Use of a mouse in vitro fertilization model to understand the developmental origins of health and disease hypothesis

Sky K Feuer; Xiaowei Liu; Annemarie Donjacour; Wingka Lin; Rhodel K Simbulan; Gnanaratnam Giritharan; Luisa Delle Piane; Kevin Kolahi; Kurosh Ameri; Emin Maltepe; Paolo F Rinaudo

doi:10.1210/en.2013-2081

Assisted Reproduction Safety and Risks

Use of a mouse in vitro fertilization model to understand the developmental origins of health and disease hypothesis

Feuer SK, Liu X, Donjacour A, Lin W, Simbulan RK, Giritharan G, Piane LD, Kolahi K, Ameri K, Maltepe E, Rinaudo PF

Published May 2014 Endocrinology

DOI 10.1210/en.2013-2081 PMID 24684304 PMC PMC3990843

RRM Academy Synopsis

IVF in mice altered adult growth, body fat and glucose metabolism

In a mouse experiment, IVF conception altered adult mouse growth, fat and glucose handling, varying by sex and medium. Researchers compared IVF-conceived mice with controls grown from embryos flushed from the body. The team also traced Txnip, a gene tied to how cells respond to nutrients and stress, from the embryo into some adult tissues.

Key Findings

IVF mice in Whitten's medium were smaller than controls by 2 weeks of age, and at 19 weeks the females had higher blood glucose after a glucose injection (P < .05).
IVF females grown in the optimized medium were heavier than controls from 17 weeks and passed control body fat by 21 weeks, before the high-fat diet began at 24 weeks.
Islets from 29-week-old IVF females in the optimized-medium group lost their insulin secretion response to glucose (IVF n = 5, controls n = 3).
In 29-week-old optimized-medium females, 35 of 280 serum metabolites differed from controls (9 increased, 26 decreased; 4 per group). Gene activity differed in liver, muscle, fat and islets (3 per group).
Txnip was nearly 4-fold higher in optimized-medium IVF blastocysts than body-grown ones. Fat tissue of adult mice from that medium had higher TXNIP protein and enriched H4 acetylation at the Txnip promoter.

Interpretation

The study is an animal experiment in laboratory mice. IVF embryos grew in one of two culture media and went to surrogate mothers. Controls were embryos flushed from the body and transferred the same way, accounting for hormone stimulation, litter size and transfer. No group came from natural mating. Groups were small, from 3 to 12 mice per adult comparison. The media differed in many ways, so the authors cannot link one culture condition to one adult outcome. In the optimized medium, males were statistically indistinguishable from controls on growth and metabolic measures, with raised Txnip in fat. The authors write that the results might not apply directly to humans.

RRM Context

The paper describes the path a conceived embryo takes from the oviduct to the uterus, with changing supplies of nutrients, oxygen and growth signals. Culture in a dish loses that setting. Restorative reproductive medicine treats the cause of infertility, so conception and early growth happen in the body. IVF bypasses the cause and leaves unresolved why conception fails. The authors call for continued follow-up of IVF-conceived offspring.

Our editorial summary of this paper, not the article's abstract.

Abstract

The Developmental Origins of Health and Disease hypothesis holds that alterations to homeostasis during critical periods of development can predispose individuals to adult-onset chronic diseases such as diabetes and metabolic syndrome. It remains controversial whether preimplantation embryo manipulation, clinically used to treat patients with infertility, disturbs homeostasis and affects long-term growth and metabolism. To address this controversy, we have assessed the effects of in vitro fertilization (IVF) on postnatal physiology in mice. We demonstrate that IVF and embryo culture, even under conditions considered optimal for mouse embryo culture, alter postnatal growth trajectory, fat accumulation, and glucose metabolism in adult mice. Unbiased metabolic profiling in serum and microarray analysis of pancreatic islets and insulin sensitive tissues (liver, skeletal muscle, and adipose tissue) revealed broad changes in metabolic homeostasis, characterized by systemic oxidative stress and mitochondrial dysfunction. Adopting a candidate approach, we identify thioredoxin-interacting protein (TXNIP), a key molecule involved in integrating cellular nutritional and oxidative states with metabolic response, as a marker for preimplantation stress and demonstrate tissue-specific epigenetic and transcriptional TXNIP misregulation in selected adult tissues. Importantly, dysregulation of TXNIP expression is associated with enrichment for H4 acetylation at the Txnip promoter that persists from the blastocyst stage through adulthood in adipose tissue. Our data support the vulnerability of preimplantation embryos to environmental disturbance and demonstrate that conception by IVF can reprogram metabolic homeostasis through metabolic, transcriptional, and epigenetic mechanisms with lasting effects for adult growth and fitness. This study has wide clinical relevance and underscores the importance of continued follow-up of IVF-conceived offspring.

Topics

Assisted Reproduction

Safety and Risks Long Term Child Outcomes

Assisted Reproduction › Safety and Risks › Long Term Child Outcomes

Sky K Feuer, Xiaowei Liu, Annemarie Donjacour, Wingka Lin, Rhodel K Simbulan, Gnanaratnam Giritharan, Luisa Delle Piane, Kevin Kolahi, Kurosh Ameri, Emin Maltepe, Paolo F Rinaudo

S Feuer, X Liu, A Donjacour, W Lin, R Simbulan, G Giritharan, L Piane, K Kolahi, K Ameri, E Maltepe, P Rinaudo

PMID 24684304 24684304 DOI 10.1210/en.2013-2081 10.1210/en.2013-2081 Feuer et al. 2014, Feuer 2014

Use of a mouse in vitro fertilization model to understand the developmental origins of health and disease hypothesis

IVF in mice altered adult growth, body fat and glucose metabolism

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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