Paolo Rinaudo, MD, PhD

Associate Professor
Department of Obstetrics Gynecology & Reproductive Sciences
+1 415 353-3040

The focus of our research is to understand how in vitro fertilization and in vitro culture during the pre-implantation period affect fetal and adult development. This has particular relevance in light of the widespread use of artificial reproductive techniques (ART). In fact, fetal adaptations in utero to adverse conditions can lead to specific diseases in the adult, including diabetes, high blood pressure and coronary heart disease. This phenomenon, termed the developmental origin of adult health and disease or the Barker hypothesis, has been extrapolated back to preimplantation development.

Our laboratory has created a mouse model of in vitro fertilization (IVF) for better analyzing long term outcome. One avenue of research analyzes glucose tolerance, fat content and growth in adult animals generated in vitro or in vivo. We have found 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

A second avenue of research analyzes if placentation is different in animal generated in vivo or in vitro. Our studies found evidence of fetal growth restriction in the earlier stages of pregnancy, followed by significant increases in placental size and accelerated fetal growth toward the end of gestation.  Further we found that amino acid transport is decreased in placentae of offspring generated by IVF.

Finally, we evaluate how different culture conditions determine gene expression changes and modify DNA methylation pattern or histone code in preimplantation embryos or adult animals generated in vivo or in vitro.  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 was associated with enrichment for H4 acetylation at the Txnip promoter that persisted from the blastocyst stage through adulthood in adipose tissue.

Our data supports the vulnerability of preimplantation embryos to environmental disturbance, and demonstrates that conception by IVF can reprogram metabolic homeostasis through metabolic, transcriptional, and epigenetic mechanisms with lasting effects for adult growth and fitness.

Primary Thematic Area: 
Tissue / Organ Biology & Endocrinology
Secondary Thematic Area: 
Developmental & Stem Cell Biology
Research Summary: 
Reprogramming of the embryo: Investigating the long term health effects of preimplantation embryo manipulation

Websites

Featured Publications: 

Effect of the method of conception and embryo transfer procedure on mid-gestation placenta and fetal development in an IVF mouse model.

Human reproduction (Oxford, England)

Delle Piane L, Lin W, Liu X, Donjacour A, Minasi P, Revelli A, Maltepe E, Rinaudo PF

Impaired placental nutrient transport in mice generated by in vitro fertilization.

Endocrinology

Bloise E, Lin W, Liu X, Simbulan R, Kolahi KS, Petraglia F, Maltepe E, Donjacour A, Rinaudo P

Effect of substrate stiffness on early mouse embryo development.

PloS one

Kolahi KS, Donjacour A, Liu X, Lin W, Simbulan RK, Bloise E, Maltepe E, Rinaudo P

Fetal programming and metabolic syndrome.

Annual review of physiology

Rinaudo P, Wang E

Preimplantation stress and development.

Birth defects research. Part C, Embryo today : reviews

Feuer S, Rinaudo P

In vitro fertilization affects growth and glucose metabolism in a sex-specific manner in an outbred mouse model.

Biology of reproduction

Donjacour A, Liu X, Lin W, Simbulan R, Rinaudo PF

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

Endocrinology

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

Sexually dimorphic effect of in vitro fertilization (IVF) on adult mouse fat and liver metabolomes.

Endocrinology

Feuer SK, Donjacour A, Simbulan RK, Lin W, Liu X, Maltepe E, Rinaudo PF

Embryonic stem cells derived from in vivo or in vitro-generated murine blastocysts display similar transcriptome and differentiation potential.

PloS one

Simbulan RK, Di Santo M, Liu X, Lin W, Donjacour A, Maltepe E, Shenoy A, Borini A, Rinaudo P

Unwind and transcribe: chromatin reprogramming in the early mammalian embryo.

Current opinion in genetics & development

Biechele S, Lin CJ, Rinaudo PF, Ramalho-Santos M