Biology subjects

Andersen, M. E.

Publications and source records attributed to Andersen, M. E..

4 recordsLinked to original sources

bioRxiv2024

Investigating the mode of action for liver toxicity and wasting-like responses produced by high dose exposures to longer chain perfluoroacid substances (PFAS) using high throughput transcriptomics

Single doses of perfluoro-n-decanoic acid (PFDA) cause wasting, a progressive loss of 30 to 50% body weight, increasing liver/body weight ratios, and death within several weeks (Olson and Andersen, 1983). Repeat high doses of perfluorooctane sulfonate (PFOS) produce a subset of these responses in rats and monkeys. The mode of action (MOA) of these wasting-like syndromes is not clear, nor is it understood if these responses are limited to a subset of perfluoroacid substances (PFAS) or a common response to high dose exposure with a larger number of PFAS. To identify pathway perturbations in liver caused by PFAS, we analyzed published in vitro gene expression studies from human primary liver spheroids treated with various PFAS for treatment times up to 14 days (Rowan-Carroll et al., 2021). With treatment times of 10 to 14 days, longer-chain PFAS compounds, specifically PFOS, perfluorodecane sulfonate (PFDS) and higher doses of perfluorooctanoic acid (PFOA), downregulated large numbers of genes in pathways for steroid metabolism, fatty acid metabolism and biological oxidations. Shorter chain PFAS compounds upregulated genes in pathways for fatty acid metabolism. Although PFDA was more toxic and could only be examined at 1-day of treatment, it also downregulated genes for lipid metabolism, steroid metabolism, and biological oxidations. Shorter chain PFAS, both carboxylic and sulfonic acids, did not lead to downregulation of pathways for fatty acid or steroid metabolism. TCDD is also known to cause wasting responses in rodents and humans. In intact rats, high dose responses of longer chain PFAS produce downregulation of batteries of genes associated with fatty acid oxidation and lipogenesis similar to those seen with TCDD. Based on our results, when combined with other literature, we propose that the longer-chain PFAS impair lipogenic pathways through inhibitory interactions between PPAR{beta}, PPAR and PPAR{gamma}.

pharmacology and toxicology↗

bioRxiv2024

Investigating the mode of action for wasting produced by tetrachlorodibenzo-p-dioxin (TCDD) in rats using transcriptomics: Evidence for roles of AHR and ARNT in circadian cycling

Single, high doses of TCDD in rats caused wasting, a progressive loss of 30 to 50% body weight and death within several weeks. To identify pathway perturbations at or near doses causing wasting, we examined differentially gene expression (DGE) and pathway enrichment in centrilobular (CL) and periportal (PP) regions of female rat livers following 6 dose levels of TCDD - 0, 3, 22, 100, 300, and 1000 ng/kg/day, 5 days/week for 4 weeks. At the higher doses, rats lost weight, had increased liver/body weight ratios and nearly complete cessation of liver cell proliferation, signs consistent with wasting. DGE curves were left shifted for the CL versus the PP regions. Canonical Phase I and Phase II genes were maximally increased at lower doses and remained elevated at all doses. At lower doses, < 22 ng/kg/day in the CL and < 100 ng/kg/day, upregulated genes showed transcription factor (TF) enrichment for AHR and ARNT. At the mid- and hi-dose doses, there was a large number of downregulated genes and pathway enrichment for DEGs showed downregulation of many cellular metabolism processes including those for steroids, fatty acid metabolism, pyruvate metabolism and citric acid cycle. There was significant TF enrichment of the hi-dose downregulated genes for RXR, ESR1, LXR, PPARalpha. At the highest dose, there was also pathway enrichment with upregulated genes for extracellular matrix organization, collagen formation, hemostasis and innate immune system. TCDD demonstrates most of its effects through binding the aryl hydrocarbon receptor (AHR) while the downregulation of metabolism genes at higher TCDD doses is known to be independent of AHR binding to DREs. Based on our results with DEG, we provide a hypothesis for wasting in which high doses of TCDD shifts circadian processes away from the resting state leading to greatly reduced synthesis of steroids and complex lipids needed for cell growth and producing gene expression signals consistent with an epithelial-to-mesenchymal transition in hepatocytes.

pharmacology and toxicology↗

bioRxiv2022

Predictive Models of Genome-wide Aryl Hydrocarbon Receptor DNA Binding Reveal Tissue Specific Binding Determinants

BackgroundThe Aryl Hydrocarbon Receptor (AhR) is an inducible transcription factor (TF) whose ligands include the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD-mediated toxicity occurs through activation of AhR and its subsequent binding to the Dioxin Response Element (DRE), comprising the DNA motif 5-GCGTG-3. However, AhR binding in human tissues is highly dynamic and tissue specific. Approximately 50% of all experimentally verified AhR binding sites do not contain a DRE. Additionally, most accessible DREs are not bound by AhR. Identification of tissue specific AhR binding determinants is crucial for understanding downstream gene regulation and potential adverse outcomes of AhR activation. ResultsWe applied XGBoost, a supervised machine learning architecture, to predict the genome wide AhR binding status of DREs in open chromatin as a function of DNA sequence flanking the DRE, chromatin accessibility, histone modifications (HM), TF binding, and proximity of the DRE to gene promoters. We trained and validated our models using 5-fold cross validation to predict the binding status of DREs in AhR-activated MCF-7 breast cancer cells, primary human hepatocytes, and lymphoblastoid GM17212 cells, as well as AhR non-activated HepG2 hepatocellular carcinoma cells. Our results demonstrate highly accurate and robust models of AhR binding; and identify patterns of transcription factor binding and histone modifications predictive of AhR binding. These patterns are consistent within tissues but highly variable across tissues, which is suggestive of tissue-specific mechanisms of AhR binding. ConclusionsAhR binding is driven by a complex interplay of tissue-agnostic DNA sequence flanking its binding motif and tissue-specific local chromatin context.

genomics↗

bioRxiv2018

Gene Coregulation and Coexpression in the Aryl Hydrocarbon Receptor-mediated Transcriptional Regulatory Network in the Mouse Liver

Tissue-specific network models of chemical-induced gene perturbation can improve our mechanistic understanding of the intracellular events leading to adverse health effects resulting from chemical exposure. The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor (TF) that activates a battery of genes and produces a variety of species-specific adverse effects in response to the potent and persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here we assemble a global map of the AHR gene regulatory network in TCDD-treated mouse liver from a combination of previously published gene expression and genome-wide TF binding data sets. Using Kohonen selforganizing maps and subspace clustering, we show that genes co-regulated by common upstream TFs in the AHR network exhibit a pattern of co-expression. Specifically, directly-bound, indirectly-bound and non-genomic AHR target genes exhibit distinct patterns of gene expression, with the directly bound targets generally associated with highest median expression. Further, among the directly bound AHR target genes, the expression level increases with the number of AHR binding sites in the proximal promoter regions. Finally, we show that co-regulated genes in the AHR network activate distinct groups of downstream biological processes, with AHR-bound target genes enriched for metabolic processes and enrichment of immune responses among AHR-unbound target genes, likely reflecting infiltration of immune cells into the mouse liver upon TCDD treatment. This work describes an approach to the reconstruction and analysis of transcriptional regulatory cascades underlying cellular stress response using bioinformatic and statistical tools.

genomics↗