Abstract
Progress towards meeting the eight United Nations Millennium Development Goals has been accompanied by a substantial change in the global pattern of disease, with a significant shift towards chronic noncommunicable diseases (NCDs). Globally, early childhood deaths have declined, but years lived with disability have increased over the 20 years 1990–2010: cardiovascular disease by 17.7%; chronic respiratory disease by 8.5%; neurologic conditions by 12.2%; diabetes by 30.0%; and mental and behavioral disorders by 5.0%. These trends are continuing with further increases in the global burden of disease related to chronic NDCs reported in the 2013 updates. There is increasing recognition that many chronic diseases are initiated in early life. This chapter will review the role that environmental exposures, especially those occurring in early life, play in increasing long-term risk of respiratory disease.
Keywords
environment, genetics, epigenetics, asthma, pneumonia, COPD
Progress towards meeting the eight United Nations Millennium Development Goals has been accompanied by a substantial change in the global pattern of disease, with a significant shift towards chronic noncommunicable diseases (NCDs). Globally, early childhood deaths have declined, but years lived with disability have increased over the 20 years 1990–2010: cardiovascular disease by 17.7%; chronic respiratory disease by 8.5%; neurologic conditions by 12.2%; diabetes by 30.0%; and mental and behavioral disorders by 5.0%. These trends are continuing with further increases in the global burden of disease related to chronic NCDs reported in the 2013 updates. There is increasing recognition that many chronic diseases are initiated in early life. This chapter will review the role that environmental exposures, especially those occurring in early life, play in increasing long-term risk of respiratory disease.
Vulnerability of Children to Adverse Environmental Exposures
In pediatrics the statement that “children are not little adults” is well known and understood. Children are in an active anabolic state as they grow and, as such, have increased requirements for air, water, and food, relative to their body size. This translates into a higher minute ventilation in liters/kg/day, increased maintenance requirements of calories (cal/kg/day) and water (mL/kg/day), especially during infancy and early childhood. In addition, children interact with their environment in ways that adults do not. Young children spend more time on the floor, where the concentration of environmental toxicants is higher. They are also more likely to put hands, feet, and objects into their mouths and noses and to ingest more toxicant-containing dust. Children also have different exposure pathways than adults ( Table 4.1 ). Taken together, these factors result in children receiving a larger dose of toxicants in any given environment than an adult in the same environment.
| Pathway | Prenatal | Infant | Child | Adolescent | Adult |
|---|---|---|---|---|---|
| Transplacental | √ | ||||
| Breast milk | √ | ||||
| Nutritive ingestion | √√√ | √√ | √ | √ | |
| Nonnutritive ingestion | √√ | √√√ | √ | √ | |
| Inhalation | √√√ | √√ | √ | √ | |
| Transdermal | √√√ | √√ | √ | √ | |
| Risk-taking behavior | √ | √√√ | √ |
Transplacental transmission is an exposure pathway that is not always taken fully into account when considering the impact of environmental exposures on increasing long-term disease risk. Previously, there was a view that the placental “barrier” protected the developing fetus from maternal exposures. However, we now know that many xenobiotics pass directly through the placenta and that maternal exposure during pregnancy can adversely affect fetal outcomes and increase long-term disease risk. Breast milk is another exposure pathway that is not always considered. Although breast milk is the ideal food for human newborn infants, the milk can contain a variety of environmental toxicants, including persistent organic pollutants, pesticides, heavy metals, plasticizers, and other chemicals that can increase disease risk.
Children are likely to be exposed to environmental toxicants in a number of different settings, depending on their age. Infants and young children will be exposed primarily in their home, whereas older children are likely to also be exposed in the local neighborhood, at daycare or school, and in the wider environment. Sources for common environmental exposures within the home are shown in Table 4.2 .
| Toxicant | Matrix | Source | Route of Exposure |
|---|---|---|---|
| Flame retardants | Dust, air, breast milk, food | Furnishings, clothing, electronic equipment | Nutritive and nonnutritive ingestion Inhalation, dermal |
| Pesticides | Air, dust, breast milk, food and beverages | Pest control sprays, agricultural practices, house and garden insecticides | Nutritive and nonnutritive ingestion Inhalation, dermal |
| Plastics/plasticizers | Food and beverages, air | Food containers (especially when heated) cosmetics, personal care products | Nutritive ingestion, dermal, inhalation |
| Combustion-related products (particulates, gaseous pollutants, polyaromatic hydrocarbons) | Air, dust | Cigarettes, candles, mosquito coils, biomass fuel, gas cooking | Inhalation, nonnutritive ingestion, dermal |
| Volatile organics | Air, dust | Furniture, building materials, glues, carpets, cigarettes, mosquito coils, personal care products | Inhalation, nonnutritive ingestion, dermal |
| Perfluorinated compounds | Food, water, dust | Teflon-coated cookware, industrial contamination of water | Nutritive and nonnutritive ingestion, inhalation, dermal |
In addition to receiving a higher dose of toxicant in any given environment, infants and young children are less able to metabolize and detoxify xenobiotics. Phase I (cytochrome P450 enzymes) and II (antioxidant defense) metabolic enzymes are immature at birth and mature relatively slowly after birth. This is likely to mean that the adverse effect of the increased dose received will be magnified by the young child’s inability to handle the toxicant.
Although many organ systems are essentially mature at birth, this is not true for the respiratory, immune, and central nervous systems. Thus these organ systems are vulnerable to both prenatal and postnatal environmental exposures. From the point of respiratory disease the vulnerability of both the respiratory and immune systems is of concern. Although a full description of the developmental profiles of the respiratory and immune systems is beyond the scope of this chapter, a brief overview is warranted. The airway branching tree develops between approximately 6 and 16 weeks’ gestation during the pseudoglandular phase of lung development. Thus environmental exposure that influences the structural development of the airways must occur during this window of susceptibility. Maternal exposure to air pollution and maternal smoking during pregnancy are two such exposures. However, environmental exposures occurring after this time, most notably ozone, can result in thicker airways and heightened responsiveness to constrictor stimuli after birth. Alveolar development begins later, at around 24 weeks’ gestation and is not complete at birth but continues in the early postnatal period. Although it is not known with certainty when alveolar development stops, the lung is especially vulnerable to environmental exposures occurring during the first 18–24 months of postnatal life. Similarly, both the innate and adaptive arms of the immune system are immature at birth and mature postnatally under the influence of environmental cues. As will be discussed later, delayed maturation of the immune system increases the risk of respiratory infections and asthma.
From a global perspective, socioeconomic factors such as poverty and poor nutrition can magnify the effects of adverse environmental exposures and increase disease risk. Poor nutrition includes both undernutrition resulting in stunting and inappropriate nutrition with high-calorie processed food resulting in obesity. Although this is especially true in low- and middle-income countries, it is also true in high-income countries where social disparities exist. Poverty, poor housing, poor nutrition resulting in trace element deficiency, stunting and underweight, excess noise, and emotional/physiologic stress are likely to increase disease risk from a given environmental exposure. Thus in determining with certainty the likely adverse health risk from adverse environmental exposures, one must consider: the developmental stage of the child (prenatal, infant, child, etc.); the social circumstances in which the exposure occurs; and the type and route of exposure. For multiple reasons outlined previously, one cannot extrapolate the risk from, or consequences of, exposures from adults to children.
Mechanisms Underlying the Increased Disease Risk From Adverse Environmental Exposures
Epidemiologic studies suggest that a wide variety of environmental exposures in early life can increase long-term disease risk. For example, exposure to traffic-related air pollution has been independently linked to: reduced fetal growth; premature birth; lower lung function at birth; increased respiratory infections; decreased lung function growth during childhood; incident asthma; an increased risk of chronic obstructive pulmonary disease (COPD); lung cancer; as well as obesity, type 2 diabetes, and cardiovascular disease. Other environmental exposures are also related to a wide range of outcomes suggesting that common mechanisms are likely to link such exposures to disease outcomes. Potential mechanisms will be discussed in the next sections.
Individual Susceptibility, Gene by Environmental Interactions, and Epigenetic Mechanisms Contributing to Respiratory Disease in Children
Being exposed to adverse environmental exposures does not, by itself, confer an increased risk of disease. Not all smokers develop lung cancer or COPD; however, some individuals are more susceptible than others. This suggests that individual susceptibility related to genetic variations is likely to be important.
There is increasing evidence that many of the risk factors for respiratory disease have a genetic contribution that may underlie individual susceptibility. Low lung function is a primary risk for both acute respiratory disease in early life and chronic respiratory disease throughout life. Several genetic variations have been associated with low lung function, reduced lung function growth, or accelerated lung function decline. Similarly, genetic variations have been associated with an increased susceptibility to lower respiratory infections, delayed maturation of the immune system, and early allergic sensitization. Genetic variations in the body systems designed to defend against environmental exposures, such as the antioxidant defense system, have also been reported as increasing individual susceptibility to respiratory disease, especially with exposure to traffic-related air pollution. Fig. 4.1 gives a schematic representation of the multiple pathways increasing disease risk in which individual susceptibility related to genetic variation has been reported. These same pathways are also susceptible to environmental exposures, opening the way to environmentally induced epigenetic processes and gene × environment interaction. Although a full description of all of these pathways is beyond the scope of this chapter, several warrant further discussion.
Epigenetic Mechanisms Increasing the Risk of Disease.
Despite a clear genetic component to asthma susceptibility—everyone knows that asthma runs in families—the failure of genetic studies, either candidate gene or genome-wide association studies, to explain more than a fraction of asthma has prompted investigation of other means by which gene variation and dysfunction could be involved. Many have turned to the study of epigenetics and global methylation. Epigenetics refers to the process whereby gene expression and function is altered without altering the DNA sequence of the gene. Several epigenetic mechanisms have been described, including DNA methylation at cytosine-guanine dinucleotide (CpG) residues, posttranslational modification of nuclear histones, and noncoding RNA-mediated gene silencing. These changes in gene function can survive cell division and can be heritable, although this is perhaps not as common in mammals as sometimes suggested because global demethylation and germline reprogramming limit transgenerational inheritance of epigenetic marks. DNA methylation changes throughout life, especially in key windows of vulnerability, but much of the epigenome is established during fetal development and provides a mechanism by which prenatal environmental exposures can increase disease risk. Maternal smoking during pregnancy has negative impacts on fetal lung development, immune system development, and somatic growth (as well as on neurodevelopment) that increase the risk of respiratory disease throughout life. Although direct data are scarce, epigenetic mechanisms are widely thought to be involved. Third-generation effects in which an increased asthma risk from grand-maternal smoking is passed to grandchildren via mothers exposed in utero is also thought to occur via epigenetic mechanisms. A likely mechanism by which environmental exposures such as tobacco smoke, household air pollution (especially biomass fuel burning), traffic-related pollution, and household chemicals can induce adverse changes in the epigenome that increase disease risk is by causing oxidative stress in the mother during pregnancy, potentially through upregulating expression of proinflammatory genes by histone modification and chromatin remodeling. Individual susceptibility to oxidative stress is increased by genetic variations in antioxidant defense genes.
Data showing that maternal factors can influence oocyte development and transfer disease risk to offspring via mitochondrial transfer present another mechanism for environmental exposures to increase disease risk. Mitochondrial transfer from mesenchymal stromal (stem) cells to injured cells has been well established in the lungs. More recently, Wu and colleagues have shown that oocytes from obese mice produce heavier fetuses when transferred to lean recipients; direct mitochondrial transfer from oocytes to blastocysts was the proposed mechanism. These data raise the probability that other environmental exposures prior to conception can modify oocytes by mechanisms other than epigenetics and suggest that more attention should be paid to the health of girls and young women to reduce NCDs.
Antioxidant Defense.
As outlined previously, antioxidant defense plays a substantial role linking environmental exposures to disease risk. Fig. 4.2 gives a schematic representation of the genetic and epigenetic mechanisms and the environmental exposures increasing disease risk when antioxidant defenses are inadequate.
Microbial Recognition.
We are all exposed to microbes and microbial products in our environment. Such exposures are critical for postnatal maturation of the innate and adaptive limbs of the immune system and for decreasing risk of respiratory disease. The interplay between resident bacteria and the immune system at times of respiratory viral infections in early life is also likely to have a significant influence on later risk of respiratory disease. Thus genetic and environmental influences on microbial recognition of microorganisms are another potentially critical factor likely to influence disease risk. Fig. 4.3 shows a schematic representation of such interactions.
Allergic Inflammation.
Allergic sensitization in early life is a major risk factor for persistent asthma, with the risk of sensitization being altered by genetic and epigenetic mechanisms and environmental exposures. In general, low-dose allergen exposure increases the risk of allergic sensitization, whereas high-dose favors the development of immune tolerance and not sensitization, especially in the presence of high concentrations of microbial products. However, environmental exposures also have the potential to alter genetic responses and modify the risk of allergic sensitization. One particular environmental exposure that has the potential to modify the risk of allergic sensitization is exposure to microbial products, including lipopolysaccharide (LPS). Exposure to microbial-rich animal barn dust during fetal development and early life has been shown to protect against allergic sensitization. However, the protection depends on the level of LPS exposure and genetic variations in the CD14 gene, with the C allele at CD14/-159 increasing the risk of allergic sensitization in the presence of low LPS levels and the T allele increasing risk with high levels of LPS. Other genetic variations can also play a role, with the A20 protein, a transcription product of TNFAIP3, in airway epithelial cells mediating LPS-induced attenuation of house dust mite allergen–induced inflammatory responses.
Fig. 4.4 shows a schematic representation of environmental, genetic, and epigenetic factors influencing the risk of allergic sensitization in early life. Whether these pathways increase the risk for other respiratory diseases is less certain, but possible, especially COPD, in which early life exposures do increase risk.
Low Lung Function/Reduced Lung Growth, Delayed Immune Maturation, and Somatic Growth Restriction Predisposing to Respiratory Disease
Low lung function is a risk factor for all respiratory diseases, both acute and chronic, throughout all stages of life. The respiratory system is not mature at birth because at least half of the adult complement of alveoli developing postnatally. The lungs are vulnerable to both prenatal and postnatal environmental insults that can limit lung function and lung function growth. Lung function “tracks” postnatally, meaning that lung function at birth is a major determinant of lung function throughout life ; however, severe respiratory infections and adverse environmental exposures can reduce lung function growth, resulting in a reduction in lung function that should have been gained. Fig. 4.5 shows a schematic representation of the interrelationships between prenatal and postnatal exposures increasing the risk for respiratory diseases in later life.
Prenatal exposures can increase the risk of postnatal respiratory disease by reducing lung function at birth, reducing somatic growth, or delaying immune system maturation during fetal development. Many exposures have more than one effect, possibly by epigenetic alteration of gene function as discussed previously. Maternal smoking during pregnancy increases the risk for all respiratory diseases by causing reduced lung function at birth, low birth weight, and delayed immune maturation. Similarly, maternal exposure to higher levels of ambient air pollution has been associated with lower birth weight, reduced lung function, and delayed immune maturation. An increasing range of prenatal environmental exposures are being linked to risk of respiratory disease, especially wheezing in early childhood and persistent asthma. However, for many of these the mechanisms are uncertain and not all studies show strong associations, Further research with both improved exposure assessments and outcome measurements is required.
Common Pathways to Respiratory Diseases
Debate continues about whether the various chronic respiratory diseases are different entities or components of a single disease spectrum. Holt and Sly postulated that atopic asthma, nonatopic asthma, and COPD could be part of a “family tree” of respiratory diseases stemming from a common origin but subject to environmental exposures occurring at different times during postnatal development and with differing frequency and severity. Fig. 4.6 shows a schematic representation of the common susceptibilities and exposures that could lead to atopic asthma, nonatopic asthma, and COPD.
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