Molecular Toxicology and Genomics Group
B A. Merrick, Ph.D.
Molecular Toxicologist/Group Leader
The Molecular Toxicology and Genomics Group, headed by B. Alex Merrick, Ph.D., uses advanced technologies and computational approaches to relate chemicals to genes, genes to pathways, and pathways to disease. Development of toxicity signatures will further our understanding of disease processes and contribute to predictive models of toxicity and chemical prioritization. In addition, next generation (NextGen) sequencing is being used to study the relationship of genomic and epigenomic structure to gene expression and chemical toxicity.
Major Areas of Research
- Identify molecular mechanisms of toxicity action and disease-associated pathways by gene and reporter expression analysis.
- Develop computational and predictive models for animal and human biological response to environmental toxicants.
- Prioritize substances for further in-depth toxicological evaluation.
- Toxicity signatures – Toxicogenomic screening by microarrays and RNA-Seq are being used for in vitro and in vivo chemical exposures to derive patterns of gene expression and novel transcripts for predicting disease (e.g., tumor formation) and target organ toxicity.
- NextGen Sequencing – Transcriptomic profiles can be generated with base pair resolution with opportunities for new transcript discovery.
- Mouse Methylome – The Mouse Methylome Project is a DIR/DNTP collaboration to determine DNA methylation patterns by whole genome bisulfite sequencing. DNA methylation patterns can be related to transcript expression in different mouse strains with variable susceptibility to liver tumors.
- Archival tissue gene expression – Studies are being conducted to evaluate new technologies (e.g., NextGen sequencing) for retrospectively interrogating changes in DNA sequence/methylation patterns and/or RNA expression, using fresh frozen and formalin-fixed, paraffin embedded tissues from animal studies that are stored in the National Toxicology Program (NTP) tissue archives.
- Endocrine active compounds – Compounds exhibiting endocrine activity in qHTS assays are being evaluated in additional assays for biological relevance.
B. Alex Merrick, Ph.D. is a Molecular Toxicologist who joined the NTP Biomolecular Screening Branch (BSB) in 2010. Merrick leads the Branch's Molecular Toxicology and Genomics Group. His responsibilities include identifying key signaling pathways and transcripts altered by environmental toxicants and participating in the Tox21 collaboration between the NTP, the NIH Chemical Genomics Center (NCGC), the Environmental Protection Agency's National Center for Computational Toxicology (NCCT) and the Food and Drug Administration (FDA). He is especially interested in performing molecular analysis in NTP archival tissues to discover gene expression and epigenetic signatures from chemical toxicology studies. Collaborative work with the Cellular and Molecular Pathology Branch aims to use NTP archival research to further pathological insight, better understand mechanisms of chemical toxicity and contribute to predictive models of toxicity and chemical prioritization as a complementary effort to the Tox21 high throughput screening program. In addition, NextGen sequencing projects will help NTP better evaluate chemically exposed tissues for differential transcript profiles that include splice variants, low copy transcripts and non-coding mRNA's.
Before joining the Biomolecular Screening Branch, Merrick was head of the Proteomics Group within the Division of Intramural Research's (DIR) National Center for Toxicogenomics. His group performed protein and gene expression profiling of hepatoxic agents to identify mechanisms of liver injury, with special interest in p53 biology.
Merrick received his Ph.D. in 1984 at the University of Nebraska Medical Center in Omaha, performing post-doctoral work in the Biology Division at Oak Ridge National Laboratory. He headed the Hepatotoxicology section at the US EPA in Cincinnati, OH from 1985 to 1988 before joining NIEHS in 1989. He currently serves as an adjunct Associate Professor in the Department of Environmental and Molecular Toxicology at NC State University.
- Dunnick JS, Merrick BA, Brix A, Morgan DL, Gerrish K, Flake G, Foley J and Shockley K. Molecular changes in the nasal cavity after N,N-Dimethyl-p-toluidine exposure. Toxicol Pathol (In Press, 2016).
- Merrick BA, Paules RS and Tice RR. Intersection of Toxicogenomics and High Throughput Screening in the Tox21 Program: An NIEHS Perspective. Int. J. Biotechnology. 2015 14(1):7-27. [Abstract]
- Chen S, Hsieh J-H, Huang R, Sakamuru S, Hsin L.-Y, Xia M, Shockley K, Auerbach S, Kanaya N, Lu H, Svoboda D, Witt KL, Merrick BA, Tice RR and Teng CT. 2015. Cell-based high-throughput screening for aromatase inhibitors in the Tox21.10K library. Tox Sci 147:446-457. [Abstract]
- Pelch KE, Tokar EJ, Merrick BA, and Waalkes MP. 2015. Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium. Toxicol Appl Pharmacol 286:159-167. [Abstract]
- Morgan D, Merrick BA, Gerrish KE, Stockton PS, Foley JF, Wang Y, Gwinn WM, Kelly FF, Palmer SM, Ton T-V T, Hoenerhoff JJ and Flake GP. 2015. Gene expression of obliterative bronchiolitis-like lesions in 2,3-pentanedione-exposed rats. PLOS ONE, 10(2):e0118459. [Abstract]
- Auerbach SS, Phadke D, Mav D, Gao Y, Xie B, Shin JH, Shah RR, Merrick BA, Tice RR. 2015. RNA-Seq-based Toxicogenomic Assessment of Fresh Frozen and Formalin Fixed Tissues Yields Similar Mechanistic Insights. J Appl Toxicol, 35:766-780. [Abstract]
- Teng CT, Beams B, Merrick BA, Martin N, Romeo C, Jetten AM. Development of a stable cell line with an intact PGC-1α/ERRα axis for screening environmental chemicals. Biochemical and biophysical research communications 2014 444(2):177-181. [Abstract]
- McPherson CA, Merrick BA and Harry GJ. 2014. Enhanced evaluation of in vivo molecular markers for pro-inflammatory cytokine M1 stage of trimethyltin-induced hippocampal injury. Neurotoxicity Research, 25:45-56. [Abstract]
- Teng CT, Goodwin B, Shockley K, Xia M, Huang R, Norris J, Merrick BA, Jetten AM, Austin CP, Tice RR. Bisphenol A affects androgen receptor function via multiple mechanisms. Chemico-Biological Interactions 2013. 203(3):556-564. [Abstract]
- Merrick BA, Phadke DP, Auerbach SS, Mav D, Stiegelmeyer SM, Shah RR, Tice RR. RNA-Seq profiling reveals novel hepatic gene expression pattern in aflatoxin B1 treated rats. PLOS ONE 2013 8(4):e61768-. [Abstract]
- Merrick BA, Auerbach SS, Stockton PS, Foley JF, Malarkey DE, Sills RC, Irwin RD and Tice RR. 2012. Testing an aflatoxin B1 gene signature in rat archival tissues. Chem Res Toxicol 25:1132-1144. [Abstract]
- Merrick BA, London RE, Bushel PR, Grissom SF and Paules RS. 2011. Platforms for biomarker analysis using high-throughput approaches in genomics, transcriptomics, proteomics, metabolomics and bioinformatics. IARC Sci Publ, 163:121-142. [Abstract]
- Merrick BA, Dhungana S, Williams JG, Aloor JJ, Peddada S, Tomer KB and Fessler MB. 2011. Proteomic profiling of S-acylated macrophage proteins identifies a role for palmitoylation in mitochondrial targeting of phospholipid scramblase 3. Molec Cellular Proteomics, M110.00607-13. [Abstract]
- Merrick BA and Witzmann FA. 2009. The role of toxicoproteomics in assessing organ specific toxicity. EXS (Experientia Supplementum) 99:367-400. [Abstract]
- Merrick BA. 2008. The plasma proteome, adductome and idiosyncratic toxicity in toxico-proteomics research. Briefings in Functional Genomics and Proteomics 7:35-49. [Abstract]