, tail anomalies). Studies that explored possible relationships between induction of minisatellite mutations at the Pc-3 locus and tumors were negative. However, gene expression analysis of tumor (hepatoma)-susceptible offspring of progeny descended from irradiated male mice showed abnormal expression of many genes. Of these, only very few were oncogenes. This lends some support to our hypothesis that cumulative changes in gene expression of many genes, which perform normal cellular functions, may contribute to the occurrence of tumors in the offspring of irradiated or chemically treated mice.

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Radiation-induced malformations after exposure of murine germ cells in various stages of spermatogenesis

Cited by 21 publications

References 22 publications

Review of recent epidemiological studies on paternal occupations and birth defects

Review of recent epidemiological studies on paternal occupations and birth defects

Base Excision Repair Is Limited by Different Proteins in Male Germ Cell Nuclear Extracts Prepared from Young and Old Mice

Transgenerational transmission of radiation- and chemically induced tumors and congenital anomalies in mice: studies of their possible relationship to induced chromosomal and molecular changes

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