Understanding exposures and latent disease risk within the National Institute of Environmental Health Sciences Superfund Research Program

Abstract

Understanding the health effects of exposures when there is a lag between exposure and the onset of disease is an important and challenging topic in environmental health research. The National Institute of Environmental Health Sciences (NIEHS) Superfund Basic Research and Training Program (SRP) is a National Institutes of Health (NIH) grant program that uses a multidisciplinary approach to support biomedical and environmental science and engineering research. Because of the multidisciplinary nature of the program, SRP grantees are well-positioned to study exposure and latent disease risk across humans, animal models, and various life stages. SRP-funded scientists are working to address the challenge of connecting exposures that occur early in life and prior to conception with diseases that manifest much later, including developing new tools and approaches to predict how chemicals may affect long-term health. Here, we highlight research from the SRP focused on understanding the health effects of exposures with a lag between exposure and the onset of the disease as well as provide future directions for addressing knowledge gaps for this highly complex and challenging topic. Advancing the knowledge of latency to disease will require a multidisciplinary approach to research, the need for data sharing and integration, and new tools and computation approaches to make better predications about the timing of disease onset. A better understanding of exposures that may contribute to later-life diseases is essential to supporting the implementation of prevention and intervention strategies to reduce or modulate exposures to reduce disease burden.

Impact Statement

This article provides an overview of the National Institute of Environmental Health Sciences (NIEHS) Superfund Basic Research and Training Program (SRP) and describes how the program is well-positioned to use multidisciplinary approaches to study the effects of exposures and later-life diseases. By explaining how the SRP is working to address this challenge of linking exposures and later-life diseases, the minireview provides an outline of needs and next steps to advance this field and improve our understanding of how exposures contribute to disease, especially when there is a lag between exposures and disease onset.

Introduction

Diseases are often detected or diagnosed in early to late adulthood, but the origins of these diseases may be a result of exposures occurring much earlier in life or even before life begins. Understanding the health effects of exposures and resultant later onset of disease is an important and challenging issue.

A large body of epidemiologic, clinical, and basic mechanistic research supports the developmental origins of health and disease (DOHaD) paradigm. DOHaD refers to the hypothesis that the diseases of adulthood can be influenced by exposures before birth and during critical periods of early fetal and childhood growth and development. ¹ Sometimes, these risks include exposures to an individual’s parents before conception and can also carry over into future generations. ²

The DOHaD paradigm originally focused on nutrition but has since expanded to include the effects of environmental chemical exposures on early-life development and subsequent development of disease across the lifespan.^3–5 For example, in addition to changes in diet and lifestyle, a subclass of endocrine-disrupting chemicals (EDCs) in the environment can contribute to obesity, type 2 diabetes, and non-alcoholic fatty liver disease. These chemicals might predispose some individuals to gain weight despite their efforts to limit caloric intake and increase levels of physical activity.^6,7 Research has also shown that carcinogens readily cross the placenta, which could provide evidence of potential early stage chemical carcinogenesis in children. ⁸ Furthermore, other studies link early-life exposures to environmental chemicals and risk for immune-related diseases and lung dysfunction later in life. ⁹ These concepts have wide implications for understanding the causes, and for developing potential prevention strategies, for a wide range of non-communicable diseases. ¹⁰

Development during the fetal and infancy stage is characterized by rapid growth and maturation of organs and systems. Variation in environmental exposures and/or the quality or quantity of nutrients consumed by parents before conception and mothers during pregnancy, as well as infants during the first year of life, can lead to enduring and significant effects on development that may lead to later-life health consequences. These effects, or “programming,” persist long after an initial exposure, predisposing the individual to disease in later life, and thus represent an important risk factor for a variety of non-communicable diseases, such as heart disease and cancer. ¹¹ There is also compelling evidence that exposures to parents before conception can affect their child’s lifetime health. ¹²

Early-life programming and transcriptional regulation supports the need to understand epigenetic mechanisms as a determinant in disease predisposition. ¹³ With epigenetic techniques, researchers have been able to examine changes in DNA, which can affect gene expression, to explore new potential mechanisms and develop new clinical and cohort studies to determine how people respond to early-life exposures. ¹ Epigenetic modifications such as DNA methylation, histone modifications, and expression of non-coding RNAs are involved in the mediation of early-life environmental exposures and may impact health later in the life course. For example, researchers have linked DNA methylation to metabolic health measures and future metabolic health status. These studies suggest that DNA methylation may mediate the effects of early-life exposures on later-life risk of obesity and obesity-related diseases. ⁵

Researchers are also exploring how mechanisms at different life stages of exposure translate to differences in disease outcomes, as well as other factors that may impact resilience and disease vulnerability. This includes the influence and effects of social inequalities and social and behavioral factors on environmental health risks. Also of interest is the role of the microbiome and how changes in gut microbiota early in life can impact windows of susceptibility and later-life disease.^1,14,15 Another mechanism that is gaining attention is environmentally induced somatic mosaicism. Exposures during critical windows of development can affect a person’s normal tissue development but may also explain tissue-specific effects of hazards in the adult organism due to genetic mosaicism. ¹⁶ In addition, transgenerational inheritance is a promising avenue of research that is under active investigation. Some health effects appear to be transmitted to offspring, suggesting that these epigenetic effects persist across generations.^17–19 Scientists are beginning to understand epigenetic inheritance or the mechanisms by which non-genetic information is transmitted to and deciphered by subsequent generations. A better understanding of how and when epigenetic inheritance occurs will advance the understanding of how organisms cope with changing environments and diseases that may be influenced by a parent’s environment. ¹⁸

Unlike models of infectious disease, in which individuals remain healthy until they contract a disease, non-communicable diseases can develop gradually over the life course. ⁴ In addition, responses to similar environmental challenges vary substantially between people, even in individuals who are genetically identical. ⁴ However, the mechanisms by which environmental insults can have long-term and later-life effects are relatively unclear; one challenge stems from translating studies in single cells to whole humans. Further exploring toxicant-mediated disruptions to epigenetic programming and how these effects may be transmitted across generations is essential for the implementation of initiatives aimed at reducing non-communicable diseases. ²⁰

The Superfund Research Program

The National Institute of Environmental Health Sciences (NIEHS) Superfund Basic Research and Training Program (SRP) is a National Institutes of Health (NIH) grant program that uses a multidisciplinary approach to support biomedical and environmental science and engineering research and to train the next generation of environmental health scientists. Since its inception in 1987, the SRP has supported researchers to better understand how exposures to hazardous substances in the environment affect health and disease ²¹ and to determine sustainable ways to prevent exposure and remediate these substances.^22,23 Moreover, a key goal of the SRP is to use basic research findings to understand the mechanisms by which exposure to contaminants leads to human disease and why some individuals may be resilient to exposures and less susceptible to disease than others.

Because of the multidisciplinary nature of the program, SRP grantees are well-positioned to study exposure and latent disease risk. More specifically, SRP-funded scientists are working to address the challenge of connecting exposures that occur early in life and prior to conception with diseases that manifest much later, including developing new tools and approaches to predict how chemicals may affect long-term health and how they may interact with each other to exacerbate effects. SRP scientists collaborate across disciplines and contribute their domain expertise to answer specific questions that are part of a larger problem that a single discipline could not answer alone, leveraging a systems approach to integrate research and data to tackle critical complex research questions. ²⁴ SRP researchers are addressing these questions from their vantage point of expertise and looking across model organisms, life stages, and developing tools to make better predictions. Some of these SRP-funded research studies are highlighted in Figure 1.

Figure 1.

Web of Science research categories Treemap created in Clarivate Analytics’ Web of Science. The journal landscape Treemap displays a set of 215 publications from SRP-funded studies related to exposures and latent disease risk, categorized by Web of Science Research Areas. Web of Science classifies the journals it indexes into approximately 250 subject categories. Journals can be assigned to multiple Categories (at least one, up to six). Publications are indexed with the Category assigned the parent Journal and therefore may have more than one Category assigned. The visualization shows how these SRP-funded studies have spanned a variety of disciplines and addressed questions in multiple fields. (A color version of this figure is available in the online journal.)

This minireview highlights research from the SRP focused on understanding the health effects of exposures when there is a lag between exposure and the onset of the disease and provides future directions for addressing knowledge gaps for this complex and challenging topic.

Looking across cells, animal models, and humans

SRP researchers have used a combination of in vitro and in vivo models as well as long-standing cohort studies to evaluate the effects of a variety of environmental exposures and later-life health effects. For example, SRP researchers have assessed the effects of flame retardants on later-life fat accumulation and obesity across various organisms. They have characterized how brominated and organophosphate flame retardants in indoor dust increase fat accumulation in mouse cells. ²⁵ These findings were confirmed in studies of humans, where researchers found that higher serum levels of chemicals in flame retardants were associated with increased formation of fat cells and fat accumulation and higher body mass index. ²⁶ In addition, using the zebrafish model, they showed how exposure to these hazardous compounds favors the development of fat cells over bone cells, ²⁷ which indicates that these changes early in life may contribute to degenerative bone diseases in adulthood.

SRP researchers have also used the mouse model to elucidate the relationship between arsenic exposure and later-life health outcomes. For example, they found that early-life exposure to arsenic permanently altered airway structure and function in mice, which could potentially lead to problems in the lungs later in life including chronic cough and obstructive or restrictive lung disease. ²⁸ SRP researchers have also found that prenatal and early-life exposure to arsenic disrupted normal metabolism and elevated the risk for fatty liver disease in mice maintained on a high-fat diet. According to the investigators, individuals exposed to arsenic during key developmental periods while on a Western-style diet may be at increased risk for metabolic disease later in life. ²⁹

Another example, and as part of a study of populations in Massachusetts and Rhode Island, SRP grantees linked early-life exposure to tetrachloroethylene (PCE) in drinking water with increased risk of cancer, epilepsy, visual dysfunction, and mental illness later in life.^30–32 They found that “risky” behaviors, particularly drug use, were more frequent among adults who were exposed to higher levels of PCE in the womb and in early childhood. ³³ The team also uncovered that prenatal exposure to both alcohol and PCE may combine to increase the risk of using multiple illicit drugs as a teenager. ³⁴

SRP researchers also revealed associations between early-life per- and polyfluoroalkyl substance (PFAS) exposure and immune dysfunction and metabolic abnormalities.^35,36 For instance, they have identified associations between PFAS exposures and impaired glycemic status in metabolically vulnerable pregnant women, which may enhance the risk of development gestational diabetes and could lead to metabolic-related outcomes in their newborns. ³⁶ They also found that childhood PFAS exposure may be associated with elevated serum lipid concentrations, which may be a risk factor for development of cardiovascular disease and hyperlipidemia later in life. ³⁷ They are currently identifying pathways by which exposure to PFAS contributes to obesity and weakened immune systems. They found evidence that PFAS disrupts metabolism by altering the regulation of hormones that help control energy storage and body composition. ³⁸

In mice, SRP researchers have provided evidence for a link between inflammation-related signaling and the development of asbestos-induced malignant mesothelioma, providing a potential early mechanistic sign of mesothelioma. ³⁹ Using serum samples from human studies, researchers also identified serum lipid biomarkers for mesothelioma and asbestos exposure, an approach that may promote early detection and treatment. ⁴⁰ By examining DNA mutations in mesothelioma patients with a family history of cancer, they identified genetic factors associated with higher incidence of asbestos-induced malignant mesothelioma. This suggests the utility of genetic testing for some patients for the purpose of early detection of cancers and clinical intervention. ⁴¹ Although the link between asbestos exposure and mesothelioma is well-documented,^42–44 SRP grantees are exploring ways to detect the disease earlier in the disease progression and/or predict whether a person may be more susceptibility to the disease later in life.

SRP grantees are also assessing how exposure to lead, arsenic, manganese, and cadmium alone or in mixtures during development alters signaling molecules in the brain to accelerate cognitive aging, which may lead to cognitive decline. ⁴⁵ They previously found that lead induces a response in neural stem cells that is dependent on NRF2, the master transcriptional factor for the oxidative stress response, and identified a potential mechanism linking lead exposure with neural stem cell function and neurodevelopment in children. ⁴⁶ SRP grantees have also found that increased progression of Parkinsonism was associated with cumulative manganese exposure. ⁴⁷

After an epidemiological study was released showing an association between in utero N-nitrosodimethylamine (NDMA) exposure and childhood cancer, an SRP Center was established to further explore and address the problem of NDMA exposure in Massachusetts. They are using mouse studies to identify mutational fingerprints of NDMA that could serve as a clue as to how NDMA contributes to cancer. They are also studying very early cellular responses to NDMA exposure, including changes in gene expression and cell signaling, to gain a better mechanistic understanding of disease causation. ⁴⁸

Looking across life stages: arsenic as a case study

In addition to evaluating exposures across various models and organisms, some SRP researchers have also initiated longitudinal cohort studies to assess the health effects of environmental exposures across the lifespan. A primary example of this work includes the Health Effects of Arsenic Longitudinal Study (HEALS) and its ancillary studies to follow a population in Bangladesh that has been exposed to varying concentrations of arsenic through contaminated well water. ⁴⁹ The cohort was first established in 2000 with 12,000 participants, ⁵⁰ and since has expanded to include over 35,000 people. Their work has been instrumental in associating long-term and early-life arsenic exposure with numerous diseases across the life course. For example, they have demonstrated an association between higher arsenic exposure and chronic disease mortality, including cardiovascular disease.^51,52 They found that arsenic exposure increased the risk of heart disease and shed light on how arsenic exposure was associated with QT interval prolongation, or irregular electrical activity of the heart, which has been associated with increased risk of cardiovascular mortality.^53,54 They also revealed that exposure to arsenic in early life can lead to increased blood pressure in adolescence. ⁵⁵ These researchers have also made important discoveries linking early-life exposure to arsenic with decreased intellectual function and motor function in adolescence.^56,57 These findings were mirrored in a population in the United States where higher arsenic exposure was associated with lower intelligence quotient (IQ). ⁵⁸

Another SRP-funded cohort focused on elucidating the effects of early-life exposure to arsenic in a group of people in northern Chile who were exposed to high levels of arsenic in drinking water before a water treatment plant was installed. Even 25 years after a major decrease in arsenic exposure, they reported that population mortality rates remained elevated compared to the unexposed group. ⁵⁹ They found an association between prenatal and childhood arsenic exposure and signs and symptoms of lung disease in adults, such as decreases in lung capacity and increases in chronic cough and bronchitis. ⁶⁰ Researchers also uncovered an association between early-life arsenic exposure and type 2 diabetes and hypertension in adults.^61,62 Early-life arsenic exposure was also found to be associated with cancer in specific kidney and ureter cells as well as lung and bladder cancer in adults.^63,64

Researchers are also exploring mechanisms by which exposure to arsenic early in development affects health throughout life and have found evidence that these later-life health effects may be tied to changes in the epigenome.^65,66 Through studies in newborn cord blood and placenta cells, investigators have shown how arsenic exposure results in epigenetic changes that can disrupt the endocrine system. This would not only explain differences in birth outcomes among children but may also be linked to onset of later-life diseases and dysfunctions.^67,68

Making better predictions

To close the gap in understanding later-life diseases resulting from early-life exposures, researchers and decision-makers need better tools and strategies to predict how different hazardous exposures may harm human health. One approach to help risk assessors predict the toxicity of chemicals is based on understanding key characteristics of chemicals that lead to toxicity. The key characteristics framework, which was work funded by the SRP, helps identify and summarize the potential health risks of different chemicals based on mechanistic data and prioritize them for further study. ⁶⁹ So far, researchers have identified key characteristics shared by chemicals that cause cancer, are toxic to male and female reproduction, and are EDCs.^69–73 They are currently working on additional key characteristics of neurotoxicants, cardiovascular toxicants, and hepatotoxicants. ⁷⁴ By understanding key characteristics of chemicals as a basis for searching, organizing, and evaluating mechanistic evidence to support hazard identification, scientists are one step closer to identifying chemicals that may lead to disease earlier on in the disease progression.

SRP researchers are also developing experimental and computational approaches to model environmental chemicals to predict their long-term adverse effects based on short-term experiments. For example, through the Carcinogenome Project, researchers developed a framework to predict long-term cancer risk from short-term chemical exposure data. This fast, cost-effective method uses gene expression profiling, which measures the activity of a thousand or more genes to capture what is happening in a cell. It then applies computer modeling to predict the ability of the chemicals to initiate a cascade of cellular events that can lead to cancer. ⁷⁵

Other models are being developed to predict the toxicity of complex polycyclic aromatic hydrocarbon (PAH) mixtures. Using zebrafish, researchers screen PAH mixtures for toxicity based on their chemical structure and bioactivity, including changes at the molecular, organ, and organism levels, to predict how early-life exposures affect long-term brain development and behavior. ⁷⁶ Through this work, they have found that zebrafish exposed to PAHs as embryos had impaired behavior as larvae and decreased learning and memory function as adults. ⁷⁷ In addition, studies are focusing on identifying how exposure to even more complex mixtures (e.g. PAHs and pesticides) early in life affects brain and metabolic outcomes later. Researchers have identified critical windows of neurodevelopment that were sensitive to harmful exposures and revealed important differences between exposure to individual PAH chemicals compared to realistic mixtures. ⁷⁸ Researchers have also reported that rats exposed to pesticides shortly after birth had altered metabolism that may contribute to obesity and other metabolic outcomes in adulthood.^79–81

Moving forward

Improving what researchers know about the association between early-life exposures and later-life effects in humans will require a multidisciplinary approach that integrates mechanistic, human, and animal studies. Future research could include animal studies that address mechanistic hypotheses integrated with studies of human populations that address exposures, molecular alterations, and latent disease outcomes. ⁶⁶ Cohort studies could test hypotheses based on mechanisms proposed by animal and cell-based studies. ¹ Multidisciplinary teams can work to share data and enhance integration of mechanistic data across fields of science and model organisms. Incorporating data on exposures and disease risk from different disciplines that are addressing similar questions can provide a broader understanding and uncover the answers to these complex research questions. ⁸²

More research is needed to explore how mechanisms at different life stages of exposure translate to differences in disease outcomes. This includes further advancing fields related to identifying critical windows of development and environmentally induced somatic mosaicism, the role of the microbiome in disease, and a better understanding of additive or synergistic effects of multiple exposures and how differences in exposure routes can impact disease susceptibility. Developing and expanding computational tools and machine learning approaches could improve what grantees know about chemical bioactivity, explore the potential combined effects of mixtures, and predict risk based on data from studies investigating effects later in life. Developing tools that integrate geospatial data can also provide an effective way to visualize how environmental factors, as well as other social stressors, contribute to community vulnerability to contaminants and potential health effects. ⁸³

Expanding knowledge about how different chemical characteristics can lead to changes in the body will provide mechanistic information that may help to predict potential health effects later in life. In addition to understanding chemical characteristics, it is also important to understand key characteristics, or hallmarks, of disease and aging to consider when predicting potential health effects. As researchers explore key hallmarks of aging, which represent the common denominators that occur with aging, it is important to integrate data on exposures that may help to explain why older adults may be more or less susceptible to health effects.^84,85 Hallmarks of aging that change throughout life relate to a combination of genetics and environmental factors, such as an individual’s lifestyle and exposure history. ⁸⁴ By utilizing the concept of the hallmarks of aging in studies, and linking these changes to hallmarks associated with disease, researchers may be able to better study factors contributing to disease latency.

Although a significant amount of research has been conducted to investigate sensitive windows of exposure early in life and later-life diseases, more research is needed that focuses on exposures that occur during all life stages of exposure, including adolescence and early adulthood (Figure 2). Specifically, most SRP and other environmental health studies on exposures and latent disease risk focus on prenatal and childhood exposures, but there is more to learn about adult exposures. Exposures during adulthood can also lead to diseases after a long latency period, so focusing on adolescents and adults, including more vulnerable time periods such as puberty, pregnancy, and menopause, and following them for long periods of time, may reveal new insights into latent disease risk.

Figure 2.

Understanding the health effects of exposures when there is a lag between exposure and the onset of disease is an important and challenging issue in environmental health. (A color version of this figure is available in the online journal.)

When looking at historical data to predict exposures, cohort studies may also inadvertently lead to sampling bias, where the data collected could be more likely to leave out traditionally marginalized groups who may be under-represented in the available health and mortality records. For example, a study assessing itemized asbestos exposure profiles for a community in 1930 using Ancestry.com and other publicly accessible databases highlights how historic cohort studies likely underestimate the impact of asbestos exposure on minority populations. ⁸⁶ Involving communities early in the research process or initiating community-based participatory research studies that closely involve the community may provide a better window into what people are exposed to and help prevent some forms of sampling bias.

Connecting exposures to later-life disease requires a better estimate of exposures and a more detailed understanding of a person’s exposome, or the totality of exposures throughout life. The exposome concept was first coined by Chris Wild in 2005 to encompass the totality of human environmental exposures from conception onwards, complementing the genome. ⁸⁷ Exposome studies use different methods to collect a large number of exposures, such as through self-reported questionnaires, exposure biomarkers, geographic information, personal sensors, and other exposure technologies. ⁸⁸ The fact that people have different habits, physically move, and are exposed to a variety of different chemicals in their everyday life makes it difficult to estimate a lifetime of exposures unless researchers have more accurate information to assess previous exposures based on biological factors. To be able to link exposures to later-life effects, researchers need to be able to better characterize exposures and develop untargeted methods to assess potential exposures and their associated effects on the body. For example, SRP researchers have developed an untargeted approach to measure DNA adducts in neonatal blood spots from a population-based case–control study of childhood leukemia to identify risk factors for childhood leukemia. ⁸⁹ NIEHS researchers are also using shed teeth to better reconstruct lifetime exposures to a variety of chemicals from the prenatal period through childhood, which helps to associate exposures during critical windows with latent diseases. ⁹⁰ For example, one study showed that essential and toxic elements are regulated differently in children with autism spectrum disorder, revealing a potential sensitive biomarker for early diagnosis. ⁹¹ These techniques are now being applied to study and predict neurodegenerative diseases that occur later in life, including amyotrophic lateral sclerosis and Parkinson’s disease. ⁹² Although they have demonstrated a broad range of chemical metabolites can be measured in a tooth, there are still many unidentified metabolites.^90,93

Large cohort studies are a rich source of data but are also expensive to maintain and can take several years to yield data for analysis. As a result, data from these existing resources should be shared and leveraged when possible to make the most use of these large and expensive longitudinal studies. SRP supports the NIEHS Human Health Exposure Analysis Resource (HHEAR) initiative, which is comprised of a consortium of NIH-funded researchers with access to high-quality analytical capabilities and exposure assessment services. ⁹⁴ The SRP has supported the HHEAR laboratory at the Icahn School of Medicine at Mount Sinai to provide state-of-the-art services for analyzing biological and environmental samples including untargeted analysis of samples such as blood, urine, stool, saliva, teeth, and hair to help link exposures and health outcomes. A second supported lab at Duke University focused on untargeted and targeted analyses to comprehensively measure chemicals in air samplers, silicone wristbands, and environmental media, including water, soil, sediment, and dust, with the goal of associating health outcomes to their environmental sources.^95,96

Together, these approaches can give a more comprehensive picture of what humans are exposed to throughout their lives and help strengthen the evidence linking exposures and disease. More research on the origins of disease also plays an important role in establishing factors that play a role in disease outcomes and developing early prevention and intervention strategies to combat these factors earlier in the disease progression. ⁹⁷

Conclusions

The complexity of exposures and underlying biology, and the complex interplay between the two, contributes to the challenge of understanding the connection between exposures and disease, especially when there is a lag between the exposure and disease onset. It requires a significant investment of time, effort, and resources. This together with the limitations of epidemiological studies and across model organisms necessitates a multidisciplinary approach so that data and research findings can be evaluated from across mechanistic, animal, and human studies. The SRP is well-poised to address research questions related to latency of disease because of its broad array of multidisciplinary projects investigating across various models and life stages and by supporting investigators that take a systems approach to their research. Advancing the field of latency to disease will also require sharing and integrating research information and the development of high-throughput, computational, and machine learning approaches to make better predications of the onset of disease. In addition, a major limitation to the studies presented in this review has been that they only establish association and not causality between early-life exposure and latency of disease. This notion indicates the need for more studies that can reliably extrapolate cellular and tissue effects from environmental exposures and identify and use early biomarkers to predict disease across all life stages. More importantly, a better understanding of the basis of exposures that may contribute to later-life diseases is essential to supporting the implementation of prevention and intervention strategies to reduce or modulate exposures to reduce disease burden.