Superfund 2014 Annual Meeting

Meeting Summary

November 12-14, 2014

The Dolce Hayes Mansion
200 Edenvale Ave
San Jose, California

The 2014 annual meeting of the Superfund Research Program (SRP), held in San Jose, California, brought together researchers, trainees, and administrators from SRP Research Centers, Research Translation Centers, and Community Engagement Cores from the U.S. and Puerto Rico. The annual meeting brings together researchers, trainees, and administrators supported by the program, representatives from partner agencies, including the U.S. Environmental Protection Agency (USEPA) and the Agency for Toxic Substances and Disease Registry (ATSDR), and other interested individuals to discuss new research, technology, communication, and community engagement in critical areas related to the SRP mission. Following greetings from William Suk, the Director of the NIEHS Superfund Research Program, and Dr. Martyn Smith, the UC Berkeley Superfund Program Director, the much anticipated 2014 SRP Annual Meeting started on November 12, 2014. The following are the highlights of the meeting from a bioscience research perspective:

A few trainees from UC Davis described their research using immunized alpacas to generate antibodies that have the ability to detect small-molecule toxicants with high sensibility and high specificity. Why alpacas? It turns out that alpacas have a unique antibody structure possessing only the heavy chain (instead of the heavy chain plus the light chain). They first created a toxicant surrogate by attaching the toxicant to a carrier protein. Following the immunization of an alpaca with the surrogate protein, UC Davis’s researchers isolated mRNA coding for a variable domain of heavy-chain antibodies (VHH) and generated a phage display library. Subsequently, the positive clones were selected through competitive binding with the toxicant. After sequencing these positive clones, they were able to identify a few diverse antibodies that possess low IC50 levels in the competition experiment. The superiority of these antibodies – characterized by sensitivity and cross-reactivity - was further supported by comparing them to the ELISA with a conventional polyclonal antibody.

Using this single-domain antibody strategy, they have targeted a wide range of small-molecule environmental chemicals, including chemical flame retardant 2,2',4,4'-tetrabrominated diphenyl ether (BDE-47), food-contaminating mycotixin ochratoxin A, and pulmonary and neurological herbicidal toxicant paraquat, among others.  This VHH-derived antibody technology can be further applied to high-throughput platforms and/or produced for use in solid-state biosensors, thus reducing the time and cost for detecting these environmental contaminants. These results were presented by Candace Spier Bever, Jiexian Dong, Yongliang Cui, and Xin Liu from Bruce Hammock’s laboratory as part of the UC Davis SRP.

2014 Superfund Research Program Annual Meeting

Dr. Keith Pezzoli presents his talk "Community-University Partnerships as Drivers of Bioregional Science, Policy, and Planning" in the Research Translation and Community Engagement Session (Day 2)

On Thursday (11/13/2014 ), the keynote address was presented by Jillian Banfield from UC Berkley. Her laboratory has been focusing on evaluating the metabolic capacities of microorganisms and linking the importance of the microbiome to health and environmental exposure.  Emerging evidence has shown that the imbalance in the composition and activity of microorganisms within their community leads to various human diseases. Dr. Banfield started her talk by emphasizing that the gut microbiome plays a critical role in influencing nutrition absorption, producing vitamins, metabolizing carcinogens, modulating immune responses, fighting pathogens, and so on. She then argued that the majority of microorganisms present have not been identified or cultivated. To address this issue and to analyze microorganisms in the context of their community, her laboratory adopted shotgun metagenomics analysis: DNA extraction and sequencing, followed by data assembly, assignment of genome fragments to specific organisms (i.e., binning), and annotation with computational tools.

When they applied this cultivation-independent approach to track species and strain level variations in microbial communities in fecal samples collected from a premature infant in different time points during the first month of life, approximately 10 complete or near-complete bacterial genomes as well as 3 viral genomes were assembled. They found that the relative abundance of these assembled bacteria and phages shifted significantly among samples collected from different time points. Factors that contribute to the gut microbial community in the initial colonization of the infant may include nutrients, antibiotic consumption, and phage abundance.

Neonatal necrotizing enterocolitis (NEC) has been linked to abnormalities in the composition of the gut microbiome. To examine the early gut colonization in infants with NEC, Dr. Banfield’s lab used the above-described genome-resolved, time series abundance analysis to analyze microbial composition of fecal samples in a NEC infant. Contrary to expectations, the microbial composition was very different and no strain was shared among 10 samples they examined. It is believed that strain variants are closely associated with the pathological outcome of NEC. Dr. Banfield concluded her talk by stating that using genome reconstructions to study microbial species and strain level variation in natural environments help understand the structure and metabolism of the microbial community.

Following the presentations regarding adverse effects of early life exposure, Ekihiro Seki presented his research entitled “Fatty liver disease changes the sensitivity to toxin exposure that enhances liver fibrosis.” CCl4 is an environmental pollutant present in approximately 20% of the superfund sites. CCL4 liver toxicity stems from the fact that it induces hepatocyte damage through reactive metabolites generated by CYP2E1 metabolic activation and leads to activation of hepatic stellate cells, resulting in liver fibrosis. In the era of the global obesity epidemic - especially in the U.S. - non-alcoholic fatty liver disease (NAFLD) has become one of the most common liver diseases that manifests in 60-70% of obese adults. Approximately 15-20% of NAFLD patients progress to non-alcoholic steatohepatitis (NASH), a severe form of liver disease that can further progress to liver cirrhosis and eventually develop hepatocellular carcinoma (HCC).

When feeding mice with a high-fat diet preceding CCL4 treatment, Dr. Seki’s group found that mice are more susceptible to liver damage: higher levels of hepatocyte necrosis, ALT values, liver inflammation, and fibrosis, compared with control mice (normal diet + CCL4). They subsequently discovered that TGF-β–activated kinase 1 (TAK1) expression was significantly decreased in mice treated with the high-fat diet. It is well established that TAK1 activates NF-ҝB and JNK signaling pathways; TAK1 is also associated with inducing autophagy through AMPK phosphorylation. To study the role of TAK1 in liver fibrosis, they generated hepatocyte-specific Tak1 knockout mice (Tak1 ∆hep). When they treated the mice with CCL4, their results show that Tak1 ∆hep mice exhibited higher levels of fibrosis and liver injury and increasing cell death, similar to the effect of the high-fat diet.

They then asked the question “why and how does Tak1-deficiency liver tissue succumb to cell death”?  Through a series of elegant experiments, they demonstrated the following results: 1) Tak1 ∆hep mice lack TNF-mediated NFҝB activation; 2) TGFβ-mediated Smad2/3 activation is augmented in Tak1 ∆hep mice; 3) Autophagy is suppressed in Tak1 ∆hep mice; this result is supported by the fact that the autophagy-inducing agent, rapamycin, suppresses hepatocyte damage and liver fibrosis in Tak1 ∆hep mice. All the above signaling pathways regulated by TAK1 contribute to liver cell death, liver inflammation, hepatic stellate cell activation, and ultimate liver fibrosis. This also explains the underlying mechanism associated with liver fibrosis induced by a high-fat diet. Dr. Seki is the Project 5 leader in the UC San Diego SRP.

Drs. Robert Tukey and Mei-Fei Yueh at the 2014 SRP Meeting

Drs. Robert Tukey and Mei-Fei Yueh get ready for the next round of science sessions at the meeting

In the poster presentation, Mei-Fei Yueh reported the potentially serious consequences of long-term exposure to triclosan, an antimicrobial commonly found in soaps, shampoos, toothpastes, and many other household products. They show that triclosan causes liver cell proliferation, fibrosis, and oxidative stress. In addition, mice exposed to triclosan are more susceptible to chemical-induced liver tumors: TCS-treated mice have a higher tumor incidence, larger tumor size, and greater tumor number. The study suggests triclosan may do its damage through oxidative stress that induces cell death. To compensate for this stress, liver cells proliferate and turn fibrotic over time. Repeated triclosan exposure and continued liver fibrosis eventually promote tumor formation.

Triclosan is perhaps the most ubiquitous consumer antibacterial. It is found in 97% of breast milk samples from lactating women and is detected in the urine of nearly 75% of people tested. Triclosan has also made its way into our environment: It is one of the seven most frequently detected compounds in streams across the United States. This study argues that triclosan causes liver fibrosis and cancer in laboratory mice through molecular mechanisms that are also relevant in humans. They believe that triclosans’s increasingly broad use in consumer products and its increasing detection in environmental samples may manifest as liver toxicity in men similar to what occurs in mice. Mei-Fei Yueh is from Robert Tukey’s Laboratory under the UC San Diego SRP.

In separate sessions from the main plenary sessions, Robert Tukey, met with other Center Directors to address matters related to budgetary issues, coordination, management, new research, overall progress, and other issues pertinent of their individual Centers.  Keith Pezzoli, presented a talk "Community-University Partnerships as Drivers of Bioregional Science, Policy and Planning" in addition to joining other Core Leaders and members of the Research Translation Cores (RTC) and Community Engagement Cores (CEC) from across the SRP Centers in interactive groups.  Also joining in these RTC and CEC groups, was Catherine Larsen, where issues relating to communicating complex science, technology transfer, strategies for linking research to risk assessment, forming stronger connections with communities, the public's participation in research, technology, communication, and community engagement in critical areas related to the SRP mission where discussed. Program Manager, Michelle Feiock, attended informal sessions regarding administration relating to P42 Centers and to discuss NIH and NIEHS policy, reporting requirements, along with best practices related to events or issues that may arise throughout the duration of the SRP grant cycle.

Andrew Kau discusses poster with a group of poster judges

Andrew Kau explains his research poster to a group of poster judges during one of the poster sessions.

Also from the UC San Diego SRP, other trainees, senior researchers, and project leaders presenting in this meeting include:

  • Andrew Cooper/Julian Schroeder: Misregulation of OPT3 results in tissue specific changes in cadmium accumulation
  • Ning Ding/Ron Evans: Vitamin D receptor is a genomic gatekeeper of wound healing response in hepatic stellate cells
  • Abantika Ganguly/Paul Russel: Functional profiling and bioassays in fission yeast for assessing genetic pathways affecting cellular sensitivity to chromium and other metal toxicants
  • Andrew Kau/Julian Schroeder: Identification of OPT4 as a plant glutathione transporter
  • Ju Youn Kim/Michael Karin: New ways to prevent non-alcoholic steatohepatitis (NASH) progression: defining the role of TNFR1 in de novo lipid synthesis through caspase2-mediated SREBP1 processing
  • Yoon-Seok Roh/Ekihiro Seki: TAK1 protects CCl4-mediated liver fibrosis in fatty liver disease
  • Genevieve Ryan/Pamela Mellon: Regulation of GnRH receptor by androgens in LβT2 immortalized gonadotrope cells and a pituitary-specific androgen receptor knockout mouse
  • Catherine Wood Larsen/Keith Pezzoli: Endocrine disrupting chemicals in dust: a pilot study from Los Laureles Canyon, Mexico

Main Contact Information

MEETING SUMMARY BY:

Mei-Fei Yueh, Ph.D.

UCSD Superfund Research Center
University of California, San Diego
9500 Gilman Drive, Mail code: 0722
La Jolla, California, 92093-0722
Phone: (858) 822-1351
E-mail: mfyueh@ucsd.edu

Poster Presentations

Abantika Ganguly at SRP 2014 Annual MTG

Abantika Ganguly, Post Doc from the Paul Russell lab, presents her poster: "Functional profiling and bioassays in fission yeast for assessing genetic pathways affecting cellular sensitivity to chromium and other metal toxicants"

Ju Youn Kim Presents her poster at the SRP 2014 Annual MTG

Ju Youn Kim, Post Doc from the Michael Karin lab, presents her poster: "New ways to prevent non-alcoholic steatohepatitis (NASH) progression: defining the role of TNFR1 in de novo lipid synthesis through caspase2-mediated SREBP1 processing"

Drs. Eki Seki and Yoonseok Noh present poster at the SRP 2014 Annual Meeting

Drs. Eki Seki and Yoonseok Noh presenting their poster "TAK1 protects CCl4-mediated liver fibrosis in fatty liver disease"

Drs. Ron Evans and Ning Ding's poster at the SRP 2014 Annual Meeting

Ning Ding of the Ron Evans lab displayed research on "Vitamin D receptor is a genomic gatekeeper of wound healing response in hepatic stellate cells"

Drs. Robert Tukey and Keith Pezzoli discuss CEC poster

Drs. Robert Tukey and Keith Pezzoli discussing the poster "Endocrine disrupting chemicals in dust: a pilot study from Los Laureles Canyon, Mexico"

Catherine Larsen discusses CEC poster with a meeting attendee

Catherine Larsen explains the poster "Endocrine disrupting chemicals in dust: a pilot study from Los Laureles Canyon, Mexico"

Genevieve Ryan, UCSD SRC 2014

Graduate Student, Genevieve Ryan, presenting her poster "Regulation of GnRH receptor by androgens in LβT2 immortalized gonadotrope cells and a pituitary-specific androgen receptor knockout mouse"

Andrew Cooper presents poster at the SRP 2014 Annual Meeting

Andrew Kau stands with Graduate Student, Andrew Cooper, who presented his poster on: "Misregulation of OPT3 results in tissue specific changes in cadmium accumulation"

Andrew Kau presents poster at the SRP 2014 Annual Meeting

Masters Student, Andrew Kau, presents his poster on the "Identification of OPT4 as a plant glutathione transporter"

Contact

UCSD Superfund Research Center
University of California, San Diego
Pharmacology Department
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722