Application of the in vivo oxidative stress reporter Hmox1 as mechanistic biomarker of arsenic toxicity

Iñesta-Vaquera, Francisco; Navasumrit, Panida; Henderson, Colin J.; Frangova, Tanya G.; Honda, Tadashi; Dinkova‐Kostova, Albena T.; Ruchirawat, Mathuros; Wolf, Charles

doi:10.1016/j.envpol.2020.116053

Cited by 15 publications

(13 citation statements)

References 77 publications

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“…This demonstrates how the models can also be used to rapidly test treatments of disease. 11 Similarly, we have used these reporter models to understand the toxicity of additional environmental chemicals, including cadmium (a nephro-and hepato-toxin found in cigarette smoke), "forever" chemicals and diesel emissions (Inesta-Vaquera, manuscripts in preparation). The information generated can be used in risk assessments and inform policy for health interventions.…”

Section: Resultsmentioning

confidence: 99%

Potential of in vivo stress reporter models to reduce animal use and provide mechanistic insights in toxicity studies

et al. 2022

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Chemical risk assessment ensures protection from the toxic effects of drugs and manmade chemicals. To comply with regulatory guidance, studies in complex organisms are required, as well as mechanistic studies to establish the relevance of any toxicities observed to man. Although in vitro toxicity models are improving, in vivo studies remain central to this process. Such studies are invariably time-consuming and often involve large numbers of animals. New regulatory frameworks recommend the implementation of “smart” in vivo approaches to toxicity testing that can effectively assess safety for humans and comply with societal expectations for reduction in animal use. A major obstacle in reducing the animals required is the time-consuming and complexity of the pathological endpoints used as markers of toxicity. Such endpoints are prone to inter-animal variability, subjectivity and require harmonisation between testing sites. As a consequence, large numbers of animals per experimental group are required. To address this issue, we propose the implementation of sophisticated stress response reporter mice that we have developed. These reporter models provide early biomarkers of toxic potential in a highly reproducible manner at single-cell resolution, which can also be measured non-invasively and have been extensively validated in academic research as early biomarkers of stress responses for a wide range of chemicals at human-relevant exposures. In this report, we describe a new and previously generated models in our lab, provide the methodology required for their use and discuss how they have been used to inform on toxic risk. We propose our in vivo approach is more informative (refinement) and reduces the animal use (reduction) compared to traditional toxicity testing. These models could be incorporated into tiered toxicity testing and used in combination with in vitro assays to generate quantitative adverse outcome pathways and inform on toxic potential.

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Section: Resultsmentioning

confidence: 99%

Potential of in vivo stress reporter models to reduce animal use and provide mechanistic insights in toxicity studies

et al. 2022

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“…Few previous studies have examined the effects of drinking arsenic water on the HO-1 expression in intestinal epithelial cells. However, the lack of induction of hepatic HO-1 expression by a 30-day exposure to 5 ppm inorganic arsenic in drinking water was recently reported [ 28 ]; the HO-1 expression in the small intestine was not examined in that study.…”

Section: Discussionmentioning

confidence: 98%

“…However, the present study is focused on HO-1 expression in the intestinal epithelial cells, the site of arsenic absorption. It remains to be determined whether the intestinal epithelial cells are more or less sensitive in their response to arsenic exposure than internal organs other than the liver, such as the kidney cortex, where robust HO-1 induction was reported for mice drinking 5 ppm arsenite for 30 days [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

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Differential Effects of Arsenic in Drinking Water on Mouse Hepatic and Intestinal Heme Oxygenase-1 Expression

Fan

et al. 2022

Antioxidants

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Arsenic exposure has been associated with the risks of various diseases, including cancers and metabolic diseases. The aim of this study was to examine the effects of arsenic exposure via drinking water on the expression of heme oxygenase-1 (HO-1), a major responsive gene to arsenic-induced oxidative stress, in mouse intestinal epithelial cells which is the first site of exposure for ingested arsenic, and the liver, a known target of arsenic toxicity. The expression of HO-1 was determined at mRNA, protein, or enzymic activity levels in mice exposed to sodium arsenite through drinking water, at various doses (0, 2.5, 10, 25, 100 ppm), and for various time periods (1, 3, 7, or 28 days). HO-1 was significantly induced in the intestine, but not liver, at arsenic doses of 25 ppm or lower. The intestinal HO-1 induction was seen in both males and females, plateaued within 1–3 days of exposure, and was accompanied by increases in microsomal HO activity. In mice exposed to 25-ppm of arsenite for 7 days, total arsenic and As(III) levels in intestinal epithelial cells were significantly higher than in the liver. These findings identify intestinal epithelial cells as likely preferential targets for arsenic toxicity and support further studies on the functional consequences of intestinal HO-1 induction.

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“…In these reporters, a short viral DNA sequence, known as a T2A sequence, is exploited to provide multiple reporter molecules to be expressed (separately) off the endogenous gene promoter. Recently, we have demonstrated the utility of these models as biomarkers for inorganic arsenic toxicity, a widespread water contaminant classified as a class 1 carcinogen [26]. We hypothesized that our stress reporters could be used as a complementary assay in environmental epidemiological studies to gain in vivo mechanistic insights into the associations observed.…”

Section: Introductionmentioning

confidence: 99%

Defining the in vivo mechanism of air pollutant toxicity using murine stress response biomarkers

Iñesta-Vaquera

Miyashita

Henderson

et al. 2022

Preprint

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Background: Air pollution can cause a wide range of serious human diseases. For the informed instigation of interventions which prevent these outcomes there is an urgent need to develop robust in vivo biomarkers which provide insights into mechanisms of toxicity and relate pollutants to specific adverse outcomes. Objective: To exemplify the application of in vivo stress response reporters in establishing mechanisms of air pollution toxicity and the application of this knowledge in epidemiological studies and potentially in disease prevention. Methods: Murine stress-reporter models (oxidative stress/inflammation, DNA damage and Ah receptor -AhR- activity) and primary mouse and primary human nasal cells were exposed to chemicals present in diesel exhaust emissions, particulate matter (PM) standards (PM2.5-SRM2975, PM10-SRM1648b) or fresh roadside PM10. Stress reporter activity was analysed by luminescence assays and histochemical approaches in a panel of murine tissues. Biochemical, genetic and pharmacological approaches were used to establish the mechanism of the stress responses observed. Pneumococcal adhesion was assessed in exposed primary human nasal epithelial cells (HPNEpC). Results: Nitro-PAHs induced Hmox1 and CYP1a1 reporters in a time- and dose-dependent, cell- and tissue-specific manner. NRF2 pathway mediated this Hmox1-reporter induction. SRM1658b, but not SRM2975, was a potent inducer of NRF2-dependent Hmox1 reporter activity in lung macrophages. Combined use of HPNEpC and in vivo reporters demonstrated that London roadside PM10 particles induced pneumococcal infection in HPNEpC mediated by oxidative stress responses. Discussion: The combined use of in vivo reporter models with HPNEpC provides a robust approach to define the relationship between air pollutant exposure and health risks. These models can be used to hazard ranking environmental pollutants by considering the complexity of mechanisms of toxicity. These data will facilitate the relationship between toxic potential and the level of pollutant exposure in populations to be established and potentially extremely valuable tools for intervention studies.

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Application of the in vivo oxidative stress reporter Hmox1 as mechanistic biomarker of arsenic toxicity

Cited by 15 publications

References 77 publications

Potential of in vivo stress reporter models to reduce animal use and provide mechanistic insights in toxicity studies

Potential of in vivo stress reporter models to reduce animal use and provide mechanistic insights in toxicity studies

Differential Effects of Arsenic in Drinking Water on Mouse Hepatic and Intestinal Heme Oxygenase-1 Expression

Defining the in vivo mechanism of air pollutant toxicity using murine stress response biomarkers

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