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Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants that occur in complex mixtures. Several PAHs are known or suspected mutagens and/or carcinogens, but developmental toxicity data is lacking for PAHs, particularly their oxygenated and nitrated derivatives. Such data are necessary to understand and predict the toxicity of environmental mixtures. 123 PAHs were assessed for morphological and neurobehavioral effects for a range of concentrations between 0.1 and 50 µM, using a high throughput early-life stage zebrafish assay, including 33 parent, 22 nitrated, 17 oxygenated, 19 hydroxylated, 14 methylated, 16 heterocyclic, and 2 aminated PAHs. Additionally, each PAH was evaluated for AHR activation, by assessing CYP1A protein expression using whole animal immunohistochemistry (IHC). Responses to PAHs varied in a structurally dependent manner. High-molecular weight PAHs were significantly more developmentally toxic than the low-molecular weight PAHs, and CYP1A expression was detected in five distinct tissues, including vasculature, liver, skin, neuromasts and yolk.

The gut microbiome produces metabolites that interact with the aryl hydrocarbon receptor (AhR), a key regulator of immune homoeostasis in the gut 1 , 2 . Here we show that oral exposure to graphene oxide (GO) modulates the composition of the gut microbiome in adult zebrafish, with significant differences in wild-type versus ahr2 -deficient animals. Furthermore, GO was found to elicit AhR-dependent induction of cyp1a and homing of lck + cells to the gut in germ-free zebrafish larvae when combined with the short-chain fatty acid butyrate. To obtain further insights into the immune responses to GO, we used single-cell RNA sequencing to profile cells from whole germ-free embryos as well as cells enriched for lck . These studies provided evidence for the existence of innate lymphoid cell (ILC)-like cells 3 in germ-free zebrafish. Moreover, GO endowed with a ‘corona’ of microbial butyrate triggered the induction of ILC2-like cells with attributes of regulatory cells. Taken together, this study shows that a nanomaterial can influence the crosstalk between the microbiome and immune system in an AhR-dependent manner. Although the toxicity of graphene‐based nanomaterials on human health has been extensively studied, their impact on the microbiome remains poorly understood. Using zebrafish as a model, we show that graphene oxide modulates the immune system in a microbiome‐dependent manner through a mechanism mediated by the aryl hydrocarbon receptor. The study suggests an interplay among graphene‐based nanomaterials, microbiome and innate immune system.

Biomarkers have been used extensively to provide the connection between external levels of contaminant exposure, internal levels of tissue contamination, and early adverse effects in organisms. To present a three-step protocol for identifying suitable biomarkers to assess fish health in coastal and marine ecosystems, using Gladstone Harbour (Australia) as a case study. Prior to applying our protocol, clear working definitions for biomarkers were developed to ensure consistency with the global literature on fish health assessment. First, contaminants of concern were identified based on the presence of point and diffuse sources of pollution and available monitoring data for the ecosystem of interest. Second, suitable fish species were identified using fisheries dependent and independent data, and prioritised based on potential pathways of exposure to the contaminants of concern. Finally, a systematic and critical literature review was conducted on the use of biomarkers to assess the health of fish exposed to the contaminants of concern. We present clear working definitions for bioaccumulation markers, biomarkers of exposure, biomarkers of effect and biomarkers of susceptibility. Based on emission and concentration information, seven metals were identified as contaminants of concern for Gladstone Harbour. Twenty out of 232 fish species were abundant enough to be potentially suitable for biomarker studies; five of these were prioritised based on potential pathways of exposure and susceptibility to metals. The literature search on biomarkers yielded 5,035 articles, of which 151met the inclusion criteria. Based on our review, the most suitable biomarkers include bioaccumulation markers, biomarkers of exposure (CYP1A, EROD, SOD, LPOX, HSP, MT, DNA strand breaks, micronuclei, apoptosis), and biomarkers of effect (histopathology, TAG:ST). Our protocol outlines a clear pathway to identify suitable biomarkers to assess fish health in coastal and marine ecosystems, which can be applied to biomarker studies in aquatic ecosystems around the world.

Aims/hypothesisExposure to environmental pollution has been consistently linked to diabetes incidence in humans, but the potential causative mechanisms remain unclear. Given the critical role of regulated insulin secretion in maintaining glucose homeostasis, environmental chemicals that reach the endocrine pancreas and cause beta cell injury are of particular concern. We propose that cytochrome P450 (CYP) enzymes, which are involved in metabolising xenobiotics, could serve as a useful biomarker for direct exposure of islets to pollutants. Moreover, functional CYP enzymes in islets could also impact beta cell physiology. The aim of this study was to determine whether CYP1A enzymes are activated in islets following direct or systemic exposure to environmental pollutants.MethodsImmortalised liver (HepG2) and rodent pancreatic endocrine cell lines (MIN6, βTC-6, INS1, α-TC1, α-TC3), as well as human islets, were treated in vitro with known CYP1A inducers 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene (3-MC). In addition, mice were injected with either a single high dose of TCDD or multiple low doses of TCDD in vivo, and islets were isolated 1, 7 or 14 days later.ResultsCYP1A enzymes were not activated in any of the immortalised beta or alpha cell lines tested. However, both 3-MC and TCDD potently induced CYP1A1 gene expression and modestly increased CYP1A1 enzyme activity in human islets after 48 h. The induction of CYP1A1 in human islets by TCDD was prevented by cotreatment with a cytokine mixture. After a systemic single high-dose TCDD injection, CYP1A1 enzyme activity was induced in mouse islets ~2-fold, ~40-fold and ~80-fold compared with controls after 1, 7 and 14 days, respectively, in vivo. Multiple low-dose TCDD exposure in vivo also caused significant upregulation of Cyp1a1 in mouse islets. Direct TCDD exposure to human and mouse islets in vitro resulted in suppressed glucose-induced insulin secretion. A single high-dose TCDD injection resulted in lower plasma insulin levels, as well as a pronounced increase in beta cell death.Conclusions/interpretationTransient exposure to TCDD results in long-term upregulation of CYP1A1 enzyme activity in islets. This provides evidence for direct exposure of islets to lipophilic pollutants in vivo and may have implications for islet physiology.

Many fish populations are exposed to harmful levels of chemical pollution and selection pressures associated with these exposures have led to the evolution of tolerance. Our understanding of the physiological basis for these adaptations is limited, but they are likely to include processes involved with the absorption, distribution, metabolism and/or excretion of the target chemical. Other potential adaptive mechanisms include enhancements in antioxidant responses, an increased capacity for DNA and/or tissue repair and alterations to the life cycle of fish that enable earlier reproduction. Analysis of single-nucleotide polymorphism frequencies has shown that tolerance to hydrocarbon pollutants in both marine and estuarine fish species involves alteration in the expression of the xenobiotic metabolism enzyme CYP1A. In this review, we present novel data showing also that variants of the CYP1A gene have been under selection in guppies living in Trinidadian rivers heavily polluted with crude oil. Potential costs associated with these adaptations could reduce fitness in unpolluted water conditions. Integrating knowledge of local adaptation to pollution is an important future consideration in conservation practices such as for successful restocking, and improving connectivity within river systems. This article is part of the themed issue ‘Human influences on evolution, and the ecological and societal consequences’.

Abstract The cytochrome P450 family 1 enzymes (CYP1s) are a diverse family of hemoprotein monooxygenases, which metabolize many xenobiotics including numerous environmental carcinogens. However, their historical function and evolution remain largely unstudied. Here we investigate CYP1 evolution via the reconstruction and characterization of the vertebrate CYP1 ancestors. Younger ancestors and extant forms generally demonstrated higher activity toward typical CYP1 xenobiotic and steroid substrates than older ancestors, suggesting significant diversification away from the original CYP1 function. Caffeine metabolism appears to be a recently evolved trait of the CYP1A subfamily, observed in the mammalian CYP1A lineage, and may parallel the recent evolution of caffeine synthesis in multiple separate plant species. Likewise, the aryl hydrocarbon receptor agonist, 6-formylindolo[3,2-b]carbazole (FICZ) was metabolized to a greater extent by certain younger ancestors and extant forms, suggesting that activity toward FICZ increased in specific CYP1 evolutionary branches, a process that may have occurred in parallel to the exploitation of land where UV-exposure was higher than in aquatic environments. As observed with previous reconstructions of P450 enzymes, thermostability correlated with evolutionary age; the oldest ancestor was up to 35 °C more thermostable than the extant forms, with a 10T50 (temperature at which 50% of the hemoprotein remains intact after 10 min) of 71 °C. This robustness may have facilitated evolutionary diversification of the CYP1s by buffering the destabilizing effects of mutations that conferred novel functions, a phenomenon which may also be useful in exploiting the catalytic versatility of these ancestral enzymes for commercial application as biocatalysts.

Indoxyl sulfate (IS), an agonist of aryl hydrocarbon receptors (AhR), can accumulate in patients with chronic kidney disease, but its direct effect on bone is not clear. The present study investigated the effect of chronic exposure to low (100 mg/kg b.w.; 100 IS) and high (200 mg/kg b.w.; 200 IS) dose of IS on bone AhR pathway, sirtuins (SIRTs) expression, oxidative DNA damage and bone mineral status in Wistar rats. The accumulation of IS was observed only in trabecular bone tissue in both doses. The differences were observed in the bone parameters, depending on the applied IS dose. The exposure to 100 IS increased AhR repressor (AhRR)-CYP1A2 gene expression, which was associated with SIRT-1, SIRT-3 and SIRT-7 expression. At the low dose group, the oxidative DNA damage marker was unchanged in the bone samples, and it was inversely related to the abovementioned SIRTs expression. In contrast, the exposure to 200 IS reduced the expression of AhRR, CYP1A, SIRT-3 and SIRT-7 genes compared to 100 IS. The level of oxidative DNA damage was higher in trabecular bone in 200 IS group. Femoral bone mineral density was decreased, and inverse relations were noticed between the level of trabecular oxidative DNA damage and parameters of bone mineral status. In conclusion, IS modulates AhR-depending signaling affecting SIRTs expression, oxidative DNA damage and bone mineral status in a dose dependent manner.

An abstract of a study by Yankey et al determinng the activity of steroid and eicosanoid metabolizing enzymes in horses with varying BCS is presented. Activity of CYP1A was not different across BCS except in adrenal tissues (P = 0.03), where BCS 5 was greater than BCS 4 and 6, which were similar. Activity of CYP1A was 100-fold greater (P < 0.0001) in the liver than in the adrenal, ovary, and kidney, whereas activity of CYP1A was undetectable in the endometrium. Activity of CYP2C was 100-fold greater (P < 0.0001) in the liver than in the adrenal, ovary, and endometrium, whereas activity of CYP2C was undetectable in the kidney. Activity of CYP3A was detectable only in the liver. Activity of UGT was not different across BCS except in the kidney (P = 0.02), where BCS 4 was lesser than BCS 5 and 6, which were similar. Activity of UGT was 3-fold greater (P < 0.0001) in the liver than in the kidney, whereas activity of UGT was 9-fold greater (P < 0.0001) in the kidney vs. the ovary and endometrium.

The environmental pollutant benzo[a]pyrene (BaP) can induce cytochrome P450 family 1 subfamily A (CYP1A) or generate metabolic products that disrupt the balance of oxidative stress, triggering inflammatory responses in the lungs and leading to tissue damage. Flavonoids, known for their natural anti-inflammatory and antioxidant properties, are potential targets for intervention. This study used phenacetin, a specific substrate probe for CYP1A, to evaluate the inhibitory effects of 40 flavonoids on CYP1A. Structure-activity relationship analysis revealed that introducing hydroxyl groups at positions 3- and 6-enhances CYP1A inhibition. Notably, 3,6-dihydroxyflavone (DHF) emerged as a significant inhibitor of CYP1A. In vitro experiments confirmed that DHF effectively inhibits BaP-induced cytochrome P450 family 1 subfamily A member 1 (CYP1A1) in airway epithelial cells and shows dose-dependent inhibition of intracellular and mitochondrial reactive oxygen species (ROS) production. In summary, DHF is a promising CYP1A inhibitor and a potential anti-inflammatory candidate for preventing and treating CYP1A-mediated lung diseases.

Over the past two decades, the pig has gained attention as a potential model for human drug metabolism. Cytochrome P450 enzymes (CYP450), a superfamily of biotransformation enzymes, are pivotal in drug metabolism. Porcine CYP450 has been demonstrated to convert typical substrates of human CYP450. Nevertheless, knowledge and insight into porcine CYP450 quantity and substrate selectivity is scant, especially regarding intestinal CYP450. The current study aimed to map the quantities of hepatic and intestinal CYP450 in the conventional pig by using a proteomic approach. Moreover, the selectivity of the six most common used probe substrates (phenacetin, coumarin, midazolam, tolbutamide, dextromethorphan, and chlorzoxazone) for drug metabolizing enzyme subfamilies (CYP1A, CYP2A, CYP3A, CYP2C, CYP2D and CYP2E respectively), was investigated. Hepatic relative quantities were 4% (CYP1A), 31% (CYP2A), 14% (CYP3A), 10% (CYP2C), 28% (CYP2D) and 13% (CYP2E), whereas for the intestine only duodenal CYP450 could be determined with 88% for CYP3A and 12% for CYP2C. Furthermore, the results indicate that coumarin (CYP2A), midazolam (CYP3A), tolbutamide (CYP2C), and dextromethorphan (CYP2D) are as selective for porcine as for human CYP450. However, phenacetin (CYP1A2) and chlorzoxazone (CYP2E1) are less selective for the specific enzyme, despite similarities in selectivity towards the different enzymes involved compared to humans.