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Inversion heterozygosity has long been noted for its ability to suppress the transmission of recombinant chromosomes, as well as for altering the frequency and location of recombination events. In our search for meiotic situations with enrichment for nonexchange and/or single distal-exchange chromosome pairs, exchange configurations that are at higher risk for nondisjunction in humans and other organisms, we examined both exchange and segregation patterns in 2728 oocytes from mice heterozygous for paracentric inversions, as well as controls. We found dramatic alterations in exchange position in the heterozygotes, including an increased frequency of distal exchanges for two of the inversions studied. However, nondisjunction was not significantly increased in oocytes heterozygous for any inversion. When data from all inversion heterozygotes were pooled, meiotic nondisjunction was slightly but significantly higher in inversion heterozygotes (1.2%) than in controls (0%), although the frequency was still too low to justify the use of inversion heterozygotes as a model of human nondisjunction.

Background: There is increasing concern that exposure to man-made substances that mimic endogenous hormones may adversely affect mammalian reproduction. Although a variety of reproductive complications have been ascribed to compounds with androgenic or estrogenic properties, little attention has been directed at the potential consequences of such exposures to the genetic quality of the gamete. Results: A sudden, spontaneous increase in meiotic disturbances, including aneuploidy, in studies of oocytes from control female mice in our laboratory coincided with the accidental exposure of our animals to an environmental source of bisphenol A (BPA). BPA is an estrogenic compound widely used in the production of polycarbonate plastics and epoxy resins. We identified damaged caging material as the source of the exposure, as we were able to recapitulate the meiotic abnormalities by intentionally damaging cages and water bottles. In subsequent studies of female mice, we administered daily oral doses of BPA to directly test the hypothesis that low levels of BPA disrupt female meiosis. Our results demonstrated that the meiotic effects were dose dependent and could be induced by environmentally relevant doses of BPA. Conclusions: Both the initial inadvertent exposure and subsequent experimental studies suggest that BPA is a potent meiotic aneugen. Specifically, in the female mouse, short-term, low-dose exposure during the final stages of oocyte growth is sufficient to elicit detectable meiotic effects. These results provide the first unequivocal link between mammalian meiotic aneuploidy and an accidental environmental exposure and suggest that the oocyte and its meiotic spindle will provide a sensitive assay system for the study of reproductive toxins.

The value of research using lab animals hinges on the ability to carry out experiments in a tightly controlled environment. Diet, caging materials (e.g., cages and water bottles), and other environmental variables have the potential to create serious disruptions in animal studies. The authors describe the inadvertent damage of polycarbonate caging materials during the course of routine cagewashing, providing an instructive example and illustrating the importance of defined and controlled environmental conditions in biomedical research.

The meiotic properties of paracentric inversion heterozygotes have been well studied in insects and plants, but not in mammalian species. In essence, a single meiotic recombination event within the inverted region results in the formation of a dicentric chromatid, which usually breaks or is stretched between the two daughter nuclei during the first meiotic anaphase. Here, we provide evidence that this is not the predominant mode of exchange resolution in female mice. In sharp contrast to previous observations in other organisms, we find that attempts to segregate the dicentric chromatid frequently result not in breakage, stretching, or loss, but instead in precocious separation of the sister centromeres of at least one homolog. This often further results in intact segregation of the dicentric into one of the meiotic products, where it can persist into the first few embryonic divisions. These novel observations point to an unusual mechanism for the processing of dicentric chromosomes in mammalian oogenesis. Furthermore, this mechanism is rare or nonexistent in mammalian spermatogenesis. Thus, our results provide additional evidence of sexual dimorphism in mammalian meiotic chromosome behavior; in “stressful” situations, meiotic sister chromatid cohesion is apparently handled differently in males than in females.

Analysis of recombination between loci (linkage analysis) has been a cornerstone of human genetic research, enabling investigators to localize and, ultimately, identify genetic loci. However, despite these efforts little is known about patterns of meiotic exchange in human germ cells or the mechanisms that control these patterns. Using recently developed immunofluorescence methodology to examine exchanges in human spermatocytes, we have identified remarkable variation in the rate of recombination within and among individuals. Subsequent analyses indicate that, in humans and mice, this variation is linked to differences in the length of the synaptonemal complex. Thus, at least in mammals, a physical structure, the synaptonemal complex, reflects genetic rather than physical distance.

Document S1. Supplemental Experimental ProceduresxDownload (.07 MB ) Document S1. Supplemental Experimental Procedures

Recent studies of Drosophila and humans indicate that aberrant genetic recombination is an important component of nondisjunction in both species. In both, a proportion of nondisjunction is associated with failure to pair and/or recombine and in both, exchanges which are either too distal or too proximal increase the likelihood of malsegregation. In this review we provide two perspectives on these observations: first, a review of exchange and chromosome segregation in model organisms, focusing on Drosophila, and secondly an overview of nondisjunction in humans. This format allows us to describe the paradigms developed from studies of model organisms and to ask whether these paradigms apply to the human situation.