David Reif named to the U.S. Environmental Protection Agency (EPA) Science Advisory Committee on Chemicals (SACC)

David Reif was named to the U.S. Environmental Protection Agency (EPA) Science Advisory Committee on Chemicals (SACC) for a four-year term by Administrator Michael Regan. The Science Advisory Committee on Chemicals provides independent scientific advice, information and recommendations to the EPA Office of Pollution Prevention and Toxics on the scientific basis for risk assessments, methodologies and pollution prevention measures or approaches. Its major objectives are to provide expert advice and recommendations to the EPA on risk assessments, models, tools, guidance documents, chemical category documents and other chemical assessment and pollution prevention products as deemed appropriate.

The COVID-19 Pandemic Vulnerability Index (PVI)

The COVID-19 Pandemic Vulnerability Index (PVI)

Dr. David Reif has led teams at North Carolina State University, NIEHS, and Texas A&M University in developing the Pandemic Vulnerability Index (PVI) dashboard, which offers a view and real-time analysis of county-level U.S. data on the coronavirus pandemic. “The dashboard helps officials allocate resources and update responses, as well as providing both county-level and a nationwide overview of various statistics” explained Dr. Reif.  The team developed risk profiles, called PVI scorecards, are available for every county in the United States. The resource has now been added to the COVID Data Tracker resources curated on the U.S. Centers for Disease Control and Prevention website

https://covid.cdc.gov/covid-data-tracker/#pandemic-vulnerability-index), and was featured in the Environmental Factor (https://factor.niehs.nih.gov/2021/2/feature/1-feature-pandemic/index.htm)

The original publication appeared  in Environmental Health Perspectives (https://ehp.niehs.nih.gov/doi/10.1289/EHP8690).

Additional NC State co-authors include Dr. Yi-Hui Zhou, Dr. Fred A. Wright, and Kuncheng Song.

Collaboration points to potential dangers of energy drinks

Collaboration points to potential dangers of energy drinks

Dr. Yi-Hui Zhou and colleagues reported on the potential dangers of popular energy drinks in the March 2021 issue of Food and Chemical Toxicology. The study, led by Dr. Ivan Rusyn, a professor in the Veterinary Integrative Biosciences at Texas A&M University, showed that cardiomyocytes – human heart cells grown in a laboratory – exposed to some energy drinks showed an increased beat rate and other factors affecting cardiac function. Dr. Zhou used complex patterns from mass spectrometry to show that certain chemical profiles from the energy drink constituents were associated with aspects such as QT prolongation,  which is associated with serious human heart conditions. “This was a great collaboration showing the power of machine learning methods to learn features of the data that have direct relevance to human health,” explained Dr. Zhou. The project has gained considerable media attention, due to the popularity of energy drinks, which has a $61 billion worldwide market. “Many consumers don’t realize that energy drinks are marketed as regular beverages or dietary supplements, and as such don’t really undergo extensive safety testing” said Dr. Zhou.  “Some ingredients may be available from natural sources but still have worrisome effects on heart function.  Further research should be performed, as some people, even children, consume these drinks every day.”

Link to the article : https://www.sciencedirect.com/science/article/abs/pii/S0278691521000132

Other NC State authors include Fred A. Wright and Erin Baker.

4D- quantitative structure–activity relationship modeling: making a comeback

Predictive Quantitative Structure–Activity Relationship (QSAR) modeling has become an essential methodology for rapidly assessing various properties of chemicals. The vast majority of these QSAR models utilize numerical descriptors derived from the two- and/or three-dimensional structures of molecules. However, the conformation-dependent characteristics of flexible molecules and their dynamic interactions with biological target(s) is/are not encoded by these descriptors, leading to limited prediction performances and reduced interpretability. 2D/3D QSAR models are successful for virtual screening, but typically suffer at lead optimization stages. That is why conformation-dependent 4D-QSAR modeling methods were developed two decades ago. However, these methods have always suffered from the associated computational cost. Recently, 4D-QSAR has been experiencing a significant come-back due to rapid advances in GPU-accelerated molecular dynamic simulations and modern machine learning techniques.

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Adipocytes as Anticancer Drug Delivery Depot

Tumor-associated adipocytes promote tumor growth by providing energy and causing chronic inflammation. Here, we have exploited the lipid metabolism to engineer adipocytes that serve as a depot to deliver cancer therapeutics at the tumor site. Rumenic acid (RA), as an anticancer fatty acid, and a doxorubicin prodrug (pDox) with a reactive oxygen species (ROS)-cleavable linker, are encapsulated in adipocytes to deliver therapeutics in a tumor-specific bioresponsive manner. After intratumoral or postsurgical administration, lipolysis releases the RA and pDox that is activated by intracellular ROS-responsive conversion, subsequently promoting antitumor efficacy. Furthermore, downregulation of PD-L1 expression is observed in tumor cells, favoring the emergence of CD4+ and CD8+ T cell-mediated immune responses.

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USDA/NIFA grants awarded to faculty members Drs. David Rasmussen & Benjamin Callahan

Two faculty members, Dr. David Rasmussen and Dr. Benjamin Callahan, were awarded USDA NIFA grants through a new program called FACT: Food and Agricultural Cyberinformatics and Tools Initiative.

Dr. Rasmussen’s project is called, “Next Generation Spatial Epidemiology for Tracking the Spread of Plant Pathogens”.  The main goal is: “To develop the next generation of phylogenetic tools for tracking the spread of plant pathogens ranging from viruses to fungi through complex agricultural landscapes. Since many of these pathogens undergo occasional recombination, another goal is to use information about recombination events across pathogen genomes to identify the spatial location of historical recombination events and the geographic source of particular genes involved in pathogenesis.”


Dr. Callahan’s project is called, “Rapid Detection and Tracking of Foodborne Pathogens with Long-read Amplicon Sequencing”. Food-borne pathogens enact substantial harms on the American people in the form of illness, lost productivity, and expenses related to mitigation and regulatory compliance. Surveillance and tracing of foodborne pathogens is a key control strategy, but its efficacy is reduced by the long-times associated with current culture and whole-genome-sequencing approaches. Rapid, accurate and comprehensive pathogen detection would improve the safety and lower the costs of our food supply.

We aim to develop a targeted metagenomics methodology that can rapidly (<24 hrs) and precisely identify a broad range of foodborne pathogens from heterogeneous environmental samples. In order to achieve this, we propose to combine the GenomeTrakr and NCBI RefSeq databases with cutting-edge bioinformatics tools developed by the PD that achieve single-nucleotide resolution from amplicon sequencing data of full-length genes to identify E. coli and Salmonella strains to the serovar level (e.g. E. coli O157:H7 or S. enterica Heidelberg). We will validate the resolution and accuracy of this new methodology in silico, on isolates of various pathogenic serovars, and in environmental samples of various types for which pathogen presence and identity were previously established by standard culture-based methods. Our methodology will be distributed to the broader food safety community as open-source and actively-supported software, alongside extensive documentation of its efficacy and best-practices guidance. Successful completion of this project will yield a powerful, usable, and broad-spectrum pathogen surveillance technique that will improve food safety by detecting foodborne pathogens before they reach consumers, and by rapidly tracing outbreaks to their source.”

“A Class Approach to Hazard Assessment of Organohalogen Flame Retardants”

A new report from the National Academies of Sciences, Engineering, and Medicine offers guidance to the Consumer Product Safety Commission (CPSC) on how to conduct a hazard assessment of nonpolymeric, additive organohalogen flame retardants (OFRs), which are used in some consumer products.

OFRs cannot be treated as a single class for hazard assessment, the report says, but they can be divided into subclasses based on chemical structure, physical and chemical properties, and predicted biologic activity. The report identifies 14 subclasses that CPSC can use to conduct a class-based hazard assessment of OFRs. Such an approach is likely to be more efficient and less costly than the traditional approach of evaluating each chemical individually, the report notes.

There is mounting evidence that many flame retardants are associated with adverse human health effects, and some flame retardants have been banned, restricted, or voluntarily phased out of use. A coalition of organizations and individuals petitioned CPSC to initiate regulatory action to ban use of OFRs in four product categories: infant, toddler, or children’s products; upholstered furniture; mattresses; and plastic electronic casings. The petitioners argued that the entire chemical class is toxic and poses a risk to consumers.

CPSC voted to grant the petition, but in order to decide whether a ban should be enacted, the agency must first conduct a hazard assessment to determine whether a chemical is toxic. CPSC asked the National Academies for guidance on how to conduct the hazard assessment for OFRs as a chemical class.

The National Academies study committee first conducted an analysis to determine whether OFRs can be treated as a single class. This involved identifying known OFRs and other structurally related organohalogen compounds. The committee found that OFRs cannot be distinguished as a single class from these other chemically similar analogues. In addition, OFRs do not have a common chemical structure or predicted biologic activity and therefore cannot be treated as a single class.

However, an approach that uses subclasses to assess the chemicals is scientifically justifiable, the committee determined.  The report outlines a process for assessing the toxicity of the 14 identified subclasses and identifies four scenarios that might occur, depending on how much data is available for the chemicals in a subclass. The report also uses two subclasses to illustrate how the proposed approach to the hazard assessment would work.

A multidisciplinary group will be needed to execute the hazard assessment, the report says. Needed expertise includes cheminformatics, computational chemistry, computational toxicology, traditional and modern toxicology, epidemiology, and risk assessment. Furthermore, integrating the evidence at various steps will require expert judgment, and policy decisions involving value judgments – for example, about what health endpoints to investigate and how much uncertainty is acceptable – will be needed to complete the assessment.

The study — undertaken by the Committee to Develop a Scoping Plan to Assess the Hazards of Organohalogen Flame Retardants — was sponsored by the Consumer Product Safety Commission. The National Academies are private, nonprofit institutions that provide independent, objective analysis and advice to the nation to solve complex problems and inform public policy decisions related to science, technology, and medicine. They operate under an 1863 congressional charter to the National Academy of Sciences, signed by President Lincoln. For more information, visit nationalacademies.org.


Visit the original press release here

System toxicological approaches to define and predict the toxicityofPerand Polyfluoroalkyl Substances

System toxicological approaches to define and predict the toxicityofPerand Polyfluoroalkyl Substances

This project will assess the toxicity of a large collection of volatile and non-volatile PFASs (Per and Polyfluroalkyl Substances). The research results will increase the knowledgebase of toxicity profiles for a large collection of PFASs, covering a wide variety of toxicological endpoints, and may provide key scientific information for prioritizing different types of PFAS for effective and efficient risk assessment and management.

Objective:

1: Study the toxicity of a large collection of volatile and non-volatile PFASs and PFAS mixtures with the zebrafish assay. Hypothesis: PFAS compounds with similar structures will bind to the same biomolecular targets, induce expression of the same or highly overlapping gene sets, and induce similar toxic responses.

2: Conduct developmental immunotoxicity (DIT) studies in mice. Hypotheses: Developmental exposure to PFASs will compromise antigen-specific antibody responses (a measure of adaptive immunity) and natural killer cell cytotoxicity (a measure of innate immunity). Developmental findings in the mouse will accord with developmental findings in the zebrafish.

3: Create pharmacokinetic models that can explain and predict the concentrations of PFASs in the organs of mice and adult zebrafish as a function of exposure dose and chemical structure. Hypotheses: The bioaccumulation and internal distribution of PFASs depend on passive diffusion, transporter-mediated membrane uptake and efflux, and protein binding. The interaction of PFASs with proteins and membranes will depend on i) the presence of polar or charged functional groups and on ii) the length of the linear fluorinated alkyl chain.

Approach:

Expose embryonic zebrafish to 100 PFASs and assess them for adverse phenotypic and behavioral effects. Identify the gene expression changes associated with the observed effects. Expose juvenile zebrafish to PFASs and assess them for adverse behavioral effects. Expose mice to PFASs that are toxic to embryonic zebrafish and assess them for developmental immunotoxicity. Create pharmacokinetic models that can explain and predict the concentrations of PFASs in the organs of mice and adult zebrafish as a function of exposure dose and chemical structure.

Expected Results:

The project will increase by 400% the number of PFASs for which the research community has tested for toxicity in vivo. It will help EPA to identify toxic PFASs that require prioritization for risk management. The models developed will improve hazard and risk assessment of many PFASs and thereby improve EPA’s ability to protect human health and the environment. Over the long term, the project could enable researchers to determine the toxicity of PFASs without animal testing, solely on the basis of chemical structure. It could help industries worldwide to understand which PFASs are most toxic and to select or develop non-toxic materials that achieve the same useful results.

For more details, please see the EPA website:

https://cfpub.epa.gov/ncer_abstracts/index.cfm/fuseaction/display.abstractDetail/abstract/10950/report/0

Five Questions with Fred Wright

NC State’s Chancellor’s Faculty Excellence Program showcases the university’s commitment to interdisciplinary excellence and field-leading faculty. Cluster faculty turn research into real-world solutions while providing students with well-rounded experiential education opportunities.

We spoke with Fred Wright, a member of the Bioinformatics cluster and director of the Bioinformatics Research Center, about his research and the impact of interdisciplinarity at NC State.


What is your role within the Bioinformatics cluster and what are your primary research interests?

I was hired as a member of the Bioinformatics cluster in 2013 — partly because of my research, but also to be the director of the Bioinformatics Research Center. This interdisciplinary research center, established in 2000, brings faculty from different colleges and departments together who have complementary interests in using quantitative reasoning to solve biological problems. We have faculty from departments like biological sciences, statistics and chemistry who represent interdisciplinary work, but physically are in the Ricks Hall third floor facility. The idea is to conduct research, pursue grants and further our work by virtue of being close together physically.

My own work covers a number of areas in statistical genetics. Most of my research concerns gene mapping or genomics and relating those to diseases in humans or model systems such as mice. I collaborate with others to gather what we call “omics data,” which could be DNA in mice or humans, or it could be what’s known as expression data, which represents the degree to which genes are turned on and turned off, and that can vary by tissue and vary over the lifespan of an individual.

What do you hope to achieve through the research being conducted in the bioinformatics cluster and the Bioinformatics Research Center?

The cluster did a lot to strengthen environmental bioinformatics instantly. Professors David Reif, Denis Fourches and I spend part of our time working on the application of genomics to toxicology, as well as chemical informatics. This is an important emerging research area that combines traditional toxicology with new omics methods. The Triangle area is quite strong in this area, even though there are relatively few people working in this combined field. To have three people in that one cluster automatically made us much stronger as an institution in bioinformatics. In addition to adding to the original strengths of statistical genetics within the center, enhanced environmental work was something the cluster was able to bring to campus. Additionally, the Bioinformatics cluster builds on existing strengths within the Bioinformatics Research Center. Our other cluster member, Dahlia Nielsen, represents strengths in statistical genetics, combining a deep understanding of biology and statistical genetics with the most modern technology.

What is your favorite part of being a researcher?

It is cliche to say that we like the excitement of discovery, but it is true. Just sitting at a computer and suddenly seeing a pattern in data that no one had ever noticed before is something that researchers have to live for, because otherwise, why are you doing that? In my role as director, I get some satisfaction in seeing that we’ve been able to grow, sometimes in the face of difficult funding situations. Much of this, due to the vision of the chancellor and provost, to have this faculty excellence program, has been one of the ways in which we have been able to grow. Helping to steer that and seeing that we’re bringing in excellent people gives me a lot of satisfaction.

How does interdisciplinarity impact both faculty and students?

Research complements training, and traditionally that’s been thought of as something most applicable to graduate students. Increasingly we’re seeing the involvement of undergraduates in research and it is something that has taken hold on other campuses and is starting to take hold here. I’ve had some undergraduates training in our group and there are other faculty involved with the center and with the cluster who are actively engaging undergraduate students.That kind of exposure in the early stages of academic development is certainly good for the students. For us it is an extra set of hands and it helps develop a researcher pipeline. There are quite a few students who remain local or they may go off and get a master’s degree somewhere else and come back here for a Ph.D. All versions of this are very good for us — for the center, the cluster and the institution. We create the research space so that research can thrive and so that students — no matter their eventual career goals — are able to see what it means to generate knowledge.

What is something people may not know about the Bioinformatics cluster or the Bioinformatics Research Center?

We’re very approachable! There are some students who have been trained in biology who may not realize that with a reasonable amount of training — maybe a few months of training in computer languages — they can do something in bioinformatics. There is a startup cost to be able to do interdisciplinary work. You have to understand at least a little bit about multiple disciplines, but it is not necessarily as high a barrier as some people think. We provide formal training opportunities as well as self-taught experiences that can often get people to the point where they understand enough to be able to engage in the process.

Another thing is people don’t realize how many jobs there are in this area in particular. Data science is increasingly something that people are focused on. We have a large number of students who have graduated and gone on to very good positions here in the Triangle and across the nation. Bioinformatics is a bigger area that many students realize.


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Periconceptional Dietary Patterns and Effects on Offspring Behavior

New research indicates that environmental factors during the periconceptional stages of pregnancy (pre-conception to early months of carrying) are associated with neurodevelopmental outcomes in offspring. Specifically, children born to mothers who adhered to a Mediterranean diet rich in fresh vegetables, whole grains, healthy fats, nuts, legumes and dairy, along with decreased red meat consumption, were found to exhibit more favorable behaviors in the second year of life. Utilizing data based on more than 300 mother/child pairs, the goals of the study were to determine if, and to what extent, a mother’s dietary patterns around the time of conception affected her child’s epigenetics and behavior.

Epigenetics, the study of DNA alterations that affect the reading and regulation of DNA, but not the sequence itself, has seen tremendous growth in recent years. Dr. John House, an NC State scientist within both the the Bioinformatics Research Center (BRC) and the Center for Human Health and the Environment (CHHE), led the research efforts. He stated that, “10 years ago, we thought a person’s inherited genetic variation would be the largest determinant of human disease susceptibility in complex diseases. We’ve since realized that epigenetic differences play just as large or a larger role than genetics in explaining both disease susceptibility and the relationship between environmental exposures and human disease. ”

The NEST cohort was started by Dr. Cathrine Hoyo of  NC State’s Center for Human Health and the Environment (CHHE) and has yielded over 55 publications to date linking maternal exposures to offspring outcomes and epigenetic. For this study, data was collected on maternal diet around the time of conception and on child behavioral characteristics in the second year of life for 325 mother/child pairs. Child behavior was assessed using the Infant Toddler Social and Emotional Assessment (ITSEA) questionnaire at 12-24 months of age. For a smaller subset, the methylation percentage of 49 CpG sites in the control regions of 9 imprinted regions were also examined in relation to maternal diet and child behaviors. These were conducted on cord-blood DNA from offspring. Initial research efforts focused on maternal Mediterranean diet adherence (MDA) as it remains one of the most highly researched dietary pattern.

 

Results

Maternal Mediterranean diet adherence was associated with favorable offspring behavioral patterns, as well as with epigenetic changes in control regions of imprinted genes. Compared to children born to mothers least adherent to a Mediterranean diet around the time of conception, children born to mom’s with high MDA were less likely to display depressive and anxiety-related behaviors, and less likely to display atypical, maladaptive and autism-related behaviors. Furthermore, maternal MDA was also associated with changes in the methylation of the control regions of MEG3, IGF2, and SGCE/PEG10, which have been associated with multiple environmental exposures and offspring outcomes. Although the study was not designed with to demonstrate that the observed methylation changes in these genes mediated the associations of maternal MDA and offspring behavior, the directions of effect were consistent (see figure link).

 

Practical Insights

Maternal obesity has been linked to increased incidence of neurodevelopmental offspring outcomes such as ADHD. Although the Mediterranean diet has been associated favorably with many human health outcomes, this is the first time that this periconceptional dietary pattern in human mothers has been associated with favorable offspring neurodevelopmental outcomes. The exciting thing is that people can change their diets and this may be a way to positively impact neurodevelopmental outcomes such as ADHD and autism, each of which have experience increased incidence in the last 3 decades.  Ultimately, understanding the role epigenetics plays in linking environmental exposures such as maternal diet to offspring outcomes will offer insights into the development and testing of early intervention measures, either in utero or during the early stages of childhood development.

These efforts require a multi-disciplinary approach, pulling from several research fields to truly understand how such insights can be leveraged. The collaborative environment at NCSU is critical to this. House said, “I am fortunate to be a part of both the Bioinformatics Research Center and the Center for Human Health and the Environment. The BRC fosters a rich, collaborative environment which has afforded me exposure to a myriad of bioinformatics data science. And it was a colleague at the BRC that introduced me to Cathrine from the CHHE, which is what allowed me to conduct this research in the first place.”

 

What’s Next?

While the MDA-centric study uncovered valuable insights, House plans to expand research efforts by examining other dietary patterns including diets high in glycemic loading. House: “I want to determine exactly what maternal nutrient clusters are associated with favorable and unfavorable offspring behaviors.” With new information regarding these patterns, specifically the impacts of glycemic loading consumption patterns in expecting mothers, early intervention studies will be the next step. House explains that “we have a current NIH proposal interrogate the entire methylome of these children to identify epigenetic signatures that are associated with increased risk of future adverse child behaviors at birth. The hope is to ameliorate such risks with early intervention of caregiving attributes and adjusting child dietary habits.”

 

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Periconceptional Maternal Mediterranean Diet Is Associated With Favorable Offspring Behaviors and Altered CpG Methylation of Imprinted Genes (2018). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137242/

Researchers and co-authors involved with this study include John S. House, Michelle Mendez, Rachel L. Maguire, Sarah Gonzalez-Nahm, Zhiqing Huang, Julie Daniels, Susan K. Murphy, Bernard F. Fuemmeler, Fred A. Wright, and Cathrine Hoyo.

The research was supported by National Institute of Environmental Health Sciences of the National Institutes of Health (P01ES022831, R21ES014947, R01ES016772, R01HD084487, and P30ES025128) and by the U.S. Environmental Protection Agency (RD-83543701). Additional support was provided by the National Center for Advancing Translational Sciences (UL1TR001117).