大神 信孝

BACKGROUND: There is no information about the clinical implications and kinetics of zinc (Zn) in the nasal cavity, a center of allergic inflammation, and serum in subjects with allergic rhinitis (AR). OBJECTIVE: Effects of intranasal Zn on symptoms before and after allergen provocation were investigated in humans and mice with or without AR. METHODS: The first clinical follow-up study for Zn levels in nasal epithelial lining fluid (ELF) and serum was conducted in 57 control subjects and 44 patients with Japanese cedar pollinosis (JCP), a representative seasonal AR, from preseason to season. The clinical implications and kinetics of Zn levels in ELF and serum were further investigated in model mice with JCP. RESULTS: This clinical study showed that the Zn level in nasal ELF from patients with JCP was increased after pollen exposure and became significantly higher than that in nasal ELF from controls in the JCP season. Conversely, the serum Zn level in patients was decreased after pollen exposure and became significantly lower than that in the controls in the JCP season. To further investigate the clinical implication of Zn level, model mice that mimicked the kinetics of intranasal and serum Zn levels as well as the symptoms in patients with JCP were established. The mouse interventional study showed that the symptoms of mice with provocative JCP were significantly improved by treatment with the putative human-equivalent dose of Zn. The relative number of mucin-secreting goblet cells, a sign of provocative allergic rhinitis, in the mice was decreased by intranasal treatment with Zn. CONCLUSION: The study's behavioral and pathologic results indicate that an increased level of intranasal Zn can alleviate symptoms of AR.

BACKGROUND: People worldwide are routinely exposed to tellurium mainly via dietary ingestion. There has been no study to clarify the contribution of tellurium to blood pressure in humans or animals. METHODS: In this cross-sectional study conducted in a general population of 2592 residents in Japan, the associations of urinary tellurium levels with blood pressure and prevalence of hypertension were investigated. The potential sources of tellurium were also investigated. An interventional study in mice confirmed the effect of tellurium exposure on blood pressure. RESULTS: Linear and logistic regression analyses with consideration of confounders including urinary sodium-potassium ratio showed significant positive associations of urinary tellurium level with prevalence of hypertension and blood pressure. Cereals/beans and vegetables/fruits were determined to be potential dietary sources of tellurium exposure. Intermediary analysis suggested that increased intake of cereals/beans, but not that of vegetables/fruits, is positively associated with the tellurium-mediated risk of hypertension. Correspondingly, the mouse study showed that exposure to a putative human-equivalent dose of tellurium via drinking water increased blood pressure with an elevated level of urinary tellurium. The temporally increased blood pressure was decreased to the normal level by a break of tellurium exposure with a reduced level of urinary tellurium. CONCLUSIONS: The interdisciplinary approach provided the first evidence that tellurium exposure is a potential risk for increase of blood pressure. Since the human urinary tellurium level in this study is comparable with the levels in general populations in other Asian and European countries in previous studies, exposure to tellurium may be a latent universal risk for hypertension.

AIMS: There has been a shortage of human studies to elucidate the association between serum arsenic levels and the prevalence of hypertension. This study multidirectionally investigated associations among arsenic exposure, dietary ingestion, and the risk of hypertension by combined human epidemiological and mouse experimental studies. METHODS AND RESULTS: This study focused on the total arsenic level in fasting serum, a biomarker of arsenic exposure. Associations among ingestion frequencies of 54 diet items of Japanese food separated into six categories, total arsenic level in fasting serum, and the prevalence of hypertension were investigated in 2709 general people in Japan. Logistic regression analysis demonstrated a dose-dependent association between serum arsenic level and hypertension and a positive association between the ingestion of fish meat and hypertension. Further analysis showed that the latter association was fully mediated by increased fasting serum arsenic levels in humans. Similarly, oral exposure to the putative human-equivalent dose of arsenic species mixture with the same ratios in a common fish meat in Japan increased systolic blood pressure and arsenic levels in fasting serum in mice. CONCLUSION: This interdisciplinary approach suggests that fish-meat ingestion is a potential risk factor for arsenic-mediated hypertension. Because the increased consumption of fish meat is a recent global trend, health risks of the increased ingestion of arsenic via fish meat should be further investigated.

Ovarian cancers derived from endometrial cysts, also known as endometriosis in ovaries, are widespread histological types in Japan. Several studies suggest that zinc deficiency plays a role in endometriosis; however, the biological mechanism of zinc deficiency and endometrial cyst remains unknown. Thus, we investigated the association between zinc status and endometrial cysts. We measured the serum zinc levels in patients who had undergone surgery for endometrial cysts (n=19) and non-endometrial benign cysts (n=36). We analyzed cell proliferation, microarray data, and gene expression using N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a zinc chelator, in human immortalized endometrial epithelial cells (EMosis). The endometrial cyst group had considerably lower serum zinc levels than the non-endometrial benign cyst group. After adjusting for age, body mass index, alcohol consumption, smoking, and supplement use, endometrial cysts were markedly associated with serum zinc levels. EMosis cells treated with 5 μM TPEN demonstrated extensively increased proliferation compared to untreated cells. In the microarray analysis of EMosis cells treated with 5 μM TPEN, the enriched cellular components contained nucleoplasm, nuclear parts, and nuclear lumen. The upregulated biological processes included responses to hypoxia and decreased oxygen levels. The upregulated Kyoto Encyclopedia of Genes and Genomes pathway included the hypoxia-inducible factor-1 signaling pathway. EMosis cells treated with 5 μM TPEN demonstrated increased activator 1 (SRA1) expression and decreased AT-rich interaction domain 1A (ARID1A) expression. Protein-protein interaction network analysis indicated that ARID1A and SRA1 were associated with SMARCD1 and ATF1 among the differentially expressed genes in the microarray. EMosis cells treated with 5 μM TPEN revealed increased SRA1 mRNA levels and decreased ARID1A mRNA expression, whereas EMosis cells treated with 5 μM TPEN together with 10 μM zinc did not reveal changes in the mRNA levels of SRA1 or ARID1A compared with those without TPEN. These results suggest that zinc deficiency contributes to endometrial cyst development. Accordingly, zinc supplementation may suppress endometrial cyst development.

Harmful health effects of exposure to low-frequency noise (LFN) defined as noise with frequencies at ≤100 Hz on the circulatory system have been a concern. However, there has been no study on the effects of exposure to LFN on the circulatory system with consideration of its frequencies and decibels. In this study, the effects of short-term exposure to broad-band LFNs and their pure-tone components (pure-tone LFNs) on cutaneous blood flow in the extremities including the hands were investigated. In our fieldwork study, we first sampled some kinds of common broad-band LFNs. Our human study then showed that broad-band LFN with a narrower frequency range more strongly increased cutaneous blood flow than did broad-band LFN with a wider frequency range. Pure-tone LFNs of 70-100 Hz at ≤85 dB(Z), but not pure-tone LFNs exceeding 100 Hz, further increased levels of cutaneous blood flow. Our wavelet-transform spectrum analysis of cutaneous blood flow next revealed that the nitric oxide (NO)-dependent and -independent vascular activities of the vascular endothelium were specifically increased by exposure to pure-tone LFN. Our animal study again indicated that exposure to pure-tone LFN increased cutaneous blood flow in mice with impairments of bilateral inner ears as well as cutaneous blood flow in control mice, suggesting a limited effect of inner ear function on the LFN-mediated increase in cutaneous blood flow. The NO-dependent suppressive effect of pure-tone LFN on cutaneous blood flow was confirmed by inhibition of vascular endothelial activity through intravenous injection of an NO inhibitor in wild-type mice. Taken together, the results of this study demonstrated that the vascular endothelium is a target tissue of LFN and that NO is an effector of the LFN-mediated increase in cutaneous blood flow. Since improvement of peripheral circulation could generally promote human health, short-term exposure to LFN may be beneficial for health.

Hexavalent chromium [Cr(VI)], which has a strong corrosive effect, has been reported to cause perforation of the eardrum. Trivalent chromium [Cr(III)] also has a weak corrosive effect. However, there has been no study on the effects of exposure to Cr, either Cr(VI) or Cr(III), on hearing levels in animals or humans. In this study, the effect of Cr(III) exposure on hearing levels was determined in a human study. Then the reproducibility of the results obtained in the human study and the etiology were investigated in an animal study. The mean levels of total chromium (t-Cr) in hair and toenails from 100 Bangladeshi tannery workers were >20-fold and >360-fold higher, respectively, than those in hair and toenails from 49 Bangladeshi non-tannery workers (office workers). Multivariate analysis revealed decreases of hearing levels (DHLs) at 1 k and 4 k Hz, frequencies that are crucial for understanding language, but not at 8 k and 12 k Hz, in the tannery workers. Since >99.99% of t-Cr in the wastewater that the workers were in direct contact with in the tanneries was Cr(III), the epidemiological results suggest Cr(III)-mediated DHLs in the tannery workers. The results of animal experiments in this study further showed that treatment with eardrops but not intraperitoneal injection with the same amount of Cr(III) that tannery workers might be exposed to resulted in DHL with a damaged eardrum in mice. Previous studies suggested that Cr(III) can directly reach the eardrums of tannery workers via droplets in the air. Cr(III) could also reach the eardrum via picking an ear canal with a finger contaminated with tannery wastewater including Cr(III). Taken together, the results of both human and animal studies suggest the risk of DHLs caused by damage of the eardrum through external exposure to Cr(III) via the ear canal.

Chronic arsenic exposure from drinking water causes a variety of diseases and it is now recognized that at least 140 million people in 50 countries have been drinking water containing arsenic at levels above the WHO provisional guideline value of 10 μg/L. Long-term exposure to arsenic is associated with various types of cancers in humans including skin cancers. However, there is limited information on key molecules regulating arsenic-promoted carcinogenesis, and methods for the prevention and therapy of arsenic-promoted carcinogenesis have not yet been fully developed. Our in vitro study in human nontumorigenic HaCaT skin keratinocytes showed that calcitriol (activated vitamin D3, 1,25(OH)2D3) inhibited arsenic-mediated anchorage-independent growth with downregulations of cancer-related activation of MEK, ERK1/2 and AKT and activity of cell cycle. Moreover, calcitriol significantly repressed arsenic uptake in HaCaT cells with inhibition of expressions of aquaporin genes (AQP7, 9 and 10) which were modified by arsenic exposure. VDR, a vitamin D receptor, expression was significantly increased by arsenic exposure whereas calcitriol had no effect on its expression. These results suggest that treatment of calcitriol inhibits arsenic uptake via suppressions of aquaglyceroporin gene expressions resulting in inhibition of arsenic-promoted tumorigenesis in keratinocytes.

Water pollution caused by tannery wastewater is an important issue in developing countries. Most studies have focused on inorganic chemicals represented by chromium as a tannery-related main pollutant. This is the first study in which pollution of water by tannery-related organic chemicals was assessed by a combination of qualitative and quantitative analyses. Our quantitative analysis showed that the maximum concentration of total phenolic compounds (phenols), consisting of phenol, bisphenol F, p-cresol and chlorocresol, in canal water in a tannery built-up area in Bangladesh was >67-fold higher than the Environmental, Health and Safety (EHS) guideline value. Mapping of our results indicated tanneries as the sources of phenols pollution. Our original depurative, a hydrotalcite-like compound consisting of magnesium and iron (MF-HT), could adsorb all kinds of phenols and exhibited the highest phenol adsorption ability (115.8 mg/g) among reported hydrotalcite-like compounds. The levels of phenols in canal water samples were reduced to levels below the guideline value by using MF-HT with assistance of a photocatalytic reaction. Moreover, the mean level of chromium (112.2 mg/L) in canal water samples was decreased by 99.7% by using the depurative. Thus, the depurative has the potential for solving the problem of tannery-related water pollution by phenols and chromium.

Abstract Despite identification of arsenic intake from well drinking water in developing countries as a crucial hazard for health, the health effects of diet-mediated intake of arsenic on health in developed countries have remained unclear. The Japanese diet, which is regarded as a healthy diet, includes a high intake of seafoods that contain high levels of arsenic. The associations among intake of Japanese food including 54 food items classified into 6 categories, arsenic exposure and hypertension were investigated in 2,709 adults in Japan. Logistic regression analysis including serum sodium and potassium levels as confounders indicated a positive association between fasting serum level of arsenic (fsl-As) and prevalence of hypertension. Seaweed, bone-edible small fish and fish meat in seafoods were strong contributors to the increased fsl-As among the food items examined. Fish meat intake was identified as the greatest contributor to prevalence of hypertension. Since 94% of arsenic has been reported to be caused by dietary intake in Japan, our results suggest that increased fsl-As caused by intake of fish meat could be a potential risk for hypertension. Considering the worldwide trend of increased fish meat intake, arsenic in fish meat might be a new global hazardous material.

BACKGROUND: Air pollutants are suspected to affect pathological conditions of allergic rhinitis (AR). OBJECTIVES: After detecting Pb (375 μg/kg) in Japanese cedar pollen, the effects of intranasal exposure to Pb on symptoms of AR were investigated. METHODS: Pollen counts, subjective symptoms, and Pb levels in nasal epithelial lining fluid (ELF) were investigated in 44 patients with Japanese cedar pollinosis and 57 controls from preseason to season. Effects of intranasal exposure to Pb on symptoms were confirmed by using a mouse model of AR. RESULTS: Pb levels in ELF from patients were >40% higher than those in ELF from control subjects during the pollen season but not before the pollen season. Pb level in ELF was positively associated with pollen counts for the latest 4 days before visiting a hospital as well as scores of subjective symptoms. Intranasal exposure to Pb exacerbated symptoms in allergic mice, suggesting Pb as an exacerbation factor. Pb levels in ELF and nasal mucosa in Pb-exposed allergic mice were higher than those in Pb-exposed nonallergic mice, despite intranasally challenging the same amount of Pb. Because the increased Pb level in the nasal mucosa of Pb-exposed allergic mice was decreased after washing the nasal cavity, Pb on the surface of but not inside the nasal mucosa may have been a source of increased Pb level in ELF of allergic mice. CONCLUSIONS: Increased nasal Pb level partially derived from pollen could exacerbate subjective symptoms of AR, indicating Pb as a novel hazardous air pollutant for AR.

Hair graying is a representative sign of aging in animals and humans. However, the mechanism for hair graying with aging remains largely unknown. In this study, we found that the microscopic appearance of hair follicles without melanocyte stem cells (MSCs) and descendant melanocytes as well as macroscopic appearances of hair graying in RET-transgenic mice carrying RET oncogene (RET-mice) are in accordance with previously reported results for hair graying in humans. Therefore, RET-mice could be a novel model mouse line for age-related hair graying. We further showed hair graying with aging in RET-mice associated with RET-mediated acceleration of hair cycles, increase of senescent follicular keratinocyte stem cells (KSCs), and decreased expression levels of endothelin-1 (ET-1) in bulges, decreased endothelin receptor B (Ednrb) expression in MSCs, resulting in a decreased number of follicular MSCs. We then showed that hair graying in RET-mice was accelerated by congenitally decreased Ednrb expression in MSCs in heterozygously Ednrb-deleted RET-mice [Ednrb(+/-);RET-mice]. We finally partially confirmed common mechanisms of hair graying with aging in mice and humans. Taken together, our results suggest that age-related dysfunction between ET-1 in follicular KSCs and endothelin receptor B (Ednrb) in follicular MSCs via cumulative hair cycles is correlated with hair graying with aging.

BACKGROUND: The process for leather material production is carried out in developing countries using a large amount of trivalent chromium [Cr(III)]. Assesment of health risks for millions of workers in tanneries worldwide that are highly polluted with Cr(III) is needed. METHODS: Levels of total Cr and its chemical species in wastewater samples from tannery built-up areas of Bangladesh were investigated. Cr-mediated renal damage was assessed in 100 male tannery workers by epidemiological analysis consisting of questionnaires and measurements of levels of urinary Cr and urinary renal damage markers [urinary levels of total protein and kidney injury molecule-1 (KIM-1)]. RESULTS: High levels of total Cr (mean ± standard deviation = 1,908,762 ± 703,450 μg/L) were detected in wastewater samples from 13 sites of tanneries. More than 99.99% of total Cr in the wastewater was Cr(III), indicating that workers in the tanneries were exposed to large concentrations of Cr(III). Cr levels (mean ± standard, 2.89 ± 4.23 μg/g creatinine) in urine samples from the workers in tanneries were >24-fold higher than the levels in a general population previously reported. Multivariate analysis showed significant correlations between urinary levels of Cr and urinary levels of renal damage biomarkers. Nagelkerke Pseudo R2 values also showed that Cr level is the strongest contributor to the levels of renal damage biomarkers in the workers. CONCLUSION: Our results newly suggest that excess exposure to Cr(III) could be a risk for renal damage in humans.

Well water could be a stable source of drinking water. Recently, the use of well water as drinking water has been encouraged in developing countries. However, many kinds of disorders caused by toxic elements in well drinking water have been reported. It is our urgent task to resolve the global issue of element-originating diseases. In this review article, our multidisciplinary approaches focusing on oncogenic toxicities and disturbances of sensory organs (skin and ear) induced by arsenic and barium are introduced. First, our environmental monitoring in developing countries in Asia showed elevated concentrations of arsenic and barium in well drinking water. Then our experimental studies in mice and our epidemiological studies in humans showed arsenic-mediated increased risks of hyperpigmented skin and hearing loss with partial elucidation of their mechanisms. Our experimental studies using cultured cells with focus on the expression and activity levels of intracellular signal transduction molecules such as c-SRC, c-RET, and oncogenic RET showed risks for malignant transformation and/or progression arose from arsenic and barium. Finally, our original hydrotalcite-like compound was proposed as a novel remediation system to effectively remove arsenic and barium from well drinking water. Hopefully, comprehensive studies consisting of (1) environmental monitoring, (2) health risk assessments, and (3) remediation will be expanded in the field of environmental health to prevent various disorders caused by environmental factors including toxic elements in drinking water.

Health risks attributed to low-frequency noise (LFN) exposure are a serious global issue. Therefore, the development of a method for a prevention based upon risk assessments for LFN is important. Previously in vivo exposure of mice to LFN at 100 Hz, 95 dB for 1 hr produced imbalance with breakage of the otoconial membrane, which covers hair cells as well as impaired activity of hair cells in the vestibule. However, methods for inhibition of LFN-mediated imbalance have not been developed. At present, there are no apparent techniques available with in vitro or ex vivo assessments to evaluate LFN-mediated imbalance by direct administration of preventive chemicals into the vestibule. Our findings demonstrated the usefulness of an explant culture of the utricle with a fluorescent styryl dye, FM1-43FX. In addition, examination of the morphology of the otoconial membrane with explant cultures of utricles was conducted to determine the risk of LFN. Ex vivo exposure of the utricle to LFN at 100 Hz, 95 dB for 1 hr induced breaks in the otoconial membrane as well as decreased uptake of FM1-43FX in hair cells. Taken together, the results of this study provide a novel technique for assessing the risk of LFN exposure using an ex vivo experiment.

<p>The inner ears contain the organ of Corti, vestibule and semicircular canal. The organ of Corti is crucial for hearing, while the vestibule and semicircular canal play important roles in maintaining balance. Exposure to noise at excessive levels is known to cause damages of the inner ears, resulting in noise-induced hearing loss. On the other hand, noise levels (dB) are used for the evaluation of health risks by exposure to noise, although noise consists of sound with broad frequencies (Hz). Thus, information about the frequency-dependent effect of noise on health is largely unknown. In this review, we first introduce noise-induced hearing loss caused by exposure to audible noise. We then describe the imbalance in mice exposed to low-frequency noise (100 Hz).</p>