Mechanisms and Risk of Chemically Induced Aneuploidy in Mammalian Germ Cells

Abstract

Aneuploidy is a pathological condition that affects 35% of human spontaneous abortions and 0.3% of livebirths. In spite of the increasing knowledge about molecular mechanisms of meiosis and chromosome segregation, maternal age remains the only ascertained aetiological factor. Genetically modified mouse models have been produced that show increased incidence of aneuploid gametes or abnormalities in meiotic recombination and synapsis. They suggest that genetic polymorphisms might also be involved in the aetiology of human germ cell aneuploidy. Experimental studies in the mouse have identified chemicals that can induce aneuploidy in male and female germ cells. Compounds affecting spindle assembly/dynamics are potent aneugens for oocytes and less so also for spermatocytes. They are active at acute doses during a short time interval preceding the metaphase-to-anaphase transition. Topoisomerase inhibitors are also meiotic aneugens which act on the recombination process; for the first time, the production of viable aneuploid mouse progeny was shown after paternal treatment with etoposide. A comparison between in vitro and in vivo effects of suspect aneugens demonstrates that there are biological mechanisms protecting mammalian oocytes from acute exposures to exogenous chemicals. Endocrine disruptors are a novel group of compounds that might affect chromosome segregation at meiosis. Data on bisphenol-A suggest that such chemicals could be active at low chronic exposure levels, but this hypothesis needs to be confirmed by further experiments. Experiments on cultured mouse oocytes treated with inhibitors of biochemical reactions involved in the regulation of chromosome segregation point to possible new mechanisms of action of environmental aneugens.

DNA ligase III and DNA ligase IV carry out genetically distinct forms of end joining in human somatic cells

“…In these survival experiments, the wild-type cells were grown for 7 days and the LIGIII mutant lines were grown for 10 days to accommodate the latter’s slower growth phenotype. Etoposide is a topoisomerase II inhibitor and a powerful radiomimetic drug that induces DNA DSBs [47]. As a positive control, a LIGIV −/− cell line [35] was, as expected, exquisitely sensitive to etoposide, even at the lowest concentration (Fig.…”

Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction

“…To experimentally determine whether this effect could be recapitulated in our somatic cell model, we carried out colony forming assays in the presence or absence of etoposide, a topoisomerase II inhibitor and a strong radiomimetic drug (53) (Figure 2B). Positive control cell lines included the parental, wild-type cell line and clone #1, which was a randomly targeted clone from the first round of gene targeting that therefore retained the LIGIV +/+ genotype.…”

Polscope Usage in In Vitro Fertilization Laboratory: GATA Experience: Scientific Letter

“…Fa re ve in san lar da ya pı lan ça lış malar da oo sit yaş lan ma sı nın ana faz II de ki oo sit ler de ma yoz bö lün me ha ta la rı nı art tır dı ğı na dik kat çe-kil miş tir. [17][18][19][20][21][22][23][24][25] Bu du rum ile ri yaş ta ge be lik oran ların da iz le nen azal ma yı açık la mak ta dır. An cak üre me ye yar dım cı te da vi ler uy gu la nır ken, oo sit lere mik ro en jek si yon ya pıl ma sı sı ra sın da ma yoz a b c RESİM 2: a. Mayoz mekiğin izlenmediği MII oosit görüntüsü.…”