Most diseases are thought to arise from interactions between environmental factors and the host genotype. To detect gene-environment interactions in the development of lifestyle-related diseases, and especially cancer, the Japan Multi-institutional Collaborative Cohort (J-MICC) Study was launched in 2005. We initiated a cross-sectional study to examine associations of genotypes with lifestyle and clinical factors, as assessed by questionnaires and medical examinations. The 4519 subjects were selected from among participants in the J-MICC Study in 10 areas throughout Japan. In total, 108 polymorphisms were chosen and genotyped using the Invader assay. The study group comprised 2124 men and 2395 women with a mean age of 55.8 ± 8.9 years (range, 35-69 years) at baseline. Among the 108 polymorphisms examined, 4 were not polymorphic in our study population. Among the remaining 104 polymorphisms, most variations were common (minor allele frequency ≥0.05 for 96 polymorphisms). The allele frequencies in this population were comparable with those in the HapMap-JPT data set for 45 Japanese from Tokyo. Only 5 of 88 polymorphisms showed allele-frequency differences greater than 0.1. Of the 108 polymorphisms, 32 showed a highly significant difference in minor allele frequency among the study areas (P < 0.001). This comprehensive data collection on lifestyle and clinical factors will be useful for elucidating gene-environment interactions. In addition, it is likely to be an informative reference tool, as free access to genotype data for a large Japanese population is not readily available.
Osteoporosis is a chronic skeletal condition characterized by impaired bone strength and increased risk of fracture. This disorder causes notable morbidity, deterioration in quality of life (QOL)and mortality in the elderly due to associated with fragility fractures of the spine, hip and wrist. Moreover, the treatment of osteoporotic fractures is also associated with a huge economic cost for society. To avoid the fragility fracture, prevention of osteoporosis and fall down are of great importance. For that purpose, not only pharmacological therapy(mainly by antiresorptive medications) in middle-aged and elderly individuals but also non-pharmacological intervention through lifestyle modification will become important in adolescents and young adults from the early life. Lifestyle modification emphasizing bone health such as adequate calcium, vitamin D and vitamin K nutrition, restriction of caffeine and alcohol consumption, and avoidance of tobacco are essential to the management of osteoporosis risk. Balance and strength training also play important roles in the improvement of bone strength. Most of the risk and preventive factors of osteoporosis are common to those of other lifestylerelated diseases. Therefore, lifestyle modification emphasizing bone health from the early life will contribute to avoid not only fragility fracture but also other lifestyle-related diseases, and will contribute to maintenance or improvement of QOL.
Mineyoshi Hiyoshi, Hiroaki Konishi, Hirokazu Uemura, Hideki Matsuzaki, Hideo Tsukamoto, Ryusuke Sugimoto, Hideo Takeda, Satoru Dakeshita, Atsushi Kitayama, Hidenobu Takami, Fusakazu Sawachika, Hiroshi Kido and Kokichi Arisawa : D-dopachrome tautomerase is a candidate for key proteins to protect the rat liver damaged by carbon tetrachloride, Toxicology, Vol.255, No.1,2, 6-14, 2009.
(要約)
Carbon tetrachloride (CCl4) is known to induce liver damage. Animal experiments with CCl4 injections have revealed many findings, especially mechanisms of liver damage and liver regeneration. Recently, proteomic approaches have been introduced in various studies to evaluate the quantitative and qualitative changes in the comprehensive proteome level. The aim of this research is to elucidate the key protein for liver damage, liver protection and liver regeneration by using proteomic techniques. 50 % (v/v) CCl4 in corn oil was administered intraperitoneally to adult male rats at a dose of 4ml/kg body weight. Approximately 24h after the injection, the liver was removed and extracted proteins were analyzed with cleavable isotope coded affinity tag (cICAT) reagents, two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS). A twelvefold increase in D-dopachrome tautomerase (DDT) was indicated. This enzyme has been reported to be involved in the biosynthesis of melanin, an antioxidant. According to the histological analysis, melanin levels were increased in un-damaged hepatocytes of CCl4-treated rats. These results suggest that the increase in DDT is a response to liver damage, accelerates melanin biosynthesis and protects the liver from oxidative stress induced by CCl4.
(キーワード)
Animals / Blotting, Western / Body Weight / COS Cells / Carbon Tetrachloride Poisoning / Cercopithecus aethiops / Cloning, Molecular / DNA, Complementary / Drug-Induced Liver Injury / Genetic Vectors / Intramolecular Oxidoreductases / Liver / Male / Mass Spectrometry / Melanins / Organ Size / Rats / Rats, Wistar / Transfection
Kokichi Arisawa, Hirokazu Uemura, Mineyoshi Hiyoshi, Hideo Takeda, Hiroshi Saito and Midori Soda : Cadmium-induced renal dysfunction and mortality in two cohorts: diappearance of the association in a generation born later, Toxicology Letters, Vol.169, No.3, 214-221, 2007.
(要約)
The association between exposure to environmental cadmium and mortality was investigated in two cohorts. The study population consisted of 275 (cohort I) and 329 (cohort II) residents (aged >or=40 years) in a cadmium-polluted area, Nagasaki Prefecture, Japan, who had participated in health surveys conducted in 1982 and 1992, respectively. The follow-up period extended from 1982 or 1992 to 2005. In the study area, the dietary cadmium intake had decreased after 1980-1983 because of the restoration of cadmium-polluted paddy fields. In cohort I, the mortality rate among those with urinary beta2-microglobulin (beta2-MG) concentration >or=1000 microg/g creatinine (cr.) was 1.41 times higher than the regional reference rate (95% confidence interval [CI] 1.07-1.83). After adjusting for age and other variables, in men, urinary N-acetyl-beta-D-glucosaminidase, and in women, serum creatinine, beta2-MG clearance, and urinary beta2-MG were significantly associated with increased mortality. However, in cohort II, urinary beta2-MG or total protein was not significantly associated with survival. These findings indicate that cadmium-induced renal dysfunction was a significant predictor of mortality, but that such an association is disappearing, probably because of the selective loss of advanced cases and reduced exposure and body burden.
(キーワード)
Adult / Aged / Aged, 80 and over / Cadmium / Cohort Studies / Environmental Monitoring / Environmental Pollutants / Female / Health Surveys / Humans / Japan / Kaplan-Meier Estimate / Kidney Diseases / Male / Middle Aged / Proportional Hazards Models / Time Factors
To elucidate the mortality characteristics of Tokushima Prefecture, the authors analyzed thetime-related change in the standardized mortality ratio (SMR) of cause-specific death and organspecificcancer death during 1983-2002, and administrative area-specific SMR during 1993-1998 and1999-2002. The gender-and 5-year-age-specific and cause-specific death rates in the entire Japanesepopulation were used as the reference mortality, and the population of sex-and-5-year-agespecificcategory in the census year(1985, 1990, 1995 and 2000)was used as the population ofTokushima Prefecture. Interval estimation of SMR was performed by the exact method, assumingthat the number of deaths followed the Poisson distribution. In the analysis of each year from1983 to 2002, the SMR of diabetes mellitus markedly increased from the mid 1990's, suggesting thechanges in the environmental factors. The SMR of bronchitis, emphysema and asthma wasconstantly high during the 20 years. In the administrative area-specific analysis, the SMR ofdiabetes was high in Tokushima and Naruto for both men and women. With regard to malignantneoplasms, the SMR of esophageal cancer was constantly low, while that of liver cancer wasconstantly high over the 20 years. The SMR of esophageal cancer was low among men inTokushima and Anan, and among women in Kamojima, while that of liver cancer was high amongmen and women in Tokushima and among men in Anan. These characteristics were consistentover the recent 10 years, suggesting the involvement of area-specific factors.
(キーワード)
diabetes / esophageal cancer / geographic distribution / liver cancer / standardized mortality ratio / time trend
Recent progress in life science technology and the availability of much information on genes obtained by genome analysis has enabled us to analyze the changes of proteins on a large scale. Sets of proteins are called proteomes, and proteomics is the scientific field of proteome analysis including differential, post translational modification and interaction analyses. Various proteomic techniques, particularly two-dimensional gel electrophoresis (2-DE), mass spectrometry, protein chip methods, and surface plasmon resonance (SPR), are very useful for acquiring proteomes in cells, tissues and body fluid, and for analyzing interactions between a protein and other biofactors including proteins. A proteomic approach is also useful for determining biomarkers of diseases and key proteins involved in various stages of metabolism such as differentiation, cell cycle and apoptosis. Environmental pollutants including endocrine disruptors inhibit activities of various organs in wild animals and humans. Proteomic approaches could be very useful tools for elucidating the mechanisms of damage caused by environmental pollutants. In this review, we describe the application of a proteomic approach to the field of environmental medicine.
Kokichi Arisawa, Midori Soda, Masazumi Akahoshi, Saeko Fujiwara, Hirokazu Uemura, Mineyoshi Hiyoshi, Hideo Takeda, Wataru Kashino and Akihiko Suyama : Human T-cell lymphotropic virus type-1 infection and risk of cancer: 15.4 year longitudinal study among atomic bomb survivors in Nagasaki, Japan, Cancer Science, Vol.97, No.6, 535-539, 2006.
(要約)
The objective of the present study was to investigate the association between human T-lymphotropic virus type-1 (HTLV-1) infection and cancer risk in a longitudinal study. The study population consisted of 2729 atomic bomb survivors in Nagasaki Prefecture, Japan, who had no previous history of cancer at baseline. The baseline survey, including analysis of antibody to HTLV-1, took place during 1985-1987 and follow-up was performed until the end of 2001. There were 553 incident cases of malignant neoplasms during the observation period. After adjustment for sex, age and other variables, HTLV-1 infection was not associated with the risk of developing cancers of all sites, excluding adult T-cell leukemia (rate ratio 1.0, 95% confidence interval [CI] 0.76-1.4), stomach, colon and rectum, lung, female breast or other minor sites, but was associated with increased risk of liver cancer (rate ratio 2.1, 95%CI 1.0-4.6). The point estimate of the rate ratio for thyroid cancer was 3.0, but this was not significantly higher than 1 because of the small number of events (n = 11) and low prevalence of HTLV-1 seropositivity. These findings support the idea that HTLV-1 infection is not associated with an increased general cancer risk. Confounding by hepatitis C virus (HCV) and the interaction between HTLV-1 and HCV may explain the increased risk of liver cancer among HTLV-1 carriers. Further follow-up may be required to determine if HTLV-1 carriers are at increased risk of thyroid cancer.
To clarify the characteristics of mortality in Tokushima Prefecture, the authors analyzed thestandardized mortality ratio(SMR)from 1993 to 1998 and 1999 to 2002. The sex-and 5-year-agespecificand cause-specific morality rates in Japan were used as the standard mortality, and thepopulation of sex-and 5-year-age-specific category in the census year(1995 and 2000)was used asthe population of Tokushima Prefecture. The 95 % confidence interva(l CI)of SMR was estimatedusing the exact method, on the assumption that the number of deaths followed the Poisson distribution.The mortality from all-cause in Tokushima Prefecture was significantly lower than that of theentire Japanese population among women during 1993-1998, while it was significantly higheramong men and women during 1999-2002. The SMRs of diabetes mellitus, bronchitis, emphysemaand asthma, and chronic hepatitis and liver cirrhosis were significantly higher than 100, with theSMR of diabetes being as high as 130-140. On the other hand, mortality rate from suicide was significantlylower than that of all of Japan. Regarding malignant neoplasms, morality rates fromcancers of all sites, esophagus, stomach, and colon and rectum were significantly lower than 100.However, the SMR of liver cancer was significantly high, suggesting that hepatitis C virus infectionwas endemic. The reason for the high mortality from diabetes should be clarified with regard toenvironmental and genetic factors, and the way of reporting diabetes as a cause of death in deathcertificates. In addition, the reason for the low mortality from cancers of the gastrointestinal tractremains unknown, and further investigations on life style factors are required.
(キーワード)
1993年 / standardized mortality ratio / diabetes / liver cancer / esophageal cancer / gastric cancer
Kokichi Arisawa, Hideo Takeda and Hiroaki Mikasa : Background exposure to PCDDs/PCDFs/PCBs and its potential health effects: a review of epidemiologic studies, The Journal of Medical Investigation : JMI, Vol.52, No.1,2, 10-21, 2005.
(要約)
Here we review epidemiologic studies dealing with the dietary intake and the body burden of polychlorinated dibenzo-p-dioxins (PCDDs)/polychlorinated dibenzo-furans (PCDFs)/ polychlorinated biphenyls (PCBs) in the general population, and potential adverse health effects of these substances, especially on the risk of diabetes mellitus and endometriosis, and on thyroid function and the neurodevelopment of infants. The mean or median intake of dioxin-related compounds among the general populations of various countries is lower than the maximum tolerable daily intake (TDI) set by the WHO in 1998 (4pg TEQ/kg/day). However, there have been few reports on the distribution of intake and the proportion of subjects whose exposure levels exceed the maximum TDL. At present, it remains unclear whether background exposure to dioxin-related compounds is associated with increased risk of diabetes (because of lack of longitudinal studies), endometriosis (because of lack of studies with sufficient statistical power), or altered thyroid function (because of inconsistent results on humans). Consistent results have been reported for the association between exposure to background levels of PCBs/dioxins, especially trans-placental PCBs, and defective neurodevelopment of infants in the U.S. and Europe. Thus, efforts should be made to further decrease the body burden among women of reproductive age by reducing the release of PCDDs/PCDFs/PCBs into the environment.
The research interest of authors has focused on the risk assessment of environmental pollutantssuch as cadmium and dioxin-related compounds, and epidemiology of human T-cell lymphotropicvirus type-I(HTLV-I)infection. The authors(1)showed that low-molecular weight proteinuriaand reduced glomerular filtration rate caused by environmental cadmium were strongly associatedwith shortened survival，(2)clarified serological risk factors for development of adult T-cellleukemia/lymphoma among asymptomatic HTLV-I carriers(plasma levels of soluble interleukin2-receptor>＝500U/ml and HTLV-I antibody titer>＝1，024)，(3)conducted the first prospectivestudy of HTLV-I infection and development of malignances other than ATL, and found a significantlyreduced risk of gastric cancer among HTLV-I carriers, and(4)by a cooperative study, clarified anew pathogenicity of HTLV-I(association with Sj¨ogren's syndrome)
Hirokazu Uemura, Toshiyuki Yasui, Y Miyatani, M Yamada, Mineyoshi Hiyoshi, Hideo Takeda, Kokichi Arisawa and Minoru Irahara : Relationships between circulating osteoprotegerin and the risk factors of vascular disorders in postmenopausal women., The 3rd Scientific Meeting of the Asian Pacific Menopause Federation (APMF), Taipei, Mar. 2007.
2.
Mineyoshi Hiyoshi, Hirokazu Uemura, Hideo Takeda, Hiroshi Kido and Kokichi Arisawa : Quantitative proteomic analysis of testes in treated and untreated mice with bisphenol A by MALDI-TOF/TOF, 20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress, Kyoto, Jun. 2006.