The Developmental Origins of Health and Disease: Today's Perspectives and Tomorrow's Challenges

Daniel B. Hardy, M.D. As a high school student working in the laboratory of Dr. John Challis at the University of Western Ontario (UWO), I still remember that early morning laboratory meeting when he recounted the events of his recent visit with Dr. David Barker and his now famous observation that birthweight could predispose people to adult-onset diseases. For me, the idea that prenatal life could influence overall fitness was an extraordinary notion to accept. But as I progressed through my Ph.D. and postdoctoral training in fetal development in the laboratories of Drs. Kaiping Yang and Carole Mendelson, my interest was heightened by the latest discoveries pertaining to the developmental origins of adult diseases. I now focus in this area in my own laboratory here at UWO. Once an outsider looking in, there was a time when I thought all the links had already been established between an adverse in utero environment and long-term disease. I also believed very little progress had been made in understanding the underlying molecular mechanisms involved and on intervention strategies that could be developed to impair the etiology of these development-based diseases. Thankfully, I was wrong. In the past 5 to 10 years, large cohort human studies and better animal models have further expanded our understanding of the fetal origins of the metabolic syndrome, demonstrating how poor conditions in perinatal life can have an impact on the health of the offspring and on subsequent generations as well. In addition, emerging fields such as epigenetics and nuclear receptor biology have enlightened our understanding of how various insults in pregnancy (e.g., undernutrition, hypoxia, excess steroid hormones, or infection) can influence organ development throughout fetal life, neonatal life, and adulthood. More importantly, recent mechanistic studies in this field have revealed that we might be able to overcome these developmental abnormalities by exploiting the plasticity of organ development in early life. To my knowledge, the theme of the developmental origins of adult diseases has never been highlighted in Seminars in Reproductive Medicine. Although many of the studies described in this issue rely on both animal models and basic research to help us link impaired fetal development to postnatal health, this work has great implications for the reproductive clinical audience of this journal. This is best illustrated by the first contribution by Drs. Padmanabhan and Veiga-Lopez, whose research focuses on the link between excess steroids in fetal development and the incidence of polycystic ovary syndrome (PCOS). Their work illustrates the great parallels between the attributes of testosterone-treated animals and women with PCOS. The next review article by Drs. Longtime and Nelson addresses the role of the placenta, an important mediator in the fetal programming of adult diseases. For a long time the placenta was only regarded as an indicator of intrauterine growth restriction (IUGR). However, we now know it plays a very significant role in the severity of postnatal outcomes. Drs. Longtime and Nelson provide a detailed overview of how early embryonic programming occurs in tandem with impaired placental development. In addition, they bring us up to date on the epigenetic mechanisms influencing placental function, noting in fact that these changes, by definition, are reversible. The role of impaired fetal development on cardiac function and the surrounding vasculature is discussed in the articles by Dr. Rueda-Clausen and colleagues from the University of Alberta and by Thompson and Regnault at UWO. Rueda-Clausen et al provide an excellent overview of the various experimental models of the early programming of cardiovascular disease (CVD), stressing the role of gender and the timing of the perinatal insult on the etiology of CVD. Thompson and Regnault's review highlights the role of the intrauterine environment on skeletal and cardiac muscle development via alterations in nuclear receptors and various modulators, leading to insulin resistance and hypertension. The importance of skeletal muscle in fetal programming, previously ignored by other groups in the field, is brought to our further attention by the contribution of Thorn et al. In addition, this University of Colorado group updates us on how IUGR offspring exhibit insulin resistance through multiple effects on glucose- and insulin-regulating organs including skeletal muscle, pancreas, liver, and the brain. Their work using the pregnant sheep model illustrates once again why the sheep continues to be an excellent model to study how short-term fetal adaptations to maternal adversity can lead to long-term diseases. The links between both IUGR and maternal obesity on the fetal programming of adipose tissue are next addressed by Drs. Desai and Ross from UCLA. Their review highlights the mechanistic similarities and differences between IUGR and overweight newborns on lipogenesis and adipocyte proliferation. What links the two together are nuclear receptors, namely peroxisome-proliferator-activated receptor γ. This raises the exciting possibility of specific drug targets in the early prevention of obesity due to an impaired in utero environment. On the related theme of IUGR and dyslipidemia, Sohi et al from my laboratory at UWO review the mechanisms whereby cholesterol homeostasis is disturbed long term in IUGR offspring, citing examples from both clinical and animal models. These include effects on posttranslational histone modifications and the lipid-sensing nuclear receptor, liver X receptor. Drs. Godfrey and colleagues, pioneers in the field, bring us up to date regarding the various mechanisms underlying fetal programming and developmental plasticity, regardless of the organ system examined. Their review highlights the role of epigenetics, organ structure, mitochondria, and homeostatic mechanisms on impaired growth and metabolism in later life. Finally, this collection of articles that focuses on the effects of impaired fetal growth on metabolic diseases is placed in perspective with the topic of fetal overgrowth as highlighted by the comprehensive review of Drs. Dyer and Rosenfeld. The incidence of this form of malnutrition is increasing in North America. Their work from the clinic and laboratory sheds light on how overnutrition and macrosomia, depending on the timing in development (prepregnancy, prenatal, perinatal, or postnatal), can lead to the metabolic syndrome in the offspring, with implications for subsequent generations. The similarities and consequences of fetal overnutrition and undernutrition are striking. As guest editor of this issue of Seminars in Reproductive Medicine , it has been a real delight to meet and interact with researchers at the forefront of fetal programming. Like a rookie on the roster of an all-star baseball team, I feel their invited contributions and insight have broadened my understanding of this field, and I hope they influence your perception of the importance of fetal well-being and postpartum health. Given the increased rates of preterm and low birthweight pregnancies in North America over the last decade, Barker's observations are now more relevant than ever. I hope this assembled collection affirms this conviction but more importantly lays out future strategies and hope for both the short-term care of low birthweight infants and the long-term prevention of adult diseases.

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