Genetic Anomalies in Mammalian Germ Cells and Their Significance for Human Reproductive and Developmental Risk

Dellarco, Vicki L.

doi:10.2307/3431369

Cited by 3 publications

(2 citation statements)

References 23 publications

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“…Embryonic aneuploidy manifests itself in a number of human health problems such as Down's syndrome or preterm fetal loss (Hassold, 1986;Dellarco, 1993). Data which summarized the incidence of aneuploidy in human gametes (Martin et al, 1991) and in aborted human fetuses (Hassold, 1986) indicated that errors in maternal meiosis account for the majority of the autosomal aneuploidy observed in humans.…”

Section: Wiley-liss Incmentioning

confidence: 99%

“…Data which summarized the incidence of aneuploidy in human gametes (Martin et al, 1991) and in aborted human fetuses (Hassold, 1986) indicated that errors in maternal meiosis account for the majority of the autosomal aneuploidy observed in humans. Despite the relatively high incidence of human oocyte and embryonic aneuploidy, the cellular mechanism(s) through which it arises remain poorly defined (Hassold, 1986;Martin et al, 1991;Dellarco, 1993).…”

Section: Wiley-liss Incmentioning

confidence: 99%

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Carbendazim (MBC) disrupts oocyte spindle function and induces aneuploidy in hamsters exposed during fertilization (meiosis II)

Zuelke

Perreault

1995

Molecular Reproduction Devel

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Peri-fertilization exposure to Carbendazim (MBC; a microtubule poison) induces infertility and early pregnancy loss in hamsters. Presently, both in vivo and in vitro techniques were employed to characterize the effects of MBC on cellular aspects of fertilization in hamsters. Exposure to MBC during either in vivo or in vitro fertilization (IVF) induced identical morphological abnormalities in the maternal chromatin of zygotes and embryos. These abnormalities included either multiple second polar bodies (PB2), and/or multiple small female pronuclei (PN), or meiotic arrest. Multiple PB2, multiple female PN, multiple PB2 with multiple female PN, or meiotic arrest were exhibited by approximately 31%, 15%, 12%, and 2% of the in vivo zygotes; and 3%, 16%, 36%, and 20% of IVF zygotes, respectively. The effects of MBC persisted to day 2 of pregnancy as indicated by decreased (P < 0.05) embryo development to the two-cell stage and the presence of micronuclei in 6% of two-cell embryos from MBC-treated females. Immunofluorescence analysis of microtubules (MTs) confirmed that MBC disrupted spindle MTs during IVF. Numerical chromosome analysis revealed that a single dose of MBC administered during in vivo fertilization induced aneuploidy in the resulting pronuclear-stage zygotes. The present data point to two mechanisms by which peri-fertilization MBC exposure may induce early pregnancy loss: 1) arrested meiosis with no zygotic cleavage; or 2) induction of zygotic aneuploidy with subsequent developmental arrest.

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Section: Wiley-liss Incmentioning

confidence: 99%

Section: Wiley-liss Incmentioning

confidence: 99%

Carbendazim (MBC) disrupts oocyte spindle function and induces aneuploidy in hamsters exposed during fertilization (meiosis II)

Zuelke

Perreault

1995

Molecular Reproduction Devel

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Culture of pachytene spermatocytes for analysis of meiosis

1995

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An impediment to the investigation of mammalian spermatogenic meiosis has been the lack of an appropriate system for experimental manipulation of meiotic prophase cells. We report here the use of a simple system for the short-term culture of pachytene spermatocytes. We have assayed parameters of cell function pertinent to meiotic prophase, namely chromosome pairing and synapsis. During the culture period of 24-48 hr, cells maintained typical pachytene morphology, chromatin condensation patterns, and chromosome pairing, as assessed by light and electron microscopy. Uridine incorporation, monitored by autoradiography, reflected the chromosomal distribution found in vivo in that the autosomal chromosomes were transcriptionally active, while the sex chromosomes were not. Thus features of chromosome pairing and sex chromatin inactivation are maintained in these cultures. We have conducted experiments to demonstrate that cultured pachytene spermatocytes can be useful for the analysis of agents, some of which may be suspected mutagens, that might affect chromosome structure and function during meiosis. Treatment of cells with actinomycin D revealed a differential effect on chromatin condensation in the autosomes versus the sex chromosomes. Camptothecin, a topoisomerase inhibitor, induced desynapsis of paired chromosomes. Okadaic acid, a phosphatase inhibitor, induced premature metaphase-I condensation of pachytene chromosomes. This last experiment suggests that these cultured cells may be useful for analysis of meiotic cell cycle controls. Taken together, these results demonstrate a culture system that can be useful for analysis of meiotic events as well as in screening for potential mutagenic agents that might affect meiotic chromosome structure and function.

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Assessment of heritable genetic effects using new genetic tools and sentinels in an era of personalized medicine

Elespuru

2011

Environ and Mol Mutagen

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The challenge of estimating human health effects from damage to the germ line may be met in the genomic era. Understanding the genetic, as opposed to postconception developmental basis of birth defects is critical to their use in monitoring heritable genetic damage. The causes of common birth defects are analyzed here: mendelian genetic, multigenic, developmental, inherited, or combinational. Only a small fraction of these (noninherited, mendelian genetic) are likely to be informative relative to germ cell mutagenesis, and these won't be discernible against the general background of birth defects. Targeted genetic testing as part of personalized medicine could be integrated into a strategy for assessing germ cell alterations in populations. Thus, "sentinel mutations," as originally proposed by Mulvihill and Ceizel, need not be restricted to X-linked or dominant mutations or conditions visible at birth. Several new sentinels related to personalized medicine are proposed, based on health impact (likelihood of monitoring), frequency, and genetic target suitability (responsiveness to diverse mutational mechanisms). Candidates could include CYP genes (related to metabolism of xenobiotics) important in optimizing drug doses and avoiding adverse reactions. High frequency LDLR mutations (related to familial high cholesterol) predict myocardial infarction in approximately50% of individuals. The more common recessive genetic diseases (cystic fibrosis, phenylketonuria, and others) monitored in newborn screening programs could be informative given parental analysis. New opportunities for genetic analyses need to be coupled with epidemiological studies on environmental exposures. These could focus on adverse outcomes related to tobacco, the mostubiquitous and potent environmental mutagen.

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Genetic Anomalies in Mammalian Germ Cells and Their Significance for Human Reproductive and Developmental Risk

Cited by 3 publications

References 23 publications

Carbendazim (MBC) disrupts oocyte spindle function and induces aneuploidy in hamsters exposed during fertilization (meiosis II)

Carbendazim (MBC) disrupts oocyte spindle function and induces aneuploidy in hamsters exposed during fertilization (meiosis II)

Culture of pachytene spermatocytes for analysis of meiosis

Assessment of heritable genetic effects using new genetic tools and sentinels in an era of personalized medicine

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