Carolyn R. Klocke and Pamela J. Lein discuss how an individual’s experiences during early life can influence their risk for disease as an adult
An individual’s experiences during early life can influence their risk for disease as an adult. Dr. David Barker first postulated this in the 1980s following his observations that infants born with low birth weight were at significantly increased risk for developing cardiovascular disease as adults. This idea was controversial at the time because it challenged the conventional thinking that unhealthy lifestyle was the primary cause of cardiovascular disease. However, subsequent epidemiologic studies confirmed Barker’s findings and the concept that early-life experiences are an important determinant of adult disease risk became known as the “Barker hypothesis”.
While the Barker hypothesis was derived from evidence linking foetal malnutrition to cardiovascular disease risk in adulthood, the concept has since expanded to include a broader spectrum of risk factors, diverse disease states targeting different organ systems, and developmental periods extending beyond gestation. In recognition of this paradigm shift, the Barker hypothesis was renamed the developmental origins of health and disease (DOHaD) hypothesis. Several decades of DOHaD research have identified at least four categories of early-life risk factors: the nutritional status of the pregnant woman and young child, psychosocial stress, immunological stress, particularly infection during pregnancy, and chemical exposures. It is now also appreciated that the risk of most, if not all, adult-onset diseases are influenced by early-life stress, but only if exposures occur during specific periods of development. These high-risk periods are referred to as “critical periods” or “critical windows of development”, and these vary depending on the early-life insult and the target organ. For many organ systems, however, the foetal period is the primary critical window.
The nervous system is particularly vulnerable to early-life stressors, perhaps because human brain development continues after birth, throughout early childhood and into adolescence. To date, research supports an association between early-life environmental insults and increased risk of neuropsychiatric disorders like schizophrenia, demyelinating diseases, such as multiple sclerosis (MS), and neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases (AD and PD, respectively). Whether an early-life stressor increases an individual’s risk for neuropsychiatric or neurologic disease depends on numerous factors. What is the type and magnitude of the stressor? Is the insult continuous, intermittent, or a single isolated incident? What is the timing of exposure relative to critical windows of development, which vary across different brain regions? Does the affected individual carry genes that confer increased susceptibility or increased resistance to the adverse effects of the stressor? Sex also influences the impacts of early-life stressors, perhaps because gonadal sex hormones influence many of the organisational aspects of neurodevelopment. Examining the sex-specificity of early-life stressors may be important for understanding why many neurological and neuropsychiatric diseases exhibit a sex bias in their incidence and clinical profile.
Maternal infection during pregnancy is strongly linked to increased risk of schizophrenia, though it does not appear that any specific pathogen or class of pathogens is responsible. While there is disagreement as to whether a specific trimester of pregnancy is most vulnerable, the pro-inflammatory environment created by maternal infection is thought to alter the pattern of cellular connections made in the foetal brain, laying the groundwork for altered behavior in adulthood. Emerging evidence also suggests that early-life exposure to the lead (Pb) may increase risk for schizophrenia, particularly in individuals that express a mutation in the disrupted in schizophrenia 1 (DISC-1) gene, a gene that is strongly associated with schizophrenia and related mental disorders. AD is the most common cause of progressive dementia in elderly adults and it is rapidly increasing in global incidence; PD is the second most common neurodegenerative disease after AD. Only a small percentage of cases of either disease can be attributed to solely genetic causes, supporting a role for environmental factors in determining individual risk. Recent studies have identified early-life risk factors for AD and PD, including low birth weight, premature birth, living in a rural area, low socioeconomic status during childhood, and prenatal or early childhood exposures to environmental pollutants, including heavy metals, pesticides, and air pollution. Air pollution has also been linked to an increased risk of MS.
A key question in the field is how do early-life events influence risk of adult-onset disease? It is believed that environmental stressors disrupt the organisational patterning and/or function of the developing brain by altering cell numbers or interfering with the differentiation of neurons or glial cells. So why do these changes not manifest as functional deficits or disease until adulthood? One explanation is that the affected cells are not functional until later in life. For example, exposure of the developing brain to high concentrations of the food additive monosodium glutamate (MSG) causes excessive death of neurons in the hypothalamus by triggering apoptosis, a form of programmed cell death. However, functional deficits associated with the foetal loss of these hypothalamic neurons (hypogonadism and infertility) become evident only in adolescence when the neuroendocrine function of these neurons is normally activated. Alternatively, the adverse impacts of the early-life stressor are masked or initially attenuated due to compensatory mechanisms or plasticity of the brain. However, these developmental perturbations predispose the individual to neural deficits following subsequent insults, such as chemical exposure, disease, or aging due to decreased brain reserve capacity. This phenomenon has been demonstrated in both animal models and humans following developmental exposures to methyl mercury or pesticides.
In summary, the experimental evidence indicates that early-life insults can fundamentally change the trajectory of brain development, thereby diminishing the ability of the brain to protect against subsequent insults, which increases susceptibility to disease in adulthood. A significant challenge in the field is to identify early-life stressors that increase adult-onset disease in humans. Detecting effects in the human population is difficult because the effects do not manifest until well after the developmental exposure. However, the effort to identify these associations merits investment of research dollars because preventing disease by identifying and reducing or eliminating risk factors is more effective than treating disease in terms of both individual and societal costs.
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