AHR2-Mediated Transcriptomic Responses Underlying the Synergistic Cardiac Developmental Toxicity of PAHs

Jayasundara, Nishad; Garner, Lindsey V.T.; Meyer, Joel N.; Erwin, Kyle N.; Giulio, Richard T. Di

doi:10.1093/toxsci/kfu245

Cited by 69 publications

(39 citation statements)

References 39 publications

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“…By incorporating in vivo metabolic profiling with multivariate pattern recognition and pathway analysis, the metabolomics data revealed that BAA and BAQ exposures were strongly associated with changes known to affect protein biosynthesis, mitochondrial dysfunction (oxidative stress), neural development, disturbance in vascular development and cardiac development function (cardiac toxicity). These findings generally concur with previous transcriptomics studies associated with the toxicological responses and effects of other PAHs and oxygenated PAHs (Goodale et al, 2013; Gurbani et al, 2013; Jayasundara et al, 2014). Our results demonstrated the utility of LC-MS-based metabolomics combined with the developmental zebrafish model to provide deeper mechanistic insights into the connections between chemical exposure and profound effects on organisms.…”

Section: Discussionsupporting

confidence: 91%

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Metabolomic analysis to define and compare the effects of PAHs and oxygenated PAHs in developing zebrafish

Elie

Choi

Nkrumah‐Elie

et al. 2015

Environmental Research

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Polycyclic aromatic hydrocarbons (PAHs) and their oxygenated derivatives are ubiquitously present in diesel exhaust, atmospheric particulate matter and soils sampled in urban areas. Therefore, inhalation or non-dietary ingestion of both PAHs and oxy-PAHs are major routes of exposure for people; especially young children living in these localities. While there has been extensive research on the parent PAHs, limited studies exist on the biological effects of oxy-PAHs which have been shown to be more soluble and more mobile in the environment. Additionally, investigations comparing the metabolic responses resulting from parent PAHs and oxy-PAHs exposures have not been reported. To address these current gaps, an untargeted metabolomics approach was conducted to examine the in vivo metabolomic profiles of developing zebrafish (Danio rerio) exposed to 4 µM of benz[a]anthracene (BAA) or benz[a]anthracene-7, 12-dione (BAQ). By integrating multivariate, univariate and pathway analyses, a total of 62 metabolites were significantly altered after 5 days of exposure. The marked perturbations revealed that both BAA and BAQ affect protein biosynthesis, mitochondrial function, neural development, vascular development and cardiac function. Our previous transcriptomic and genomic data were incorporated in this metabolomics study to provide a more comprehensive view of the relationship between PAH and oxy-PAH exposures on vertebrate development.

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Section: Discussionsupporting

confidence: 91%

“…Numerous embryonic zebrafish transcriptional and genetic studies have been conducted to assess the developmental toxicity of PAH and oxy-PAHs (Timme-Laragy et al, 2009; Van Tiem and Di Giulio, 2011; Goodale et al, 2013; Jayasundara et al, 2014). However, metabolic information is currently lacking.…”

Section: Introductionmentioning

confidence: 99%

Metabolomic analysis to define and compare the effects of PAHs and oxygenated PAHs in developing zebrafish

Elie

Choi

Nkrumah‐Elie

et al. 2015

Environmental Research

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“…At 6 dpf, 5–8 randomly selected larvae were removed from exposure solutions, rinsed once in 65 mg/l ASW, and oxygen consumption rates or heart rates were subsequently assessed. ASW and Danieau solution were chosen based on similar studies previously conducted in our laboratory (Jayasundara et al, 2015a, 2015b) to facilitate comparison of results across experiments. The presence of HEPES and other buffering chemicals can affect OCR measurements by the extracellular flux analyzer.…”

Section: Methodsmentioning

confidence: 99%

A bioenergetics assay for studying the effects of environmental stressors on mitochondrial function in vivo in zebrafish larvae

Raftery

Jayasundara

Giulio

2017

Comparative Biochemistry and Physiology Part C: Toxicology &

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Mitochondria, an integral component of cellular energy metabolism and other key functions, are extremely vulnerable to damage by environmental stressors. Although methods to measure mitochondrial function in vitro exist, sensitive, medium- to high-throughput assays that assess respiration within physiologically-relevant whole organisms are needed to identify drugs and/or chemicals that disrupt mitochondrial function, particularly at sensitive early developmental stages. Consequently, we have developed and optimized an assay to measure mitochondrial bioenergetics in zebrafish larvae using the XFe24 Extracellular Flux Analyzer. To prevent larval movement from confounding oxygen consumption measurements, we relied on MS-222-based anesthetization. We obtained stable measurement values in the absence of effects on average oxygen consumption rate and subsequently optimized the use of pharmacological agents for metabolic partitioning. To confirm assay reproducibility we demonstrated that triclosan, a positive control, significantly decreased spare respiratory capacity. We then exposed zebrafish from 5 hours post-fertilization (hpf) – 6 days post-fertilization (dpf) to three polycyclic aromatic hydrocarbons (PAHs) – benzo(a)pyrene (BaP), phenanthrene (Phe), and fluoranthene (FL) – and measured various fundamental parameters of mitochondrial respiratory chain function, including maximal respiration, spare respiratory capacity, mitochondrial and non-mitochondrial respiration. Exposure to all three PAHs decreased spare respiratory capacity and maximal respiration. Additionally, Phe exposure increased non-mitochondrial respiration and FL exposure decreased mitochondrial respiration and increased non-mitochondrial respiration. Overall, this whole organism-based assay provides a platform for examining mitochondrial dysfunction in vivo at critical developmental stages. It has important implications in biomedical sciences, toxicology and ecophysiology, particularly to examine the effects of environmental chemicals and/or drugs on mitochondrial bioenergetics.

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“…Benzo[a]pyrene (BaP) is another well-known ubiquitous polycyclic aromatic hydrocarbon (Zhang et al, 2006) that affects chondrocytes, osteoblasts and osteoclasts through Ahr (Voronov et al, 2008;Jayasundara et al, 2015) resulting in the alteration of steroid hormone metabolism (Jayasundara et al, 2015) and a decrease of circulating levels of 17β-estradiol (E2; Zhao et al, 2013), a steroid hormone involved in bone development and maintenance through estrogen receptors. A transgenerational osteotoxic effect was also observed in zebrafish (Corrales et al, 2014a) and medaka (Seemann et al, 2015) upon exposure to BaP.…”

Section: Aryl Hydrocarbon Receptormentioning

confidence: 99%

Fish as a model to assess chemical toxicity in bone

et al. 2018

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Environmental toxicology has been expanding as growing concerns on the impact of produced and released chemical compounds over the environment and human health are being demonstrated. Among the toxic effects observed in organisms exposed to pollutants, those affecting skeletal tissues (osteotoxicity) have been somehow overlooked in comparison to hepato-, immune-, neuro- and/or reproductive toxicities. Nevertheless, sub-lethal effects of toxicants on skeletal development and/or bone maintenance may result in impaired growth, reduced survival rate, increased disease susceptibility and diminished welfare. Osteotoxicity may occur by acute or chronic exposure to different environmental insults. Because of biologically and technically advantagous features - easy to breed and inexpensive to maintain, external and rapid rate of development, translucent larvae and the availability of molecular and genetic tools - the zebrafish (Danio rerio) has emerged in the last decade as a vertebrate model system of choice to evaluate osteotoxicity. Different experimental approaches in fish species and analytical tools have been applied, from in vitro to in vivo systems, from specific to high throughput methodologies. Current knowledge on osteotoxicity and underlying mechanisms gained using fish, with a special emphasis on zebrafish systems, is reviewed here. Osteotoxicants have been classified into four categories according to the pathway involved in the transduction of the osteotoxic effects: activation/inhibition of membrane and/or nuclear receptors, alteration of redox condition, mimicking of bone constituents and unknown pathways. Knowledge on these pathways is also reported here as it may provide critical insights into the development, production and release of future chemical compounds with none or low osteotoxicity, thus promoting the green/environmental friendly chemistry.

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AHR2-Mediated Transcriptomic Responses Underlying the Synergistic Cardiac Developmental Toxicity of PAHs

Cited by 69 publications

References 39 publications

Metabolomic analysis to define and compare the effects of PAHs and oxygenated PAHs in developing zebrafish

Metabolomic analysis to define and compare the effects of PAHs and oxygenated PAHs in developing zebrafish

A bioenergetics assay for studying the effects of environmental stressors on mitochondrial function in vivo in zebrafish larvae

Fish as a model to assess chemical toxicity in bone

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