Terry Hassold

To err (meiotically) is human: the genesis of human aneuploidy

Aneuploidy (trisomy or monosomy) is the most commonly identified chromosome abnormality in humans, occurring in at least 5% of all clinically recognized pregnancies. Most aneuploid conceptuses perish in utero, which makes this the leading genetic cause of pregnancy loss. However, some aneuploid fetuses survive to term and, as a class, aneuploidy is the most common known cause of mental retardation. Despite the devastating clinical consequences of aneuploidy, relatively little is known of how trisomy and monosomy originate in humans. However, recent molecular and cytogenetic approaches are now beginning to shed light on the non-disjunctional processes that lead to aneuploidy.

A cytogenetic study of 1000 spontaneous abortions

Cytogenetic analysis of 1000 spontaneous abortions showed 463 to have an abnormal chromosome constitution. The proportion of chromosome abnormalities varied with the gestational age of the abortus and the type of tissue cultured but was not significantly different among the five racial groups represented in the study population. It was suggested that differences in the rate of chromosome abnormalities among cytogenetic studies of spontaneous abortions were the result of methodological differences in sample selection rather than real biological variation among study populations. The only factor found to be unequivocally associated with the aetiology of chromosome abnormalities in spontaneous abortions was increasing maternal age in trisomies.

Bisphenol A Exposure Causes Meiotic Aneuploidy in the Female Mouse

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.

Human aneuploidy: Incidence, origin, and etiology

Chromosome abnormalities occur with astonishing frequency in humans, being present in an estimated 1030% of all fertilized eggs. Of the different classes of chromosome abnormality, aneuploidy (trisomy and monosomy) is by far the most common and, clinically, the most important. For example, over 25% of all miscarriages are monosomic or trisomic, making aneuploidy the leading known cause of pregnancy loss. Furthermore, among those conceptions that survive to term, aneuploidy is the leading genetic cause of mental retardation. Over the past 25 years, a considerable body of information has accrued on the incidence of aneuploidy in human gametes, fetuses, and newborns. More recently, the application of molecular biological techniques to the study of aneuploidy has begun to uncover some of the underlying causes of human aneuploidy. In this review, we first summarize the cytogenetic data on the incidence of aneuploidy in humans, and then discuss recent molecular data on the mechanism of origin of different aneuploid conditions, the basis of the maternal age effect on aneuploidy, and the importance of aberrant genetic recombination to the genesis of aneuploidy.

Maternal age-specific rates of numerical chromosome abnormalities with special reference to trisomy.

SummaryThe effect of maternal age on the incidence of chromosomally normal spontaneous abortion and different categories of chromosome abnormality among all clinically recognized human pregnancies was evaluated. The results provide no evidence for a significant association of age with sex chromosome monosomy or polyploidy, but clearly demonstrate an effect of age on the frequency of trisomy and chromosomally normal spontaneous abortions. Estimated maternal age-specific rates of trisomy among all recognized pregnancies were calculated and suggest that a majority of oocytes of women aged 40 years and older may be aneuploid.

Human aneuploidy: mechanisms and new insights into an age-old problem

Trisomic and monosomic (aneuploid) embryos account for at least 10% of human pregnancies and, for women nearing the end of their reproductive lifespan, the incidence may exceed 50%. The errors that lead to aneuploidy almost always occur in the oocyte but, despite intensive investigation, the underlying molecular basis has remained elusive. Recent studies of humans and model organisms have shed new light on the complexity of meiotic defects, providing evidence that the age-related increase in errors in the human female is not attributable to a single factor but to an interplay between unique features of oogenesis and a host of endogenous and exogenous factors.

Stra8 and its inducer, retinoic acid, regulate meiotic initiation in both spermatogenesis and oogenesis in mice

In eukaryotes, diploid cells give rise to haploid cells via meiosis, a program of two cell divisions preceded by one round of DNA replication. Although key molecular components of the meiotic apparatus are highly conserved among eukaryotes, the mechanisms responsible for initiating the meiotic program have diverged substantially among eukaryotes. This raises a related question in animals with two distinct sexes: Within a given species, are similar or different mechanisms of meiotic initiation used in the male and female germ lines? In mammals, this question is underscored by dramatic differences in the timing of meiotic initiation in males and females. Stra8 is a vertebrate-specific, cytoplasmic factor expressed by germ cells in response to retinoic acid. We previously demonstrated that Stra8 gene function is required for meiotic initiation in mouse embryonic ovaries. Here we report that, on an inbred C57BL/6 genetic background, the same factor is also required for meiotic initiation in germ cells of juvenile mouse testes. In juvenile C57BL/6 males lacking Stra8 gene function, the early mitotic development of germ cells appears to be undisturbed. However, these cells then fail to undergo the morphological changes that define meiotic prophase, and they do not display the molecular hallmarks of meiotic chromosome cohesion, synapsis and recombination. We conclude that, in mice, Stra8 regulates meiotic initiation in both spermatogenesis and oogenesis. Taken together with previous observations, our present findings indicate that, in both the male and female germ lines, meiosis is initiated through retinoic acid induction of Stra8.

Population-based study of congenital heart defects in Down syndrome.

Mental retardation and hypotonia are found in virtually all Down syndrome (DS) individuals, whereas congenital heart defects (CHDs) are only present in a subset of cases. Although there have been numerous reports of the frequency of CHDs in DS, few of the studies have had complete ascertainment of DS in a defined geographic area. The Atlanta Down Syndrome Project, a population-based study of infants born with trisomy 21, provides such a resource. In the first 6.5 years of the study, 243 trisomy 21 livebirths were identified in the five-county Atlanta area (birth prevalence: 9.6/10,000). Cardiac diagnoses were available on 227 (93%) of the cases and 89% of these evaluations were made by echocardiography, cardiac catheterization, surgery, or autopsy. Of the 227 DS infants, 44% had CHDs including 45% atrioventricular septal defect (with or without other CHDs), 35% ventricular septal defect (with or without other CHDs), 8% isolated secundum atrial septal defect, 7%, isolated persistent patent ductus arteriosus, 4% isolated tetralogy of Fallot, and 1% other. This report is unique in that it contains the largest number of trisomy 21 infants ascertained in a population-based study where modern techniques for diagnosing cardiac abnormalities predominate.

Bisphenol A Exposure In Utero Disrupts Early Oogenesis in the Mouse

Estrogen plays an essential role in the growth and maturation of the mammalian oocyte, and recent studies suggest that it also influences follicle formation in the neonatal ovary. In the course of studies designed to assess the effect of the estrogenic chemical bisphenol A (BPA) on mammalian oogenesis, we uncovered an estrogenic effect at an even earlier stage of oocyte development—at the onset of meiosis in the fetal ovary. Pregnant mice were treated with low, environmentally relevant doses of BPA during mid-gestation to assess the effect of BPA on the developing ovary. Oocytes from exposed female fetuses displayed gross aberrations in meiotic prophase, including synaptic defects and increased levels of recombination. In the mature female, these aberrations were translated into an increase in aneuploid eggs and embryos. Surprisingly, we observed the same constellation of meiotic defects in fetal ovaries of mice homozygous for a targeted disruption of ERβ, one of the two known estrogen receptors. This, coupled with the finding that BPA exposure elicited no additional effects in ERβ null females, suggests that BPA exerts its effect on the early oocyte by interfering with the actions of ERβ. Together, our results show that BPA can influence early meiotic events and, importantly, indicate that the oocyte itself may be directly responsive to estrogen during early oogenesis. This raises concern that brief exposures during fetal development to substances that mimic or antagonize the effects of estrogen may adversely influence oocyte development in the exposed female fetus.

SMC1β-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction

Mitotic chromosome segregation is facilitated by the cohesin complex, which maintains physical connections between sister chromatids until anaphase. Meiotic cell division is considerably more complex, as cohesion must be released sequentially to facilitate orderly segregation of chromosomes at both meiosis I and meiosis II. This necessitates meiosis-specific cohesin components; recent studies in rodents suggest that these influence chromosome behavior during both cell division and meiotic prophase. To elucidate the role of the meiosis-specific cohesin SMC1β (encoded by Smc1l2) in oogenesis, we carried out meiotic studies of female SMC1β-deficient mice. Our results provide the first direct evidence that SMC1β acts as a chiasma binder in mammals, stabilizing sites of exchange until anaphase. Additionally, our observations support the hypothesis that deficient cohesion is an underlying cause of human age-related aneuploidy.