Reproductive Toxicology, May 1, 2007
THE DEVELOPMENTAL BASIS OF HEALTH AND DISEASE
[Rachel's introduction: A new hypothesis undergoing scientific testing and scrutiny is called the developmental basis of health and disease: "If true, then it says that the focus on disease prevention and intervention must change from the time of disease onset to perhaps decades prior: during the in utero and neonatal period. Perhaps the reason it has been so difficult to link environmental exposure to disease susceptibility is that scientists have been looking at the wrong time!"]
Jerrold J. Heindel**
There is a major paradigm shift taking place in science that while simple is profound. It states that the root of many diseases, including reproductive diseases and dysfunctions, will not be found by examination of disease onset or etiology hours, days, weeks, or even years prior to disease onset. The new paradigm suggests that susceptibility to disease is set in utero or neonatally as a result of the influences of nutrition and exposures to environmental stressors/toxicants.
In utero nutrition and/or in utero or neonatal exposures to environmental toxicants alters susceptibility to disease later in life as a result of their ability to affect the programming of tissue function that occurs during development. This concept, that is still a hypothesis undergoing scientific testing and scrutiny, is called the developmental basis of health and disease. If true, then it says that the focus on disease prevention and intervention must change from the time of disease onset to perhaps decades prior: during the in utero and neonatal period. Perhaps the reason it has been so difficult to link environmental exposure to disease susceptibility is that scientists have been looking at the wrong time! Certainly not all exposures that result in increased disease or dysfunction occur during development. This paradigm shift just suggests that this is a sensitive window of exposure that should be examined more thoroughly.
This concept has its origins in two disciplines, epidemiology studies of humans and developmental toxicology studies in animals. The underlying scientific hypothesis behind the developmental basis of adult diseases has been developed by epidemiology studies and emphasized by Dr. David Barker in the United Kingdom. He has shown that during development fetuses respond to adverse conditions, mainly severe undernutrition, by favoring the metabolic demands of the growing brain/CNS and heart at the expense of other tissues. The growing brain/CNS and heart tissue may not, however, escape entirely unscathed. The long-term consequences of this response are that the fetus is protected from death, is live-born, but has a low birth weight and is more prone to diseases later in life.
These epidemiology studies show that low birth weight (LBW), small for gestation age (SGA), frank intra-uterine growth retardation (IUGR) or clinically abnormal thinness at birth strongly predicts the subsequent occurrence of hypertension, hyperlipidemia, insulin resistance, type 2 diabetes, ischemic heart disease, breast or prostate cancer in adult life. Fetuses that are clinically malnourished during the first trimester of development are also three times more likely to be obese as adults (reviewed in ).
The concept of fetal programming of structural-functional formations during development has been proposed to explain these findings. Programming is the term used to describe lifelong changes in function that follow a particular event in an earlier period of the life span. While epidemiology studies have identified the phenomenon of metabolic programming, little is known about the mechanism(s) by which fetal insults lead to altered programming and to disease later in life. In addition, emphasis thus far has been on alterations in nutrition during development with virtually no focus on the role that exposures to environmental agents, such as air or water pollution, either alone or in combination with qualitative alterations in macro- or micro- nutrition (i.e. soy protein, phytoestrogens, isoflavones or other chemicals in herbal supplements or dietary sources), might have on this phenomenon.
With regard to developmental toxicology, it is known that between 2 and 5% of all live-born infants have major developmental defects. Up to 40% of these defects have been estimated to result from maternal exposure(s) to harmful environmental agents that directly or indirectly create an unfavorable intrauterine environment. A spectrum of adverse effects can occur, including death, structural malformation, and/or functional alteration of the fetus/embryo. The traditional focus of the science of developmental toxicology has been on the role of agents (environmental or drugs) that cause either premature death of the fetus or birth defects. In recent years, attention has turned to examining the effects of in utero or neonatal exposure to environmental agents on functional changes in tissues, e.g. permanent changes in tissue function that are not the result of overtly or grossly teratogenic effects but that result in increased susceptibility to disease/dysfunction later in life. This new focus on functional changes has been made possible by the development and use of "omics" technology that has allowed the examination of gene expression changes in tissues during development. It should be noted that this hypotheses was actually formulated over 20 years ago by Dr. Howard Bern when he described the "fragile fetus syndrome" . It has been revived and is now receiving significant attention due to advancement in genomics and proteomics technology that has allowed scientist to detect changes in gene expression and protein levels in tissues, presenting a possible mechanism for the phenomenon described.
The epidemiology data that support the Barker hypothesis on the fetal basis of adult disease, together with the preliminary data showing alterations in gene expression and tissue imprinting due to in utero or neonatal exposures to some environmental agents, provide an attractive framework for understanding delayed functional effects of toxicant exposures. Thus it has been proposed that exposure to certain environmental chemicals alone or in combination with altered nutrition, leads to aberrant developmental programming that permanently alters gland, organ or system potential. These states of altered potential or compromised function are hypothesized to result from epigenetic changes, e.g. altered gene expression due to toxicant- induced effects on imprinting, and the underlying methylation-related protein-DNA relationships associated with chromatin remodeling. The end result is an animal that is sensitized so that it will be more susceptible to diseases later in life.
The following key points serve to elaborate this general hypothesis:
** There is a unique sensitivity to the developing fetus which may be due to multiple factors including undeveloped DNA repair, or immature immune system, lack of detoxifying enzymes, primitive liver metabolism, lack of blood/brain barrier, increased metabolic rate and increased sensitivity to epigenetic changes.
** This unique sensitivity is during tissue development, which in many cases extends well into neonatal life.
** The initiating in utero environmental insult may act alone or in concert with in utero nutrition and/or with later exposures. That is, there could be an in utero exposure that would lead by itself to pathophysiology later in life or there could be in utero exposure combined with a neonatal exposure (same or different compound(s)) or adult exposure that would trigger or exacerbate the pathophysiology.
** The pathophysiology may manifest as: the occurrence of a disease that otherwise would not have happened; an increase in risk for a disease that would normally be of lower prevalence or an earlier onset of a disease that would normally have occurred; or an exacerbation of the disease.
** The pathophysiology may have a variable latent period from onset in the neonatal period, early childhood, puberty, early adulthood, or late adulthood; depending on the toxicant, time of exposure and tissue/organ affected.
** The effects may be transmitted to future generations through the germ line.
** The effects of in utero exposure to toxic environmental chemicals may occur in the absence of reduced birth weight. This makes it more difficult to assess, than effects due to severe nutritional deficits during development.
In addition, extrapolation of risk may be difficult since effects may not follow a monotonic dose-response relationship, the toxicant may have an entirely different effect on the embryo, fetus, or perinatal organism, compared to the adult and exposure of one individual to an environmental toxicant may have little effect, whereas another individual will develop overt disease or dysfunctions.
The short-term approach to addressing this paradigm is to produce in utero or neonatal exposure to an environmental agent at environmentally relevant doses. Then to correlate exposure measurements with measurements of gene expression in target tissues at or near birth or the termination of dosing. Some animals are then allowed to mature and onset of disease/dysfunction is quantitated. Gene expression studies are carried out on the diseased tissues. Finally gene expression changes noted after dosing are correlated with gene expression changes in the diseased tissue to show that in utero exposure has resulted in altered programming of gene expression and this effect correlates with disease. In the long term it is necessary to show cause and effect relationship between in utero or neonatal exposures, altered gene expression in target tissues and disease. Finally, the mechanism responsible for the altered gene expression that is responsible for the increased incidence or severity of disease must be determined. Once completed, the intervention and prevention strategies can be developed to reduce the incidence of disease. There are several recent reviews on this paradigm , ,  and .
This special edition of reproductive toxicology is intended to highlight recent data that show proof-of-principle for the hypothesis that in utero or neonatal exposures to environmental agents alone or in combination with altered nutrition can provide the developmental basis for a number of later-occurring diseases. Some articles are research manuscripts, some are reviews and some are combinations, all are focused on the developmental basis of adult disease paradigm.
The main focus is on animal studies as the developmental basis of disease paradigm is particularly difficult to assess in humans at this point in time; as in utero exposures must be linked to gene expression or other tissue potential changes at birth and then linked to an adult disease. Nonetheless, humans are exposed to a variety of environmental chemicals in utero, many are the same chemicals that have been shown to cause increased incidences of disease/dysfunction later in life in animal studies and at similar concentrations to those used in the animal studies ,  and . Indeed a recent publication by The Environmental Working Group  showed that a variety of industrial chemicals, pollutants, and pesticides could be measured in human umbilical cord blood. They tested newborns for 413 environmental chemicals and found that 287 of them were found at some levels including various PCBs, mercury, DDT and dioxins. In addition, the Centers for Disease Control and Prevention (CDC), has recently released its Third National Report on Human Exposures to Environmental Chemicals . It reports on blood and urine levels for 148 chemicals, 38 for the first time, by age, sex, race or ethnicity, in a random sample from participants from the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2002. These data indicate low exposure to multiple chemicals including mercury, phthalates, bisphenol A, phytoestrogens, organochlorine pesticides, herbicides and dioxin-like chemicals. Thus the potential exists for extrapolation of the animal data on the developmental basis of health and disease to human health.
Indeed the first article in this edition focuses on human exposures during development. This is followed by an examination of epigenetics as the mechanism for the developmental basis of adult disease. The following 21 articles describe the state of the science in this exciting and emerging area highlighting the developmental basis of obesity, reproductive diseases, cardiovascular disease, respiratory disease, and neurological disease. It will take years to discern the actual importance of this new paradigm to disease processes. It is hoped that this special edition will stimulate research in this direction.
**Division of Extramural Research and Training, National Institute of Environmental Health Sciences, Department of Health and Human Service, 79 T.W. Alexander Drive, Building 4401 3rd Floor, Mail Drop: EC-23, Room 3413, Research Triangle Park, NC 27709, United States
 P.D. Gluckman and M.A. Hanson, Developmental origins of disease paradigm: a mechanistic and evolutionary perspective, Pediatr Res 56 (2004), pp. 311-317.
 H. Bern, The fragile fetus. In: T. Colborn and C. Clement, Editors, Chemically-induced alternations in sexual and functional development: the wildlife/human connection (1992).
 K.P. Miller, C. Gorgeest, C. Greenfeld, D. Tomic and J.A. Flaws, In utero effects of chemicals on reproductive tissues in females, Toxicol Appl Pharmacol 198 (2004), pp. 111-131.
 A.C. Vidaeff and L.E. Sever, In utero exposure to environmental estrogens and male reproductive health: a systematic review of biological and epidemiologic evidence, Reprod Toxicol 12 (2005), pp. 5-20.
 C. Lau and J.M. Rogers, Embryonic and fetal programming of physiological disorders in adulthood, Birth Defects Res (Part C) 72 (2005), pp. 300-302.
 A.J. Drake and B.R. Walker, The intergenerational effects of fetal programming: non-genomic mechanisms for the inheritance of low birth weight and cardiovascular risk, J Endocrinol 180 (2005), pp. 1-16.
 L.L. Needam and K. Sexton, Assessing children's exposure to hazardous environmental chemicals: an overview of selected research challenges and complexities, J Expos Anal Environ Epidemiol 10 (2000), pp. 611-629.
 C. Mori, M. Komiyama, T. Adachi, T. Sakurai, D. Nishimura and K. Takashima et al., Application of toxicogenomic analysis to risk assessment of delayed long-term effects of multiple chemicals including endocrine disruptors in human fetuses, Environ Health Perspect 111 (2002), pp. 803-809.
 E.V. Younglai, W.G. Foster, E.G. Hughes, K. Trim and J.F. Farrell, Levels of environmental contaminants in human follicular fluid serum and seminal plasma of couples undergoing in vitro fertilization, Arch Environ Contamin Toxicol 43 (2002), pp. 121-126.
 Environmental Working Group. 2005; http://www.ewg.org/reports/bodyburden2.
 CDC. National report on human exposures to environmental chemicals. 2005; http://www.cdc.gov/exposurereport.
Reproductive Toxicology Volume 23, Issue 3, April-May 2007, Pages 257-259
Copyright 2007 Elsevier