Annual Meeting of the Japanese Society of Toxicology

Arsenic in drinking water is a worldwide health problem that is associated with cardiovascular disease, but the exact mechanism was unknown 15 years ago. Treatment with inorganic arsenite (As^III) inhibited acetylcholine-induced relaxation of aortic rings by inhibiting production of nitric oxide in endothelium and increased vasoconstrictions induced by several agonists mediated through calcium-sensitization in smooth muscles. In vivo studies revealed that intravenous administration of arsenite altered the blood pressure by agonists in conscious rats. In addition, arsenite induced in vitro aggregation when platelets were exposed to sub-threshold challenge by several agonists. Moreover, arsenite significantly enhanced procoagulant activity of human platelets as well. Consistent with the in vitro studies, 4-week ingestion of arsenite-contaminated drinking water resulted in enhanced arterial thrombosis. All these results provided new insights into the mechanisms of arsenic-induced cardiovascular disease. Until now, mechanism remains elusive for arsenic-associated cancer. Very recently, we demonstrated that arsenic promotes tumor metastasis through activating platelets and thereby, stimulating tumor cell-induced platelet aggregation (TCPA), a central contributor to immune-evasion and extravasation of tumor. In human platelets, arsenite promoted TCPA induced by cancer cells that include melanoma, lung carcinoma and sarcoma. Consistently, arsenite enhanced tumor cell extravasation; namely, the adhesion of tumor cells to vascular endothelial cells and extracellular matrix, and invasion in vitro. Importantly, subchronic ingestion of drinking water contaminated with arsenic lead to increased tumor metastasis in mouse. Of a particular note, arsenite-promoted metastasis was abolished by blockers of platelet activation like aspirin, demonstrating that anti-platelet agents may be effective for preventing arsenic-associated cancer death.

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In the modern day, risk analysis is applied to almost all activities concerning food safety. The international organization such as Codex, the risk analysis is the main policy of the commission and it has been the obligation of every codex committee to use risk analysis as the guiding principle of its work. The risk analysis principle composes of three components, comprising of risk assessment, risk management, and risk communication. The purely scientific component is risk assessment as known. Toxicology is very essential science for the risk assessment component. Risk assessment component composes of four main steps, all steps need different scientific knowledge and techniques. The four steps are hazard identification, hazard characterization, exposure assessment, and risk characterization. Especially, the steps on hazard identification and hazard characterization need knowledge and technique of Toxicology. Both steps need toxicological testing, mainly in animals. However, at present toxicologist and allied scientists are trying to find some in vitro toxicity testing method to avoid using animal, as the animal welfare and ethic become more and more restricted. Anyhow, there is still no appropriate technique found to be able to totally replace animal toxicity testing.
The exposure step need some toxicological knowledge and other related science as food consumption survey in case of food safety, exposure study model in case of inhalation and skin penetration as in household and environmental hazard. The last step, risk characterization need the outcome of the toxicology testing, exposure assessment and risk calculation techniques to assess the risk level of the chemical concern. The detail discussion will be presented on the essential of toxicology on the risk assessment steps. Some techniques on the exposure assessment will also be mentioned. The establishment of Thailand Risk Assessment and Surveillance Center (TRAC) for food safety will be briefly presented.

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Obesity is commonly ascribed to an imbalance between caloric intake and energy expenditure - the thermodynamic, or "calories in - calories out" model. However a growing body of evidence points supports the contributions of other factors in the obesity epidemic. We previously showed that in utero exposure of pregnant F0 mice to the obesogen tributyltin (TBT) led to increased white adipose depot weight, increased hepatic fat storage and a bias of mesenchymal stem cells toward the adipogenic fate through the F3 generation. In a replicated transgenerational study, we found that exposure of F0 animals to TBT throughout pregnancy and lactation predisposed male F4 descendants of TBT-treated animals to weight gain and obesity when challenged with a higher fat diet later in life. The TBT group showed impaired ability to mobilize fat during fasting periods of fasting, accompanied by elevated serum levels of leptin. Limited fat mobilization and elevated leptin levels suggest that fat accumulation results from leptin resistance. These are hallmarks of the "thrifty phenotype" in which an individual stores more of the calories consumed and resists weight loss during times of limited food availability. Integrated methylome and transcriptome analysis from fat and liver of F4 animals revealed that ancestral TBT exposure led to changes in global DNA methylation and concomitant changes in gene expression. Our results show that ancestral, in utero exposure to TBT alters chromatin structure to modulate expression of genes important for fat storage and mobilization

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Nuclear factor erythroid 2-related factor 1 (NFE2L1, also known as NRF1), an ubiquitously expressed CNC-bZIP protein, is an important regulator of antioxidant response, proteasome homeostasis, genetic stability, mitochondrial respiration, inflammation, lipid metabolism and cell differentiation. With regard to the relevance of NRF1 to toxicology, emerging evidence reveals that toxic metals, such as arsenic, may activate NRF1-mediated adaptive antioxidant response. In addition, silencing of Nfe2l1 may affect various types of cells to the toxicity of oxidative stressors and other toxicants. Recently, we found that silencing of Nfe2l1 in mouse pancreatic β-cells, led to a phenotype markedly resembling pre-T2D conditions with disrupted glucose metabolism and impaired insulin secretion. The impaired glucose responsiveness due to Nfe2l1 silencing is likely a result of aberrant expression of a group of glucose metabolic enzymes. The findings demonstrated an important role of NRF1 in regulating glucose metabolism and insulin secretion in pancreatic β-cells and characterized NRF1 as a key transcription factor that regulates the coupling between glycolysis and mitochondrial metabolism as well as insulin secretion. On the other hand, mature adipocyte-specific knockout mice (Nfe2l1(f)-KO) developed age-dependent leanness and abnormal fat distribution. Notably, adult Nfe2l1(f)-KO mice exhibited a dramatically reduced mass of subcutaneous adipose tissue (SAT). Histomorphometric analysis of SAT and visceral adipose tissue invariably showed adipocyte hypertrophy and severe adipose inflammation in Nfe2l1(f)-KO mice. Moreover, Nfe2l1(f)-KO mice exhibited a metabolic syndrome with reduced ectopic lipid accumulation. Mechanistic studies revealed that Nfe2l1 deficiency disturbed the dynamic of lipolysis in adipocytes, leading to adipocyte hypertrophy followed by inflammation, pyroptosis, and insulin resistance. The findings established a novel role of NRF1 in regulating adipose tissue plasticity and metabolic profile, the disruption of which can lead to altered fat distribution and impaired glucose and lipid homeostasis. Taken together, our studies highlight the important regulatory roles of NRF1 in metabolic homeostasis of glucose and lipid. Clearly, the relevance and importance of NRF1 in mechanistic toxicology and risk assessment of toxicants, in particular oxidative stressors, need further investigation.

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