Perfluorooctanesulfonic acid exposure leads to downregulation of 3-hydroxy-3-methylglutaryl-CoA synthase 2 expression and upregulation of markers associated with intestinal carcinogenesis in mouse intestinal tissues.

Perfluorooctanesulfonic acid (PFOS) is a widely recognized environment pollutant known for its high bioaccumulation potential and a long elimination half-life. Several studies have shown that PFOS can alter multiple biological pathways and negatively affect human health. Considering the direct exposure to the gastrointestinal (GI) tract to environmental pollutants, PFOS can potentially disrupt intestinal homeostasis. However, there is limited knowledge about the effect of PFOS exposure on normal intestinal tissues, and its contribution to GI-associated diseases remains to be determined. In this study, we examined the effect of PFOS exposure on the gene expression profile of intestinal tissues of C57BL/6 mice using RNAseq analysis. We found that PFOS exposure in drinking water significantly downregulates mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting ketogenic enzyme, in intestinal tissues of mice. We found that diets containing the soluble fibers inulin and pectin, which are known to be protective against PFOS exposure, were ineffective in reversing the downregulation of HMGCS2 expression in vivo. Analysis of intestinal tissues also demonstrated that PFOS exposure leads to upregulation of proteins implicated in colorectal carcinogenesis, including ß-catenin, c-MYC, mTOR and FASN. Consistent with the in vivo results, PFOS exposure leads to downregulation of HMGCS2 in mouse and human normal intestinal organoids in vitro. Furthermore, we show that shRNA-mediated knockdown of HMGCS2 in a human normal intestinal cell line resulted in increased cell proliferation and upregulation of key proliferation-associated proteins such as cyclin D, survivin, ERK1/2 and AKT, along with an increase in lipid accumulation. In summary, our results suggest that PFOS exposure may contribute to pathological changes in normal intestinal cells via downregulation of HMGCS2 expression and upregulation of pro-carcinogenic signaling pathways that may increase the risk of colorectal cancer development.

13C-Stable isotope resolved metabolomics uncovers dynamic biochemical landscape of gut microbiome-host organ communications in mice.

BACKGROUND: Gut microbiome metabolites are important modulators of host health and disease. However, the overall metabolic potential of the gut microbiome and interactions with the host organs have been underexplored. RESULTS: Using stable isotope resolved metabolomics (SIRM) in mice orally gavaged with 13C-inulin (a tracer), we first observed dynamic enrichment of 13C-metabolites in cecum contents in the amino acids and short-chain fatty acid metabolism pathways. 13C labeled metabolites were subsequently profiled comparatively in plasma, liver, brain, and skeletal muscle collected at 6, 12, and 24 h after the tracer administration. Organ-specific and time-dependent 13C metabolite enrichments were observed. Carbons from the gut microbiome were preferably incorporated into choline metabolism and the glutamine-glutamate/GABA cycle in the liver and brain, respectively. A sex difference in 13C-lactate enrichment was observed in skeletal muscle, which highlights the sex effect on the interplay between gut microbiome and host organs. Choline was identified as an interorgan metabolite derived from the gut microbiome and fed the lipogenesis of phosphatidylcholine and lysophosphatidylcholine in host organs. In vitro and in silico studies revealed the de novo synthesis of choline in the human gut microbiome via the ethanolamine pathway, and Enterococcus faecalis was identified as a major choline synthesis species. These results revealed a previously underappreciated role for gut microorganisms in choline biosynthesis. CONCLUSIONS: Multicompartmental SIRM analyses provided new insights into the current understanding of dynamic interorgan metabolite transport between the gut microbiome and host at the whole-body level in mice. Moreover, this study singled out microbiota-derived metabolites that are potentially involved in the gut-liver, gut-brain, and gut-skeletal muscle axes. Video Abstract.

Inflammation and cardiometabolic diseases induced by persistent organic pollutants and nutritional interventions: Effects of multi-organ interactions.

The development and outcome of inflammatory diseases are associated with genetic and lifestyle factors, which include chemical and nonchemical stressors. Persistent organic pollutants (POPs) are major groups of chemical stressors. For example, dioxin-like polychlorinated biphenyls (PCBs), per- and polyfluoroalkyl substances (PFASs), and polybrominated diphenyl ethers (PBDEs) are closely associated with the incidence of inflammatory diseases. The pathology of environmental chemical-mediated inflammatory diseases is complex and may involve disturbances in multiple organs, including the gut, liver, brain, vascular tissues, and immune systems. Recent studies suggested that diet-derived nutrients (e.g., phytochemicals, vitamins, unsaturated fatty acids, dietary fibers) could modulate environmental insults and affect disease development, progression, and outcome. In this article, mechanisms of environmental pollutant-induced inflammation and cardiometabolic diseases are reviewed, focusing on multi-organ interplays and highlighting recent advances in nutritional strategies to improve the outcome of cardiometabolic diseases associated with environmental exposures. In addition, advanced system biology approaches are discussed, which present unique opportunities to unveil the complex interactions among multiple organs and to fuel the development of precision intervention strategies in exposed individuals.

The role of perfluorooctane sulfonic acid (PFOS) exposure in inflammation of intestinal tissues and intestinal carcinogenesis.

PFAS (per- and polyfluoroalkyl substances) are organofluorine substances that are used commercially in products like non-stick cookware, food packaging, personal care products, fire-fighting foam, etc. These chemicals have several different subtypes made of varying numbers of carbon and fluorine atoms. PFAS substances that have longer carbon chains, such as PFOS (perfluorooctane sulfonic acid), can potentially pose a significant public health risk due to their ability to bioaccumulate and persist for long periods of time in the body and the environment. The National Academies Report suggests there is some evidence of PFOS exposure and gastrointestinal (GI) inflammation contributing to ulcerative colitis. Inflammatory bowel diseases such as ulcerative colitis are precursors to colorectal cancer. However, evidence about the association between PFOS and colorectal cancer is limited and has shown contradictory findings. This review provides an overview of population and preclinical studies on PFOS exposure and GI inflammation, metabolism, immune responses, and carcinogenesis. It also highlights some mitigation approaches to reduce the harmful effects of PFOS on GI tract and discusses the dietary strategies, such as an increase in soluble fiber intake, to reduce PFOS-induced alterations in cellular lipid metabolism. More importantly, this review demonstrates the urgent need to better understand the relationship between PFOS and GI pathology and carcinogenesis, which will enable development of better approaches for interventions in populations exposed to high levels of PFAS, and in particular to PFOS.

Metabolomic, Lipidomic, Transcriptomic, and Metagenomic Analyses in Mice Exposed to PFOS and Fed Soluble and Insoluble Dietary Fibers.

BACKGROUND: Perfluorooctane sulfonate (PFOS) is a persistent environmental pollutant that has become a significant concern around the world. Exposure to PFOS may alter gut microbiota and liver metabolic homeostasis in mammals, thereby increasing the risk of cardiometabolic diseases. Diets high in soluble fibers can ameliorate metabolic disease risks. OBJECTIVES: We aimed to test the hypothesis that soluble fibers (inulin or pectin) could modulate the adverse metabolic effects of PFOS by affecting microbe-liver metabolism and interactions. METHODS: Male C57BL/6J mice were fed an isocaloric diet containing different fibers: a) inulin (soluble), b) pectin (soluble), or c) cellulose (control, insoluble). The mice were exposed to PFOS in drinking water (3µg/g per day) for 7 wk. Multi-omics was used to analyze mouse liver and cecum contents. RESULTS: In PFOS-exposed mice, the number of differentially expressed genes associated with atherogenesis and hepatic hyperlipidemia were lower in those that were fed soluble fiber than those fed insoluble fiber. Shotgun metagenomics showed that inulin and pectin protected against differences in microbiome community in PFOS-exposed vs. control mice. It was found that the plasma PFOS levels were lower in inulin-fed mice, and there was a trend of lower liver accumulation of PFOS in soluble fiber-fed mice compared with the control group. Soluble fiber intake ameliorated the effects of PFOS on host hepatic metabolism gene expression and cecal content microbiome structure. DISCUSSIONS: Results from metabolomic, lipidomic, and transcriptomic studies suggest that inulin- and pectin-fed mice were less susceptible to PFOS-induced liver metabolic disturbance, hepatic lipid accumulation, and transcriptional changes compared with control diet-fed mice. Our study advances the understanding of interaction between microbes and host under the influences of environmental pollutants and nutrients. The results provide new insights into the microbe-liver metabolic network and the protection against environmental pollutant-induced metabolic diseases by high-fiber diets. https://doi.org/10.1289/EHP11360.

Untargeted Stable Isotope Probing of the Gut Microbiota Metabolome Using 13C-Labeled Dietary Fibers.

The gut microbiome generates numerous metabolites that exert local effects and enter the circulation to affect the functions of many organs. Despite extensive sequencing-based characterization of the gut microbiome, there remains a lack of understanding of microbial metabolism. Here, we developed an untargeted stable isotope-resolved metabolomics (SIRM) approach for the holistic study of gut microbial metabolites. Viable microbial cells were extracted from fresh mice feces and incubated anaerobically with 13C-labeled dietary fibers including inulin or cellulose. High-resolution mass spectrometry was used to monitor 13C enrichment in metabolites associated with glycolysis, the Krebs cycle, the pentose phosphate pathway, nucleotide synthesis, and pyruvate catabolism in both microbial cells and the culture medium. We observed the differential use of inulin and cellulose as substrates for biosynthesis of essential and non-essential amino acids, neurotransmitters, vitamin B5, and other coenzymes. Specifically, the use of inulin for these biosynthetic pathways was markedly more efficient than the use of cellulose, reflecting distinct metabolic pathways of dietary fibers in the gut microbiome, which could be related with host effects. This technology facilitates deeper and holistic insights into the metabolic function of the gut microbiome (Metabolomic Workbench Study ID: ST001651).

Co-exposure to PCB126 and PFOS increases biomarkers associated with cardiovascular disease risk and liver injury in mice.

Polychlorinated biphenyl (PCB)126 and perfluorooctane sulfonic acid (PFOS) are halogenated organic pollutants of high concern. Exposure to these chemicals is ubiquitous, and can lead to potential synergistic adverse effects in individuals exposed to both classes of chemicals. The present study was designed to identify interactions between PCB126 and PFOS that might promote acute changes in inflammatory pathways associated with cardiovascular disease and liver injury. Male C57BL/6 mice were exposed to vehicle, PCB126, PFOS, or a mixture of both pollutants. Plasma and liver samples were collected at 48 h after exposure. Changes in the expression of hepatic genes involved in oxidative stress, inflammation, and atherosclerosis were investigated. Plasma and liver samples was analyzed using untargeted lipidomic method. Hepatic mRNA levels for Nqo1, Icam1, and PAI1 were significantly increased in the mixture-exposed mice. Plasma levels of PAI1, a marker of fibrosis and thrombosis, were also significantly elevated in the mixture-exposed group. Liver injury was observed only in the mixture-exposed mice. Lipidomic analysis revealed that co-exposure to the mixture enhanced hepatic lipid accumulation and elevated oxidized phospholipids levels. In summary, this study shows that acute co-exposure to PCB126 and PFOS in mice results in liver injury and increased cardiovascular disease risk.

Prebiotic inulin consumption reduces dioxin-like PCB 126-mediated hepatotoxicity and gut dysbiosis in hyperlipidemic Ldlr deficient mice.

Exposure to some environmental pollutants increases the risk of developing inflammatory disorders such as steatosis and cardiometabolic diseases. Diets high in fermentable fibers such as inulin can modulate the gut microbiota and lessen the severity of pro-inflammatory diseases, especially in individuals with elevated circulating cholesterol. Thus, we aimed to test the hypothesis that hyperlipidemic mice fed a diet enriched with 8% inulin would be protected from the pro-inflammatory toxic effects of PCB 126. Four groups of male Ldlr-/- mice were fed a high cholesterol diet containing 8% inulin or 8% cellulose (control) for 12 weeks. At weeks 2 and 4, mice were exposed to PCB 126 or vehicle (control). PCB 126 exposure induced wasting and impaired glucose tolerance, which were attenuated by inulin consumption. PCB 126 exposure induced hepatic lipid accumulation and increased inflammatory gene expression, which were both decreased by inulin consumption. In addition, inulin feeding decreased atherosclerotic lesion development in the aortic root and modulated the expression of enzymes related to glycolysis. Finally, 16S rRNA sequencing of gut microbial populations showed that PCB 126 modulated multiple microbiota genera (e.g., 3-fold decrease in Allobaculum and 3-fold increase in Coprococcus) which were normalized in inulin fed mice. Overall our data support the hypothesis that a dietary intervention that targets the gut microbiota may be an effective means of attenuating dioxin-like pollutant-mediated diseases.

Dietary inulin decreases circulating ceramides by suppressing neutral sphingomyelinase expression and activity in mice.

Elevated circulating levels of ceramides (Cers) are associated with increased risk of cardiometabolic diseases, and Cers may play a causative role in metabolic dysfunction that precedes cardiac events, such as mortality as a result of coronary artery disease. Although the mechanisms involved are likely complex, these associations suggest that lowering circulating Cer levels could be protective against cardiovascular diseases. Conversely, dietary fibers, such as inulin, have been reported to promote cardiovascular and metabolic health. However, the mechanisms involved in these protective processes also are not well understood. We studied the effects of inulin on lipid metabolism with a model of atherosclerosis in LDL receptor-deficient mice using lipidomics and transcriptomics. Plasma and tissues were collected at 10 days and/or 12 weeks after feeding mice an atherogenic diet supplemented with inulin or cellulose (control). Compared with controls, inulin-fed mice displayed a decreased C16:0/C24:0 plasma Cer ratio and lower levels of circulating Cers associated with VLDL and LDL. Liver transcriptomic analysis revealed that Smpd3, a gene that encodes neutral SMase (NSMase), was downregulated by 2-fold in inulin-fed mice. Hepatic NSMase activity was 3-fold lower in inulin-fed mice than in controls. Furthermore, liver redox status and compositions of phosphatidylserine and FFA species, the major factors that determine NSMase activity, were also modified by inulin. Taken together, these results showed that, in mice, inulin can decrease plasma Cer levels through reductions in NSMase expression and activity, suggesting a mechanism by which fiber could reduce cardiometabolic disease risk.

Application of metabolomics to characterize environmental pollutant toxicity and disease risks.

The increased incidence of non-communicable human diseases may be attributed, at least partially, to exposures to toxic chemicals such as persistent organic pollutants (POPs), air pollutants and heavy metals. Given the high mortality and morbidity of pollutant exposure associated diseases, a better understanding of the related mechanisms of toxicity and impacts on the endogenous host metabolism are needed. The metabolome represents the collection of the intermediates and end products of cellular processes, and is the most proximal reporter of the body's response to environmental exposures and pathological processes. Metabolomics is a powerful tool for studying how organisms interact with their environment and how these interactions shape diseases related to pollutant exposure. This mini review discusses potential biological mechanisms that link pollutant exposure to metabolic disturbances and chronic human diseases, with a focus on recent studies that demonstrate the application of metabolomics as a tool to elucidate biochemical modes of actions of various environmental pollutants. In addition, classes of metabolites that have been shown to be modulated by multiple environmental pollutants will be discussed with an emphasis on their use as potential early biomarkers of disease risks. Taken together, metabolomics is a useful and versatile tool for characterizing the disease risks and mechanisms associated with various environmental pollutants.

PCB 126 induces monocyte/macrophage polarization and inflammation through AhR and NF-κB pathways.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that contribute to inflammatory diseases such as atherosclerosis, and macrophages play a key role in the overall inflammatory response. Depending on specific environmental stimuli, macrophages can be polarized either to pro-inflammatory (e.g., M1) or anti-inflammatory (e.g., M2) phenotypes. We hypothesize that dioxin-like PCBs can contribute to macrophage polarization associated with inflammation. To test this hypothesis, human monocytes (THP-1) were differentiated to macrophages and subsequently exposed to PCB 126. Exposure to PCB 126, but not to PCB 153 or 118, significantly induced the expression of inflammatory cytokines, including TNFα and IL-1ß, suggesting polarization to the pro-inflammatory M1 phenotype. Additionally, monocyte chemoattractant protein-1 (MCP-1) was increased in PCB 126-activated macrophages, suggesting induction of chemokines which regulate immune cell recruitment and infiltration of monocytes/macrophages into vascular tissues. In addition, oxidative stress sensitive markers including nuclear factor (erythroid-derived 2)-like 2 (NFE2L2; Nrf2) and down-stream genes, such as heme oxygenase 1 (HMOX1) and NAD(P)H quinone oxidoreductase 1 (NQO1), were induced following PCB 126 exposure. Since dioxin-like PCBs may elicit inflammatory cascades through multiple mechanisms, we then pretreated macrophages with both aryl hydrocarbon receptor (AhR) and NF-κB antagonists prior to PCB treatment. The NF-κB antagonist BMS-345541 significantly decreased mRNA and protein levels of multiple cytokines by approximately 50% compared to PCB treatment alone, but the AhR antagonist CH-223191 was protective to a lesser degree. Our data demonstrate the involvement of PCB 126 in macrophage polarization and inflammation, indicating another important role of dioxin-like PCBs in the pathology of atherosclerosis.

Proteomic Analysis Reveals Novel Mechanisms by Which Polychlorinated Biphenyls Compromise the Liver Promoting Diet-Induced Steatohepatitis.

Environmental pollution contributes to fatty liver disease pathogenesis. Polychlorinated biphenyl (PCB) exposures have been associated with liver enzyme elevation and suspected steatohepatitis in cohort studies. Male mice treated with the commercial PCB mixture, Aroclor 1260 (20 mg/kg), and fed high fat diet (HFD) for 12 weeks developed steatohepatitis. Receptor-based modes of action including inhibition of the epidermal growth factor (EGF) receptor were previously proposed, but other mechanisms likely exist. Objectives were to identify and validate the pathways, transcription factors, and mechanisms responsible for the steatohepatitis associated with PCB and HFD coexposures. Comparative proteomics analysis was performed in archived mouse liver samples from the aforementioned chronic exposure study. Pathway and transcription factor analysis (TFA) was performed, and selected results were validated. Liver proteomics detected 1103 unique proteins. Aroclor 1260 upregulated 154 and downregulated 93 of these. Aroclor 1260 + HFD coexposures affected 55 pathways including glutathione metabolism, intermediary metabolism, and cytoskeletal remodeling. TFA of Aroclor 1260 treatment demonstrated alterations in the function of 42 transcription factors including downregulation of NRF2 and key nuclear receptors previously demonstrated to protect against steatohepatitis (e.g., HNF4α, FXR, PPARα/δ/γ, etc.). Validation studies demonstrated that Aroclor 1260 significantly reduced HNF4α protein levels, while Aroclor 1260 + HFD reduced expression of the HNF4α target gene, albumin, in vivo. Aroclor 1260 attenuated EGF-dependent HNF4α phosphorylation and target gene activation in vitro. Aroclor 1260 reduced levels of NRF2, its target genes, and glutathione in vivo. Aroclor 1260 attenuated EGF-dependent NRF2 upregulation, in vitro. Aroclor 1260 indirectly activated hepatic stellate cells in vitro via induction of hepatocyte-derived TGFß. PCB exposures adversely impacted transcription factors regulating liver protection, function, and fibrosis. PCBs, thus, compromised the liver by reducing its protective responses against nutritional stress to promote diet-induced steatohepatitis. The identified mechanisms by which environmental pollutants influence fatty liver disease pathogenesis require confirmation in humans.

Hepatic metabolomics reveals that liver injury increases PCB 126-induced oxidative stress and metabolic dysfunction.

The deleterious effects of PCB 126 are complex, and the role of the liver in modifying toxic insult is not well understood. We utilized metabolomics approaches to compare liver metabolites significantly affected by PCB 126 in control mice and a diet induced liver injury mouse model. In this 14-week study, mice were fed either an amino acid supplemented control diet (CD) or a methionine-choline deficient diet (MCD) which promoted nonalcoholic steatohepatitis (NASH) and were subsequently exposed to PCB 126. The liver metabolome was profiled by a global metabolomic analysis using LC-MS. There were clear differences between PCB 126 exposed and control mice in the hepatic metabolomic profiles (216 and 266 metabolites were altered in CD-fed and MCD-fed mice respectively after PCB 126 exposure). PCB 126 modulated glycerophospholipid metabolism, glutathione metabolism, and CoA biosynthesis pathways irrespective of diet; indicating that the disturbance in lipid metabolism and thiol metabolites are general markers of PCB 126 exposure irrespective of liver health. Additionally, metabolites associated with oxidative stress and mitochondrial dysfunction were greatly elevated in PCB 126 exposed mice with compromised livers (e.g., 4-hydroxy-nonenal glutathione, oxylipids, uric acid, and acylcarnitines). Moreover, PCB 126 exposure downregulated redox genes, and the effect was more pronounced in liver injury mice. In conclusion, this study demonstrates that PCB 126 could induce oxidative stress and metabolic dysfunction, and pre-existing liver injury can markedly modify PCB 126-induced metabolic changes. Using metabolic profiling, this study suggests mechanism of enhanced PCB 126 toxicity under liver injury settings.

Environmental pollutant-mediated disruption of gut microbial metabolism of the prebiotic inulin.

Exposure to environmental pollutants is associated with a greater risk for metabolic diseases including cardiovascular disease. Pollutant exposure can also alter gut microbial populations that may contribute to metabolic effects and progression of inflammatory diseases. Short-chain fatty acids (SCFAs), produced from gut fermentation of dietary carbohydrates, such as inulin, exert numerous effects on host energy metabolism and are linked to a reduced risk of diseases. The hypothesis was that exposure to dioxin-like pollutants modulate gut microbial viability and/or fermentation processes. An inulin-utilizing isolate was collected from murine feces, characterized and used in subsequent experiments. Exposure to polychlorinated biphenyl, PCB 126 impeded bacterial viability of the isolate at concentrations of 20 and 200 µM. PCB 126 exposure also resulted in a significant loss of intracellular potassium following exposure, indicating cell membrane disruption of the isolate. Furthermore, total fecal microbe samples from mice were harvested, resuspended and incubated for 24 h in anaerobic media containing inulin with or without PCB 126. HPLC analysis of supernatants revealed that PCB 126 exposure reduced succinic acid production, but increased propionate production, both of which can influence host glucose and lipid metabolism. Overall, the presented evidence supports the idea that pollutant exposure may contribute to alterations in host metabolism through gut microbiota-dependent mechanisms, specifically through bacterial fermentation processes or membrane disruption.

Dioxin-like PCB 126 increases intestinal inflammation and disrupts gut microbiota and metabolic homeostasis.

The gut microbiome is sensitive to diet and environmental exposures and is involved in the regulation of host metabolism. Additionally, gut inflammation is an independent risk factor for the development of metabolic diseases, specifically atherosclerosis and diabetes. Exposures to dioxin-like pollutants occur primarily via ingestion of contaminated foods and are linked to increased risk of developing cardiometabolic diseases. We aimed to elucidate the detrimental impacts of dioxin-like pollutant exposure on gut microbiota and host gut health and metabolism in a mouse model of cardiometabolic disease. We utilized 16S rRNA sequencing, metabolomics, and regression modeling to examine the impact of PCB 126 on the microbiome and host metabolism and gut health. 16S rRNA sequencing showed that gut microbiota populations shifted at the phylum and genus levels in ways that mimic observations seen in chronic inflammatory diseases. PCB 126 reduced cecum alpha diversity (0.60 fold change; p = 0.001) and significantly increased the Firmicutes to Bacteroidetes ratio (1.63 fold change; p = 0.044). Toxicant exposed mice exhibited quantifiable concentrations of PCB 126 in the colon, upregulation of Cyp1a1 gene expression, and increased markers of intestinal inflammation. Also, a significant correlation between circulating Glucagon-like peptide-1 (GLP-1) and Bifidobacterium was evident and dependent on toxicant exposure. PCB 126 exposure disrupted the gut microbiota and host metabolism and increased intestinal and systemic inflammation. These data imply that the deleterious effects of dioxin-like pollutants may be initiated in the gut, and the modulation of gut microbiota may be a sensitive marker of pollutant exposures.

The role of nutrition in influencing mechanisms involved in environmentally mediated diseases.

Human exposure to environmental contaminants such as persistent chlorinated organics, heavy metals, pesticides, phthalates, flame retardants, electronic waste and airborne pollutants around the world, and especially in Southeast Asian regions, are significant and require urgent attention. Given this widespread contamination and abundance of such toxins as persistent organic pollutants (POPs) in the ecosystem, it is unlikely that remediation alone will be sufficient to address the health impacts associated with this exposure. Furthermore, we must assume that the impact on health of some of these contaminants results in populations with extraordinary vulnerabilities to disease risks. Further exacerbating risk; infectious diseases, poverty and malnutrition are common in the Southeast Asian regions of the world. Thus, exploring preventive measures of environmental exposure and disease risk through new paradigms of environmental toxicology, optimal and/or healthful nutrition and health is essential. For example, folic acid supplementation can lower blood arsenic levels, and plant-derived bioactive nutrients can lower cardiovascular and cancer risks linked to pollutant exposure. Data also indicate that diets enriched with bioactive food components such as polyphenols and omega-3 polyunsaturated fatty acids can prevent or decrease toxicant-induced inflammation. Thus, consuming healthy diets that exhibit high levels of antioxidant and anti-inflammatory properties, is a meaningful way to reduce the vulnerability to non-communicable diseases linked to environmental toxic insults. This nutritional paradigm in environmental toxicology requires further study in order to improve our understanding of the relationship between nutrition or other lifestyle modifications and toxicant-induced diseases. Understanding mechanistic relationships between nutritional modulation of environmental toxicants and susceptibility to disease development are important for both cumulative risk assessment and the design and implementation of future public health programs and behavioral interventions.

Relationship between serum trimethylamine N-oxide and exposure to dioxin-like pollutants.

Trimethylamine N-oxide (TMAO) is a diet and gut microbiota-derived metabolite that has been linked to cardiovascular disease risk in human studies and animal models. TMAO levels show wide inter and intra individual variability in humans that can likely be accounted for by multiple factors including diet, the gut microbiota, levels of the TMAO generating liver enzyme Flavin-containing monooxygenase 3 (FMO3) and kidney function. We recently found that dioxin-like (DL) environmental pollutants increased FMO3 expression to elevate circulating diet-derived TMAO in mice, suggesting that exposure to this class of pollutants might also contribute to inter-individual variability in circulating TMAO levels in humans. To begin to explore this possibility we examined the relationship between body burden of DL pollutants (reported by serum lipid concentrations) and serum TMAO levels (n = 340) in the Anniston, AL cohort, which was highly exposed to polychlorinated biphenyls (PCBs). TMAO concentrations in archived serum samples from the Anniston Community Health Survey (ACHS-II) were measured, and associations of TMAO with 28 indices of pollutant body burden, including total dioxins toxic equivalent (TEQ), were quantified. Twenty-three (22 after adjustment for multiple comparisons) of the 28 indices were significantly positively associated with TMAO. Although the design of ACHS-II does not enable quantitative assessment of the contributions of previously known determinants of TMAO variability to this relationship, limited multivariate modeling revealed that total dioxins TEQ was significantly associated with TMAO among females (except at high BMIs) but not among males. Our results from this cross-sectional study indicate that exposure to DL pollutants may contribute to elevated serum TMAO levels. Prospective longitudinal studies will be required to assess the joint relationship between DL pollutant exposures, other determinants of TMAO, and health outcomes.