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Annual Report for Fiscal Year 2017

Annual Report for Fiscal Year 2017
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NTP at NIEHS

Most NTP research testing and analysis activities are carried out at NIEHS. The following Division of NTP branches at NIEHS are actively involved in NTP research activities.

Biomolecular Screening

The Biomolecular Screening Branch develops and implements programs in medium- and high-throughput screening of environmental substances for rapid detection of biological activities of significance to toxicology. A focus is to develop analysis tools and approaches that integrate screening assessments with findings from traditional toxicology. The branch also administers the NTP High-Throughput Screening Initiative, which includes NTP’s Tox21 activities. Tox21 emphasizes the use of alternative assays for targeting the key pathways, molecular events, or processes linked to disease or injury, with the goal of incorporating the assays into a research and testing framework. An important priority for moving forward is to expand the biological coverage of the screening program and enhance the human relevance of alternative tests’ findings. Key to this effort is the integration of high-throughput transcriptomic screening into Tox21 and other NTP studies. The development of the S1500+ gene set and its use in targeted sequencing approaches provides a new, cost-effective methodology for capturing broad biological responses to chemical exposures in a variety of in vitro and in vivo model systems, allowing for quantitative dose-response measurements and kinetic studies. Linking this high-throughput transcriptomic approach with novel organotypic cell culture model systems allows for a more rapid and deeper investigation of biological responses for chemicals of concern and a better understanding of potential implications for human health.

Genetic and epigenetic differences between individuals in the human population have been proposed as major factors for determining individual susceptibility to environmental stressors. Safety assessments of environmental substances and drugs are currently conducted with a few commonly used animal models that have limited genetic diversity. Further, many layers of biological regulation can influence individual genetic susceptibility to chemical and drug toxicity. Animal models have inherent limitations for extrapolating results to human toxicity and disease. NTP is developing more sophisticated genetic analyses to make better use of current animal models while adopting biological systems that are more appropriate for modeling human toxicity and disease. The NTP Biomolecular Screening Branch conducts in-house projects aimed at understanding individual susceptibility.

Epigenetics involves the study of modifications to DNA and related cellular structures that affect gene expression and an organism’s ability to adapt to the environment. In FY 2017, work continued on an epigenetic study of mouse strains, led by Alex Merrick, Ph.D., and Paul Wade, Ph.D., to examine DNA methylation and its possible role in the susceptibility of mice to develop liver tumors. Male and female C57BL/6N mice were crossed with C3H/HeN mice. Five tissue types—brain, liver, cardiac and skeletal muscle, brown and white fat, and epididymal sperm—from first-generation offspring were collected and flash frozen for DNA/RNA isolation and liver sequencing. Progress in FY 2017 included computational analysis of genomic methylation sites in relation to known genes and transcriptionally active regions in both parental strains and first-generation offspring. The relationships between DNA methylation, gene expression, and possible heredity in offspring are being determined, and the genomic variations in mouse strains, genders, and first-generation offspring are being catalogued. The epigenetic landscape in the two mouse strains and their offspring will be described to help interpret the contribution of differences in DNA methylation to differential susceptibility to hepatic malignancy. The data will be publicly released following completion of a manuscript. Additional studies in FY 2017 addressed the impact of sex hormone signaling on DNA methylation at a genome-wide level and the impact of DNA methylation at distal regulatory regions.

NTP Laboratory

NTP Laboratory conducts in-house, agent-specific, targeted research on the development and application of modern toxicology and molecular biology tools. These tools are used to: NTP Laboratory also studies the developmental origins of adult diseases. NTP Laboratory projects for FY 2017 are listed below. Click the project title for a brief summary.

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