The concept of adult disease having a fetal basis started with a focus on severe malnutrition during pregnancy in humans and the susceptibility during adulthood to type 2 diabetes, high blood pressure, and cardiovascular disease, indicated by a range of early studies, and later expanded by David Barker and colleagues. Concurrently with those studies, the adverse health effects of diethylstilboestrol (DES), an estrogenic drug given to pregnant women to protect pregnancy loss, became apparent in the offspring of both sexes, thus indicating that maternal exposures had consequences that affect the health of their children. Howard Bern coined the term “the fragile fetus” to indicate fetal vulnerability to endocrine disrupting chemicals. This was followed by the experimental demonstration that developmental exposure to environmental chemicals in laboratory animals could lead to increased susceptibility to disease and dysfunction later in life. While these two fields of science started independently, it is now clear that both are reflections of the life-course implications of the developmental environment. Both nutritional imbalance and environmental chemical exposure, during sensitive windows of development, act when tissues are forming, to affect the phenotype, thereby impacting on organ functions and disease susceptibility later in life. So while the fetus may not only be ‘fragile’, it is plastic and is able to respond adaptively to a wide range of challenges and stimuli during development. Nonetheless this plasticity can set the scene for enhanced risk of disease later in life.
Both scientific areas are presently supported by extensive laboratory animal and human studies. Predisposition to many diseases has been shown to result from, or at least to correlate with, early changes in nutrition or chemical exposures. The two related disciplines are now starting to be integrated both in terms of basic and clinical science, and in terms of their public health implications, as nutrients and environmental chemicals can act on the same developmental systems over the same time frames and via similar mechanisms. In some cases, one factor may compensate for the effects of another, or the two may act synergistically to generate a stronger impact. The following features are common to both fields.
· Both nutritional imbalance and environmental chemicals act during specific windows of sensitivity and thus show time-, sex-, and tissue-specific effects. The windows of sensitivity are known only in general terms, with most research focused on the in utero and early childhood time periods. The effects on disease risk are likely to be due to multiple impacts by nutritional challenges and chemical exposures accumulated from embryonic development throughout the life-course. These may include early childhood, puberty, pregnancy, menopause and aging (Figure ).
· While the adverse effects of nutritional imbalance during development can result in diseases and dysfunctions later in life, some effects are mediated by adaptive changes that protect the fetus and child, but are to the long-term detriment of specific tissue and organ function, thereby resulting in increased susceptibility to disease, depending on the differences between neonatal and adult environments. Similarly, exposure to environmental chemicals during development can cause abnormal gene regulation (e.g., via epigenetic mechanisms) which may persist and may become apparent later in life as increased risk of dysfunctions or diseases (Figure ). Thus, developmental disruption can result from multiple impacts by nutritional imbalance and chemical exposures, accumulated from embryonic development throughout the life-course.
· Neither nutritional imbalance nor chemical exposures need to affect birth weight to generate a longer-term effect on disease risk. Indeed, there is a continuum of risk even among those within the normal range of nutrition (and birth weight) and with very low doses of environmental chemicals. For chemical exposures, the effects are most often not accompanied by a clear change in birth weight. Thus, new biomarkers, for example, epigenetic parameters, at birth are needed to assess the potential for increased disease risk.
· The changes that occur during development due to nutritional imbalance or environmental chemicals are often functional in nature, and include alterations in gene expression, protein concentrations, cell metabolism and differentiation, and in cell numbers or location, thus affecting interactions between cell types and the establishment of cell lineages. These changes can lead to subtle morphological changes detected only during detailed histologic examination and/or changes in the functional characteristics of tissues, organs or systems. However, the effects of nutrient imbalance or chemical exposure need not necessarily be functional at birth: epigenetic changes in particular can produce permanent effects on the promoter regions of specific genes, which will not become apparent until the appropriate stimuli for expression, e.g. levels of transcription factors, are present. This emphasizes again the need for effective biomarkers, especially epigenetic marks, which can be measured at birth and which not only indicate responses to prenatal challenges, but also potential later responses to risk factors for disease.
· Functional changes result in changed susceptibility to non-communicable diseases that will likely show up later in life, with a latency that may vary from months to years or even decades. The disease or functional outcome will depend on the stressor, its concentration and timing. Again, the latency before the appearance of health impacts necessitates the development of biomarkers of exposure and the future risk of ill health that can be measured early in life.
· A combination of developmental stressors, whether nutritional or toxic, could cause effects jointly with similar or other exposures at different times to trigger or exacerbate adverse effects. While such combinations may result in additive effects on similar pathways, cells and tissues, the details vary. The adverse effects resulting from such stresses can become apparent as an increased incidence of a disease or dysfunction, an earlier onset or an increased severity of the trait. However, the possibility exists that some interactions between nutrients and toxicants may lead to reduced disease risk.
· The effect of either nutritional imbalance or environmental chemical exposures, depending on the dose and timing of exposures, can be transmitted via the germ line to subsequent generations, thus resulting in transgenerational inheritance of increased disease risks.
· The major mechanism, as currently understood, involves epigenetic processes, i.e., altered DNA methylation, chromatin remodelling and small non-coding RNAs. The overall result is differential modulation of epigenetic systems that control gene expression that persists through mitosis.
· The effects of these stressors can also depend on genetic background, e.g. genetic polymorphisms. The effects may be sex-specific and may include changes in normal sexual dimorphism.