Associations between maternal obesity and adverse fetal outcomes are well documented, but the mechanisms involved are largely unknown. Most previous work has focused on postconceptional events, however, our laboratory has shown pre- and periconceptional aberrations in maternal glucose metabolism have adverse effects on oocytes and embryos that carry on to the fetus. To demonstrate effects of maternal obesity in the pre- and periconceptional periods, we compared reproductive tissues from diet-induced obese female mice to those of control mice. Ovaries were either stained for follicular apoptosis or dissected and evaluated for oocyte size and meiotic maturation. Mice were also mated and followed for reproductive outcomes including preimplantation embryonic IGF-I receptor (IGF-IR) immunostaining, midgestation fetal growth, and midgestational placental IGF receptor 2 (Igf2r) mRNA. Delivered pups were followed for growth and development of markers of metabolic syndrome. Compared with controls, obese mice had significantly more apoptotic ovarian follicles, smaller and fewer mature oocytes, decreased embryonic IGF-IR staining, smaller fetuses, increased placental Igf2r mRNA, and smaller pups. All weaned pups were fed a regular diet. At 13 wk pups delivered from obese mice were significantly larger, and these pups demonstrated glucose intolerance and increased cholesterol and body fat suggesting early development of a metabolic-type syndrome. Together, our findings suggest maternal obesity has adverse effects as early as the oocyte and preimplantation embryo stage and that these effects may contribute to lasting morbidity in offspring, underscoring the importance of optimal maternal weight and nutrition before conception.

As women age egg dysfunction increases, with meiotic nondisjunction, embryonic arrest, apoptosis, and miscarriage. Egg dysfunction results from two 'hits' - reduced formation of chiasmata during fetal oogenesis, and accumulation of reactive oxygen damage during the prolonged interval until ovulation. Late exit from a production line during oogenesis presumably contributes to the first hit. The later insult also involves meiotic spindle abnormalities. Telomeres, repetitive sequences of DNA, cap chromosome ends and dissipate during divisions. Oocytes do not divide, but oogonia do, and telomerase, the enzyme responsible for maintaining telomere length, is inefficient, and remains inactive in oocytes and embryos until blastocyst stage. Reactive oxygen also shortens telomeres, so the prolonged interval between birth and ovulation would further shorten telomeres from chronic exposure to reactive oxygen. In support of this theory, experimental shortening of telomeres in mice produced a phenotype similar to reproductive aging in women, with abnormal chiasmata, spindles, cell cycles, apoptosis, and genomic instability, and telomere length in human eggs correlated with in-vitro fertilization outcome.

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In order to determine the impact of maternal metabolic state on oocyte development in women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI), we retrospectively analyzed a cohort of women with PCOS undergoing IVF/ICSI from 2008-2009 in a university-based fertility center. We determined that women with PCOS and obesity have smaller oocytes compared to controls, and that when further subdivided by BMI, both PCOS and obesity influence oocyte size independent of one another.

These results suggest for the first time that Adipoq signaling may play an important role in preimplantation embryo development and uterine receptivity by autocrine and paracrine methods in the mouse. Implantation failures and pregnancy loss, specifically those experienced in women with maternal metabolic conditions such as diabetes, obesity and PCOS, may be the result of aberrant Adipoq and AdipoR1 and AdipoR2 expression and suboptimal decidualization in the uterus.

Meiotic dysfunction increasingly afflicts women as they age, resulting in infertility, miscarriage and handicapped offspring. How aging disrupts meiotic function in women remains unclear, but as women increasingly delay childbearing, this issue becomes urgent. Telomeres, which mediate aging in mitotic cells, may also mediate aging during meiosis. Telomeres shorten during DNA replication. In mammals, oocytes remain quiescent, but their precursors replicated during fetal oogenesis. Moreover, eggs ovulated from older women entered meiosis later during fetal oogenesis than eggs ovulated when younger, and therefore underwent more replications. Telomeres also shorten from reactive oxygen, which triggers a DNA repair response, so the prolonged interval between fetal oogenesis and ovulation in some women would further shorten telomeres. Mice normally do not exhibit age-related meiotic dysfunction (interestingly, their telomeres are manyfold longer than telomeres in women), but genetic or pharmacologic shortening of mouse telomeres recapitulates the reproductive aging phenotype of women. This has led to a telomere theory of age-related meiotic dysfunction in women, and underlined the importance to human health of a mechanistic understanding of telomeres and meiosis.

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openAccessArticle: FalsePage Range: v-vdoi: 10.1016/B978-1-4377-0134-0.10164-7Harvest Date: 2016-01-12 15:15:33issueName:cover date: 2012-01-01pubType