PubMed · 10726839
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F Elmslie. 1998. Epilepsy (update).. https://doi.org/10.1016/s1090-3798(98)80033-0
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Since the beginning of in vitro fertilization (IVF), basic research has provided insight in the field of human reproduction, especially in genetics. Indeed, the contribution of chromosomal abnormalities to oocyte disorders and impaired embryonic development is now well known. Of oocytes that fail to fertilize after in vitro insemination, 26.5% have been found to be abnormal, with 13.3% showing hypohaploidy, 8.1% hyperhaploidy, 1.6% structural abnormalities and 3.5% diploidy. The total incidence of abnormalities seems to be correlated with the fertility status of the woman. It is higher in oocytes from women with tubal or unexplained infertility than in those from women whose husband's infertility is the sole cause of infertility in the couple. Although few oocytes recovered during natural cycles have been studied, gonadotropins, which are widely used to stimulate follicle growth and ovulation, do not increase the risk of abnormalities. The effect of maternal age on fetal aneuploidy, well documented at birth, has not been unambiguously shown to result from an increase in the frequency of aneuploid oocytes. Intra- and extra-follicular influences (perifollicular microvasculature, oxygenation, and the presence of residues from cigarette smoke) may disturb maturation, leading to immaturity and aneuploidy. Thus, oocyte meiosis is very sensitive to endogenous and exogenous factors that could result in oocytes with chromosomal abnormalities and therefore, abnormal zygotes.
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Glutathione S-transferases (GSTs) detoxify potentially mutagenic and toxic DNA-reactive electrophiles, including metabolites of several chemotherapeutic agents, some of which are suspected human carcinogens. Functional polymorphisms exist in at least three genes that encode GSTs, including GSTM1, GSTT1, and GSTP1. We hypothesize, therefore, that polymorphisms in genes that encode GSTs alter susceptibility to chemotherapy-induced carcinogenesis, specifically to therapy-related acute myeloid leukemia (t-AML), a devastating complication of long-term cancer survival. Elucidation of genetic determinants may help to identify individuals at increased risk of developing t-AML. To this end, we have examined 89 cases of t-AML, 420 cases of de novo AML, and 1,022 controls for polymorphisms in GSTM1, GSTT1, and GSTP1. Gene deletion of GSTM1 or GSTT1 was not specifically associated with susceptibility to t-AML. Individuals with at least one GSTP1 codon 105 Val allele were significantly over-represented in t-AML cases compared with de novo AML cases [odds ratio (OR), 1.81; 95% confidence interval (CI), 1.11-2.94]. Moreover, relative to de novo AML, the GSTP1 codon 105 Val allele occurred more often among t-AML patients with prior exposure to chemotherapy (OR, 2.66; 95% CI, 1.39-5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4.34; 95% CI, 1.43-13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95% CI, 0.50-2.07). These data suggest that inheritance of at least one Val allele at GSTP1 codon 105 confers a significantly increased risk of developing t-AML after cytotoxic chemotherapy, but not after radiotherapy.