UCSF

The Developmental Origins of Health and Disease hypothesis holds that during critical periods in development, organisms exhibit an enhanced plasticity enabling them to fine-tune their metabolism and patterns of gene expression in accordance with environmental cues. Such changes often confer immediate survival advantages, however, transient stresses experienced in utero may induce inappropriate adaptive changes that conflict with postnatal environments and consequently impair adult metabolic health. Preimplantation development has been recognized as a window of notable environmental sensitivity, and several animal studies have reported that nutritional, oxidative, and in vitro stresses restricted exclusively to this period are sufficient to alter developmental, growth and metabolic trajectories, leading to pathologies such as hypertension, dyslipidemia, and β-cell dysfunction in adulthood. This is particularly relevant to the over 5 million children conceived by in vitro fertilization (IVF), although it remains controversial whether in vitro embryo manipulation will have lasting effects on offspring health. Although IVF is considered safe, these children display modest changes in growth kinetics, fasting glucose levels, fat deposition and vascular function, which may signify a lasting and possibly dangerous effect of IVF on subsequent development and metabolic homeostasis.

To address this controversy, we developed a mouse model to assess the long-term effects of IVF and found that even clinically optimized IVF conditions are sufficient to reprogram adult metabolism. In particular, female animals exhibit latent overgrowth, increased fat deposition and evidence of β-cell dysfunction, including impaired glucose-stimulated insulin secretion, basal hyperglycemia and insulinemia. Interestingly, males display no overt phenotype. Integrated microarray and metabolomics analyses of adult insulin-sensitive tissues identified sex- and tissue-specific IVF molecular signatures characterized by systemic oxidative stress, mitochondrial dysfunction, impaired insulin and adipogenic signaling, indicating that preimplantation stress can have unique and lasting developmental consequences. Additionally, female-specific increases in adipogenic and oxidative stress markers may explain the predisposition of IVF females to more severe phenotypes.

Our data support the vulnerability of preimplantation embryos to environmental disturbance and demonstrate that conception by IVF can permanently reprogram growth trajectory and metabolic homeostasis through transcriptional and metabolic mechanisms with lasting consequences for adult growth and energy homeostasis. This has wide clinical relevance, underscoring the importance of continued follow-up of IVF offspring and future attention towards increasing the safety and efficacy of assisted conception.