January — July 2019
- Genetic and Epigenetic Research at NCTR
- Effect of Carcinogens on Transcriptomic and Epigenetic Alterations in Liver Cells
- Epigenome-Wide Association Study of Systemic Lupus Erythematosus (SLE) Based on Ethnicity
- Minimally Invasive Gene-Mutation Assay May Identify Mutagens and Carcinogens
- Detection of Rare Genomic Mutations Using Next-Generation Sequencing (NGS)
August — December 2019
- NCTR on the World Stage
- Global Summit on Regulatory Science (GSRS19)
- Indo-US Professorship Offered to NCTR Microbiologist
- NCTR Scientist to Serve as Advisor at International Agency for Research on Cancer Meetings
- Encouraging Neuroscience in Nigeria
Effect of Carcinogens on Transcriptomic and Epigenetic Alterations in Liver Cells
NCTR scientists, in collaboration with the University of New Mexico Comprehensive Cancer Center, investigated the utility of high-throughput microarray gene expression and next-generation sequencing for the in vitro identiﬁcation of genotoxic and non-genotoxic carcinogens. This approach may substantially enhance the identiﬁcation and assessment of potential liver carcinogens. The increasing number of man-made chemicals in the environment that may pose a carcinogenic risk highlights the need for developing reliable time- and cost-effective approaches for carcinogen detection and identiﬁcation.
Transcriptomic analysis of human-liver HepaRG cells treated at minimally toxic concentrations with three different carcinogens generated distinct gene-expression proﬁles. In contrast to transcriptomic alterations, treatment of liver cells with the carcinogenic and non-carcinogenic chemicals resulted in profound changes in the DNA methylation footprint; however, the correlation between gene-speciﬁc DNA methylation and gene expression changes was minimal. Among the carcinogen-altered genes, transferrin (TF) emerged as a sensitive marker for an initial screening of chemicals for their potential liver carcinogenicity. Potential liver carcinogens (i.e., chemicals causing altered TF gene expression) could then be subjected to gene-expression analyses to differentiate genotoxic from non-genotoxic liver carcinogens. Information about this study can be found in Food and Chemical Toxicology.
For more information, contact Volodymyr Tryndyak, Ph.D. or Igor Pogribny, M.D., Ph.D., Division of Biochemical Toxicology, FDA/NCTR.
Epigenome-Wide Association Study of Systemic Lupus Erythematosus (SLE) Based on Ethnicity
NCTR scientists published findings from an epigenome-wide association study of lupus and non-lupus patients, and within those populations examined methylation profiles between African-American and European-American women. In addition, they studied the SLE disease activity status of those individuals — those with less disease (SLE score<6) to those with increased disease (SLE score>6). Autoimmune diseases affect women at a higher ratio (9:1) than men and at a higher rate among African-American women. Lupus is an autoimmune disease where the body attacks its own cells and organs. The SLE form of lupus is known to cause damage to several organs such as the kidney, heart, lung, and to joints in the body. Lupus was thought to be a genetic disease because it often occurred in families, but now research has established the importance of epigenetics (no alterations in gene structure) in lupus pathogenesis.
Until 2011, FDA had not approved a drug for lupus in fifty years, so research to spur development of lupus therapeutics is greatly needed. Different DNA profiles were observed in genes involved in the Type-1 interferon pathway in lupus versus age-matched control subjects. Furthermore, African-American women with lupus had a more robust DNA profile than European women with lupus. The identification of these epigenetic biomarkers can greatly improve diagnosis of this disease in lupus patients. Several epigenetic drugs are currently in various stages of development in clinical trials for other diseases, but data from these trials and other data suggest that epigenetic drugs may be potentially useful in lupus patients. This study was recently published in the Journal of Autoimmunity.
For additional information, contact Beverly Lyn-Cook, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.
Minimally Invasive Gene-Mutation Assay May Identify Mutagens and Carcinogens
The Pig-a assay is an emerging test for rapidly monitoring gene mutation(s) in rats, mice, and humans. The assay is minimally invasive, conducted on erythrocytes from peripheral blood. One drop of blood contains enough erythrocytes to conduct the most sensitive assays.
NCTR scientists are currently validating this assay as a regulatory test suitable for identifying mutagens and potential carcinogens. A recent study has developed a novel version of the assay for rat bone-marrow erythroid cells. These cells are the direct precursors of red blood cells found in circulating blood. Mammalian erythrocytes lack genomic DNA; therefore, confirmation of mutation induction — a necessary step for assay validation — is not possible in erythrocytes. The data from an NCTR study conclusively demonstrate that the Pig-a mutant erythrocytes (red blood cells) measured in the circulating blood of mutagenized rats were descendent from cells containing Pig-a mutations. In contrast, bone marrow erythroid precursor cells have nuclei and DNA, and thus are suitable for sequencing Pig-a mutations. The two publications below describing these findings are now available in Environmental Molecular Mutagenesis.
- “Analysis of mutation in the rat Pig-a assay: I) Studies with bone marrow erythroid cells.”
- “Analysis of mutation in the rat Pig-a assay: II) Studies with bone marrow granulocytes.”
For more information, please contact Javier Revollo, Ph.D. or Azra Nfn, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR.
Detection of Rare Genomic Mutations Using Next-Generation Sequencing (NGS)
FDA scientists from NCTR and the Center for Drug Evaluation and Research are developing a sensitive method to detect mutations induced by chemicals. Mutations are changes in the DNA sequence of an organism, ranging from small point mutations to large chromosome alterations that can cause adverse health effects, such as cancer and genetic disease. The goal of the ongoing study is to establish a new next generation sequencing (NGS) assay that may become a powerful, rapid, and practical tool to routinely evaluate the mutagenicity of FDA-regulated products. The scientists treated bacteria and mammalian cells with different types of mutagenic chemicals, then the DNA from cloned cells was isolated and sequenced using NGS. The sequencing data were analyzed by a bioinformatics pipeline established for the study.
For the bacterial part of the study, the NGS results showed that the mutagens caused significant mutation induction over the controls. The frequencies and types of mutations were like those previously reported with traditional mutation assays. For the mammalian cell part of the study, mouse lymphoma cells were treated with mutagenic chemicals, then the DNA samples from large and small colony clones were isolated for whole genome sequencing. The mutagens induced mutation frequencies greater than their concurrent untreated controls and the types of mutations suggested a mechanism for the mutagenesis. Data from this study have been interpreted and reported in Archives of Toxicology.
For more information, please contact Tao Chen, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR.
Global Summit on Regulatory Science (GSRS19)
Because of the importance for international regulators, policy makers, and scientists to exchange views on how to develop and implement innovative methodologies into regulatory assessments, NCTR established an annual internationally renowned Global Summit on Regulatory Science (GSRS). Now in its ninth year, the GSRS’s goal is to engage the global community and harmonize research strategies via collaborations that aim to build knowledge of and promote regulatory science, define research needs, and strengthen product safety worldwide by training regulatory scientists. The GSRS is led by the Global Coalition for Regulatory Science and is comprised of regulatory science leaders from around the world. NCTR’s Director, Dr. William Slikker, Jr. and European Food Safety Authority’s Chief Scientist, Dr. Marta Hugas, serve as co-chairs of the Coalition’s executive committee and work with the Coalition to promote global interaction.
The GSRS19 will be held in Lake Maggiore, Italy on September 24-26, 2019, at the Joint Research Centre – European Commission. The focus of this year’s summit will be on nanotechnology, as it relates to advances in standards, medical products, drugs, medical devices, food, cosmetic (personal care) products, and the emerging pollutant nanoplastics. Last year’s GSRS was held September 26-27, 2018, in Beijing, China at the National institute for Food and Drug Control. The topics that were discussed and presented covered the risks and benefits of dietary supplements and herbal medicine in the era of data science. A paper about GSRS18 is being reviewed internally to submit for publication. The GSRS18 presenters represented 10 countries, including four countries from Asia (China, Korea, Japan, and India), two European Union countries (Belgium and Italy), two from North America (USA and Canada), and Australia. The summit drew over 200 attendees from 13 countries.
Indo-US Professorship Offered to NCTR Microbiologist
Sangeeta Khare, Ph.D., in NCTR’s Division of Microbiology was awarded a 2019 Indo-US Professorship by the American Society for Microbiology and the Indo-US Science and Technology Forum (IUSSTF). The IUSSTF Professorship Program seeks to broaden scientific collaboration between India and the United States though travel grants that support research and teaching partnerships. The two-week training course is in partnership with the Indian Institute of Technology in Kanpur, India and is titled “Nanotechnology applications in healthcare: toxicological risk assessment using in vitro, ex vivo and in vivo host-microbiome interaction models.”
NCTR Scientist to Serve as Advisor at International Agency for Research on Cancer Meetings
Frederick Beland, Ph.D., Director of NCTR’s Division of Biochemical Toxicology was selected in 2019 to serve as advisor for the International Agency for Research on Cancer (IARC) meetings. According to its web site, IARC is the specialized cancer research agency of the World Health Organization (WHO) and is a multidisciplinary research institute with expertise in epidemiology, laboratory sciences, biostatistics, and bioinformatics. IARC leads and coordinates research projects around the world, with a strong focus on low- and middle-income countries, and is headquartered in Lyon, France. Scientists must meet rigorous requirements to be eligible for selection and generally have published significant research related to carcinogenicity of environmental, behavioral, or occupational factors that can increase the risk of human cancer. They may also have expertise in carcinogen testing and/or in carcinogen-hazard evaluation.
Encouraging Neuroscience in Nigeria
A former post-doctoral fellow who trained at NCTR in 2016-2017, Chinna Orish, Ph.D., keeps in touch with NCTR management to share her latest endeavours in the field of neuroscience in her home country of Nigeria. Dr. Orish’s efforts seek to inspire the younger generation of students to focus on the topic she is so passionate about – neuroscience.
Dr. Orish established the Espirisa Chinna Orish (ECO) Foundation to recognize and reward excellence in the field of neuroscience. This year she established an annual ECO Awards Day offering cash awards and presented plaques to the “Best Graduating Neuroscience Student” and the “Best Female Neuroscience Student” at the University of Port-Harcourt, Nigeria. Additionally, the ECO Foundation sponsored the Youth Neuroscience Association president’s attendance at the 2019 Society for Neuroscience in Africa (SONA) Conference held in Lagos, Nigeria on March 24-28, 2019.
Additionally, Dr. Orish coordinated and organized the second annual event to promote Brain Awareness Week in March 2019, at the University of Port-Harcourt, Nigeria. Brain Awareness Week is a worldwide celebration of the brain that brings together scientists, families, schools, and communities. New at this year’s event was the introduction of a Brain Bee that involved younger participants. There was so much excitement around the Brain Bee that Dr. Orish plans to continue and even expand the program next year.