Adapting to Climate Change: Leveraging Systems-Focused Multidisciplinary Research to Promote Resilience.

Approximately 2000 official and potential Superfund sites are located within 25 miles of the East or Gulf coasts, many of which will be at risk of flooding as sea levels rise. More than 60 million people across the United States live within 3 miles of a Superfund site. Disentangling multifaceted environmental health problems compounded by climate change requires a multidisciplinary systems approach to inform better strategies to prevent or reduce exposures and protect human health. The purpose of this minireview is to present the National Institute of Environmental Health Sciences Superfund Research Program (SRP) as a useful model of how this systems approach can help overcome the challenges of climate change while providing flexibility to pivot to additional needs as they arise. It also highlights broad-ranging SRP-funded research and tools that can be used to promote health and resilience to climate change in diverse contexts.

Enhancing Data Integration, Interoperability, and Reuse to Address Complex and Emerging Environmental Health Problems.

Environmental health sciences (EHS) span many diverse disciplines. Within the EHS community, the National Institute of Environmental Health Sciences Superfund Research Program (SRP) funds multidisciplinary research aimed to address pressing and complex issues on how people are exposed to hazardous substances and their related health consequences with the goal of identifying strategies to reduce exposures and protect human health. While disentangling the interrelationships that contribute to environmental exposures and their effects on human health over the course of life remains difficult, advances in data science and data sharing offer a path forward to explore data across disciplines to reveal new insights. Multidisciplinary SRP-funded teams are well-positioned to examine how to best integrate EHS data across diverse research domains to address multifaceted environmental health problems. As such, SRP supported collaborative research projects designed to foster and enhance the interoperability and reuse of diverse and complex data streams. This perspective synthesizes those experiences as a landscape view of the challenges identified while working to increase the FAIR-ness (Findable, Accessible, Interoperable, and Reusable) of EHS data and opportunities to address them.

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

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.

Benefits of basic research from the Superfund Research Program.

The National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) Hazardous Substances Basic Research and Training Program [Superfund Research Program (SRP)] funds transdisciplinary research projects spanning the biomedical and environmental sciences to address issues related to potentially hazardous substances. We used a case study approach to identify how SRP-funded basic biomedical research has had an impact on society. We examined how transdisciplinary research projects from the SRP have advanced knowledge and led to additional clinical, public health, policy, and economic benefits. SRP basic biomedical research findings have contributed to the body of knowledge and influenced a broad range of scientific disciplines. It has informed the development of policies and interventions to reduce exposure to environmental contaminants to improve public health. Research investments by the SRP have had a significant impact on science, health, and society. Documenting the benefits of these investments provides insight into how basic research is translated to real-world applications.

Sharing SRP data to reduce environmentally associated disease and promote transdisciplinary research.

The National Institute of Environmental Health Sciences (NIEHS) Superfund Basic Research and Training Program (SRP) funds a wide range of projects that span biomedical, environmental sciences, and engineering research and generate a wealth of data resulting from hypothesis-driven research projects. Combining or integrating these diverse data offers an opportunity to uncover new scientific connections that can be used to gain a more comprehensive understanding of the interplay between exposures and health. Integrating and reusing data generated from individual research projects within the program requires harmonization of data workflows, ensuring consistent and robust practices in data stewardship, and embracing data sharing from the onset of data collection and analysis. We describe opportunities to leverage data within the SRP and current SRP efforts to advance data sharing and reuse, including by developing an SRP dataset library and fostering data integration through Data Management and Analysis Cores. We also discuss opportunities to improve public health by identifying parallels in the data captured from health and engineering research, layering data streams for a more comprehensive picture of exposures and disease, and using existing SRP research infrastructure to facilitate and foster data sharing. Importantly, we point out that while the SRP is in a unique position to exploit these opportunities, they can be employed across environmental health research. SRP research teams, which comprise cross-disciplinary scientists focused on similar research questions, are well positioned to use data to leverage previous findings and accelerate the pace of research. Incorporating data streams from different disciplines addressing similar questions can provide a broader understanding and uncover the answers to complex and discrete research questions.

The Importance of Community Engagement and Research Translation within the NIEHS Superfund Research Program.

The National Institute of Environmental Health Sciences Superfund Research Program (SRP) funds university-based, solution-oriented research to understand how hazardous substances contribute to disease and how to prevent exposures to these hazardous substances. A unique aspect of the SRP is that, beyond the biomedical, environmental sciences, and engineering research projects, SRP-funded centers are required to include community engagement to build partnerships with affected communities and research translation to communicate and facilitate the use of research findings. The SRP views both as effective ways to inform and advance science for protection of public health. The purpose of community engagement within the centers is to ensure bidirectional communication between the researchers and the community, identify best practices and activities in community engagement for prevention and intervention activities, enhance knowledge, and support the needs of the communities impacted by hazardous waste sites. The SRP views research translation as communicating and facilitating the use of research findings emanating from the center in a manner most appropriate for their application and for the advancement of a center's research objectives. The SRP has a strong history of seeking opportunities to work with communities and stakeholders, by translating and sharing research findings in an impactful and informative manner with long-lasting benefits to improve public health.

Assessing the Economic and Societal Benefits of SRP-Funded Research.

BACKGROUND: The National Institute of Environmental Health Sciences (NIEHS) Superfund Basic Research and Training Program (SRP) funds a wide range of transdisciplinary research projects spanning the biomedical and environmental sciences and engineering, supporting and promoting the application of that research to solving real-world problems. OBJECTIVES: We used a case study approach to identify the economic and societal benefits of SRP-funded research, focusing on the use of potentially hazardous substance remediation and site monitoring tools. We also identified successes and challenges involved in translating SRP grantees' research findings and advances into application. DISCUSSION: We identified remediation and detection research projects supported by the SRP with the most potential for economic and societal benefits and selected 36 for analysis. To examine the benefits of these applied technologies, we interviewed 28 SRP-supported researchers and 41 partners. Five case studies emerged with the most complete information on cost savings-total savings estimated at >$100 million. Our analysis identified added societal benefits such as creation of small businesses, land and water reuse, sustainable technologies, exposure reduction, and university-industry partnerships. CONCLUSIONS: Research funded by the SRP has yielded significant cost savings while providing additional societal benefits. https://doi.org/10.1289/EHP3534.

Base excision repair and design of small molecule inhibitors of human DNA polymerase ß.

Base excision repair (BER) can protect a cell after endogenous or exogenous genotoxic stress, and a deficiency in BER can render a cell hypersensitive to stress-induced apoptotic and necrotic cell death, mutagenesis, and chromosomal rearrangements. However, understanding of the mammalian BER system is not yet complete as it is extraordinarily complex and has many back-up processes that complement a deficiency in any one step. Due of this lack of information, we are unable to make accurate predictions on therapeutic approaches targeting BER. A deeper understanding of BER will eventually allow us to conduct more meaningful clinical interventions. In this review, we will cover historical and recent information on mammalian BER and DNA polymerase ß and discuss approaches toward development and use of small molecule inhibitors to manipulate BER. With apologies to others, we will emphasize results obtained in our laboratory and those of our collaborators.

Alkylation DNA damage in combination with PARP inhibition results in formation of S-phase-dependent double-strand breaks.

The combination of poly(ADP-ribose)polymerase (PARP) inhibitors and alkylating agents is currently being investigated in cancer therapy clinical trials. However, the DNA lesions producing the synergistic cell killing effect in tumors are not fully understood. Treatment of human and mouse fibroblasts with the monofunctional DNA methylating agent methyl methanesulfonate (MMS) in the presence of a PARP inhibitor has been shown to trigger a cell cycle checkpoint response. Among other changes, this DNA damage response to combination treatment includes activation of ATM/Chk2 and phosphorylation of histone H2A.X. These changes are consistent with DNA double-strand break (DSB) formation during the response, but the measurement of DSBs has not been addressed. Such DSB evaluation is important in understanding this DNA damage response because events other than DSB formation are known to lead to ATM/Chk2 activation and H2A.X phosphorylation. Here, we examined the structural integrity of genomic DNA after the combined treatment of cells with MMS and a PARP inhibitor, i.e., exposure to a sub-lethal dose of MMS in the presence of the PARP inhibitor 4-amino-1,8-napthalimide (4-AN). We used pulsed field gel electrophoresis (PFGE) for measurement of DSBs in both human and mouse embryonic fibroblasts, and flow cytometry to follow the phosphorylated form of H2A.X (gamma-H2A.X). The results indicate that DSBs are formed with the combination treatment, but not following treatment with either agent alone. Our data also show that formation of gamma-H2A.X correlates with PARP-1-expressing cells in S-phase of the cell cycle. The observations support the model that persistence of PARP-1 at base excision repair intermediates, as cells move into S-phase, leads to DSBs and the attendant checkpoint responses.

Telomere dynamics and fusion of critically shortened telomeres in plants lacking DNA ligase IV.

In the absence of the telomerase, telomeres undergo progressive shortening and are ultimately recruited into end-to-end chromosome fusions via the non-homologous end joining (NHEJ) double-strand break repair pathway. Previously, we showed that fusion of critically shortened telomeres in Arabidopsis proceeds with approximately the same efficiency in the presence or absence of KU70, a key component of NHEJ. Here we report that DNA ligase IV (LIG4) is also not essential for telomere joining. We observed only a modest decrease (3-fold) in the frequency of chromosome fusions in triple tert ku70 lig4 mutants versus tert ku70 or tert. Sequence analysis revealed that, relative to tert ku70, chromosome fusion junctions in tert ku70 lig4 mutants contained less microhomology and less telomeric DNA. These findings argue that the KU-LIG4 independent end-joining pathway is less efficient and mechanistically distinct from KU-independent NHEJ. Strikingly, in all the genetic backgrounds we tested, chromosome fusions are initiated when the shortest telomere in the population reaches approximately 1 kb, implying that this size represents a critical threshold that heralds a detrimental structural transition. These data reveal the transitory nature of telomere stability, and the robust and flexible nature of DNA repair mechanisms elicited by telomere dysfunction.

The role of the nonhomologous end-joining DNA double-strand break repair pathway in telomere biology.

Double-strand breaks are a cataclysmic threat to genome integrity. In higher eukaryotes the predominant recourse is the nonhomologous end-joining (NHEJ) double-strand break repair pathway. NHEJ is a versatile mechanism employing the Ku heterodimer, ligase IV/XRCC4 and a host of other proteins that juxtapose two free DNA ends for ligation. A critical function of telomeres is their ability to distinguish the ends of linear chromosomes from double-strand breaks, and avoid NHEJ. Telomeres accomplish this feat by forming a unique higher order nucleoprotein structure. Paradoxically, key components of NHEJ associate with normal telomeres and are required for proper length regulation and end protection. Here we review the biochemical mechanism of NHEJ in double-strand break repair, and in the response to dysfunctional telomeres. We discuss the ways in which NHEJ proteins contribute to telomere biology, and highlight how the NHEJ machinery and the telomere complex are evolving to maintain genome stability.