It is recognized that 2–5% of all live-born infants have a major developmental defect. Approximately 40% of these defects are thought to be due to the effect(s) of an adverse exposure of a genetically predisposed fetus to intrauterine environmental factors. It is now clear that in many cases the fetus is more sensitive than the adult to the same environmental insults. Exposure to environmental agents during early development can result in death, structural malformation, and/or functional alteration of the embryo/fetus. While the focus of developmental toxicology has been on understanding the effects of toxicants on malformations, recently the focus has changed to an important and emerging area of developmental toxicology: the effects of in utero exposures that cause permanent functional changes that are not overtly, grossly teratogenic yet that result in increased susceptibility to disease/dysfunction later in the life span. This new area of developmental toxicology is termed the fetal or developmental basis of disease. Most of the supporting studies in this area have concentrated on grossly altered nutrition in utero and its striking influence on multiple aspects of adult health and disease risk, including increased susceptibility to heart disease, diabetes, and cancers. There is, however, evidence that some environmental agents, especially those with endocrine agonist or antagonist activity, may cause functional deficits that do not become apparent until later in life. In the reproductive tract, the classic example of this phenomenon is the action of diethylstilbestrol (DES). In humans, in utero exposure to DES leads to an increase in vaginal adenocarcinoma around the time of puberty. In mice, neonatal DES exposure leads to an increase in uterine adenocarcinoma in adulthood. Although the direct connection has not been made between in utero programming changes due to DES and later life disease, it is known that DES (in the animal studies) results in altered gene expression in the uterus that is irreversible without any noticeable gross alterations in uterine morphology. Other examples in the reproductive area include: developmental exposures of the monkey to androgens that lead to polycystic ovary syndrome–like effects in the adult; maternal in utero exposures to methoxychlor and reduced reproduction in male offspring; alterations in gene expression in the developing rat prostate due to dioxin that are correlated with increased prostate cancer risk; and in utero exposure to dioxin and endometriosis later in life in primates and rodents. There are also preliminary data that indicate a possible role for in utero exposure to environmental estrogens in the etiology of obesity, as well as alterations in the development of the immune and nervous systems that may lead to increased susceptibility to disease. On the basis of epidemiology data that support the hypothesis of the developmental basis of disease and the preliminary data showing alterations in gene expression and imprinting due to in utero exposures to some environmental agents, it is proposed that exposure to certain environmental chemicals as well as altered nutrition, or in combination with altered nutrition, will in some situations, not lead to easily identifiable structural malformations but instead to alterations in developmental programming expressed as a permanently altered gland, organ, or system potential. These states of altered potential would be a result of changes in gene expression, due to altered imprinting, and the underlying methylation-related protein-DNA relationships associated with chromatin remodeling. These effects will occur in a time-specific (i.e., vulnerable window) and tissue-specific manner, and such alterations may be irreversible. The end result is an animal that is sensitized such that it will be more susceptible to diseases later in life. The environmental insult could act via a one-hit or two/three-hit scenario. 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 the pathophysiology. The pathophysiology or functional change that results from the exposures/insult could lead to: 1) the occurrence of a disease that otherwise would not have happened, 2) an increase in risk for a disease that would normally be of lower prevalence, or 3) either an earlier onset of a disease that would normally have occurred or an exacerbation of the disease. Finally, the pathophysiology could have a variable latent period from onset in the neonatal period, to early childhood, to puberty, to early adulthood, or to late adulthood, depending on the toxicant, time of exposure, and tissue/organ affected. The effects could potentially be transgenerational. The scientific approach to this area is to expose animal models to environmental agents in utero at concentrations that do not cause overt malformations and to examine the effect of this exposure on gene expression profiles in specific tissues over time. Some exposed animals are allowed to mature, and they are examined for an increase in specific diseases or dysfunctions at various times during the lifespan. If an increased incidence or severity of diseases is noted, then gene expression in the diseased tissue is compared to that in controls to determine if the increased disease could be correlated with altered gene expression. These data would show a correlation between exposure, altered gene expression, and increased incidence or severity of a disease/dysfunction. The next steps would involve proving cause and effect between the in utero exposure altered gene expression and subsequent increased incidence or severity of disease. Finally, the mechanism responsible for this phenomenon needs to be determined, and the most logical approach at this time would be to examine alterations in gene methylation, as that is one mechanism to alter the timing of gene expression. It should be noted that there are numerous combinations that can be examined, including the interaction of altered nutrition in utero with exposure to environmental agents, the interaction of infectious agents that may alter the developing immune system with exposure to environmental agents, and, finally, in utero exposure in combination with other exposures throughout a lifetime. It may be that the reason that it has been difficult to determine a role for environmental chemicals, including endocrine disruptors, in the etiology of disease is that scientists have been looking at exposures in the adult; thus this new approach holds promise for having a major impact on our understanding of gene-environment interactions in disease. The following presentations are from a National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS)–sponsored symposium at the 2003 Teratology Society meeting in Philadelphia. They show the status of research in this area. It is noteworthy that at this point in time the fetal basis of adult disease remains a hypothesis. As will be evident from the presentations, there are no definitive data showing cause and effect between in utero exposure to environmental chemicals and functional changes in tissues that lead to increased susceptibility or incidence of disease later in life. The present data provide intriguing preliminary data and proof of general concept. The NIEHS continues to provide funds to stimulate this area of research in order to develop the data in animal models that will set the stage for human studies.
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Jerrold J. Heindel (2005) studied this question.