Mice generated by in vitro fertilization exhibit vascular dysfunction and shortened life span.
ABSTRACT Children conceived by assisted reproductive technologies (ART) display a level of vascular dysfunction similar to that seen in children of mothers with preeclamspia. The long-term consequences of ART-associated vascular disorders are unknown and difficult to investigate in healthy children. Here, we found that vasculature from mice generated by ART display endothelial dysfunction and increased stiffness, which translated into arterial hypertension in vivo. Progeny of male ART mice also exhibited vascular dysfunction, suggesting underlying epigenetic modifications. ART mice had altered methylation at the promoter of the gene encoding eNOS in the aorta, which correlated with decreased vascular eNOS expression and NO synthesis. Administration of a deacetylase inhibitor to ART mice normalized vascular gene methylation and function and resulted in progeny without vascular dysfunction. The induction of ART-associated vascular and epigenetic alterations appeared to be related to the embryo environment; these alterations were possibly facilitated by the hormonally stimulated ovulation accompanying ART. Finally, ART mice challenged with a high-fat diet had roughly a 25% shorter life span compared with control animals. This study highlights the potential of ART to induce vascular dysfunction and shorten life span and suggests that epigenetic alterations contribute to these problems.
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ABSTRACT: The pre-implantation period is a time of reprogramming that may be vulnerable to disruption. This question has wide clinical relevance, since the number of children conceived by in vitro fertilization (IVF) is rising. To examine this question, outbred mice (CF1xB6D2F1) conceived by IVF and cultured using Whitten medium and 20% O2 (IVFWM group, less optimal), or K simplex optimized medium with amino acids and 5% O2 (IVFKAA group, more optimal and similar to conditions used in human IVF), were studied postnatally. We found that flushed blastocysts transferred to recipient mice provided the best control group (FB group), as this accounted for the effects of superovulation, embryo transfer, and litter size. We observed that many physiological parameters were normal. Reassuringly, IVFKAA offspring did not differ significantly from FB offspring. However, male IVFWM mice (but not females) were larger during the first 19 wk of life and exhibited glucose intolerance. Male IVFWM mice also showed enlarged left heart despite normal blood pressure. Expression of candidate imprinted genes (H19, Igf2, and Slc38a4) in multiple adult tissues did not show differences among the groups; only Slc38a4 was down-regulated following IVF (in both culture conditions) in female adipose tissue. These studies demonstrate that adult metabolism is affected by the type of conditions encountered during the pre-implantation stage. Further, the postnatal growth trajectory and glucose homeostasis following ex-vivo manipulation may be sexual dimorphic. Future work on the long-term effects of IVF offspring should focus on glucose metabolism and the cardiovascular system.Biology of Reproduction 03/2014; 90(4). DOI:10.1095/biolreprod.113.113134 · 3.45 Impact Factor
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ABSTRACT: In-vitro fertilization (IVF) may influence the metabolic health of children. However, in humans, it is difficult to separate out the relative contributions of genetics, environment, or the process of IVF, which includes ovarian stimulation and embryo culture. Therefore, we examined glucose metabolism in young adult humans and in adult male C57BL/6J mice conceived by IVF versus naturally, under energy balanced and high-fat overfeeding conditions. In humans, peripheral insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp (80mU/m(2)/min), was lower in IVF (n=14) versus controls (n=20) after 3 days of an energy-balanced diet (30% fat). In response to 3-days of overfeeding (+1250 kcal/day, 45% fat), there was a greater increase in systolic blood pressure in IVF versus controls (P=0.02). Mice conceived following either ovarian stimulation alone or IVF weighed significantly less at birth versus controls (P<0.01). However, only mice conceived by IVF displayed increased fasting glucose, impaired glucose tolerance and reduced insulin-stimulated Akt phosphorylation in liver following 8 weeks of either chow or high-fat diet (60% fat). Thus, ovarian stimulation impaired fetal growth in mouse, but only embryo culture resulted in changes in glucose metabolism that may increase the risk of developing metabolic diseases later in life, and in both mouse and humans.Diabetes 04/2014; 63(10). DOI:10.2337/db14-0103 · 8.47 Impact Factor
Article: Parenting from before conception[Show abstract] [Hide abstract]
ABSTRACT: At fertilization, the gametes endow the embryo with a genomic blueprint, the integrity of which is affected by the age and environmental exposures of both parents. Recent studies reveal that parental history and experiences also exert effects through epigenomic information not contained in the DNA sequence, including variations in sperm and oocyte cytosine methylation and chromatin patterning, noncoding RNAs, and mitochondria. Transgenerational epigenetic effects interact with conditions at conception to program the developmental trajectory of the embryo and fetus, ultimately affecting the lifetime health of the child. These insights compel us to revise generally held notions to accommodate the prospect that biological parenting commences well before birth, even prior to conception.Science 08/2014; 345(6198):756-760. DOI:10.1126/science.1254400 · 31.48 Impact Factor