Michihiro Kamijima

Bisphenol A may cause testosterone reduction by adversely affecting both testis and pituitary systems similar to estradiol.

Bisphenol A (BPA) causes reproductive toxicities, but the mechanisms are still unclear. In the present study, we sought to clarify these mechanisms in comparison with those of 17beta-estradiol (E2). Prepubertal Wistar/ST male rats (4 weeks old) were subcutaneously administered BPA (0, 20, 100 and 200 mg/kg/day) or E2 (10 and 100 microg/kg/day) for 6 weeks. Both BPA and E2 treatments decreased plasma and testicular testosterone levels, and plasma luteinizing hormone (LH), but not E2 and follicle-stimulating hormone levels, though E2 treatment increased its plasma level. In relation to the decreased testosterone levels, BPA and E2 decreased expressions of steroidogenic enzymes and cholesterol carrier protein in Leydig cells. Thus, decreased testosterone levels in plasma might have resulted from decreased expressions of these enzymes and protein as well as from decreased plasma LH levels. Interestingly, the changes in steroidogenic enzymes and carrier protein were observed at lower levels of exposure to BPA or E2 than those inhibiting plasma LH levels. Microscopically, 200 mg/kg BPA and 100 microg/kg E2 significantly decreased Leydig cell numbers in the testis. In addition, BPA and E2 also decreased expression of estrogen receptor alpha-mRNA, which might be related to the decreased numbers of Leydig cells. Thus, BPA directly affects not only the Leydig cells but also the pituitary gland, but the former may be impaired at lower exposure concentrations than the latter.

A comparison of indoor air pollutants in Japan and Sweden: formaldehyde, nitrogen dioxide, and chlorinated volatile organic compounds ☆

Indoor and outdoor concentrations of formaldehyde (HCHO), nitrogen dioxide (NO2), and selected chlorinated volatile organic compounds (chlorinated VOC) were measured in 37 urban dwellings in Nagoya, Japan, and 27 urban dwellings in Uppsala, Sweden, using the same sampling procedures and analytical methods. Indoor as well as outdoor air concentrations of HCHO, NO2, and chlorinated VOC were significantly higher in Nagoya than in Uppsala (P<0.01), with the exception of tetrachlorocarbon in outdoor air. In Nagoya, HCHO and NO2 concentrations were significantly higher in modern concrete houses than in wooden houses and higher in newer (less than 10 years) than in older dwellings (P<0.01), possibly due to less natural ventilation and more emission sources in modern buildings. Dwellings heated with unvented combustion sources had significantly higher indoor concentrations of NO2 than those with clean heating (P<0.05). Moreover, dwellings with moth repellents containing p-dichlorobenzene had significantly higher indoor concentrations of p-dichlorobenzene (P<0.01). In conclusion, there appear to be differences between Nagoya and Uppsala with respect to both indoor and outdoor pollution levels of the measured pollutants. More indoor pollution sources could be identified in Nagoya than in Uppsala, including construction and interior materials emitting VOC, use of unvented combustion space heaters, and moth repellents containing p-dichlorobenzene.

Di(2-ethylhexyl)phthalate Induces Hepatic Tumorigenesis through a Peroxisome Proliferator-activated Receptor α-independent Pathway

Di(2‐ethylhexyl)phthalate Induces Hepatic Tumorigenesis through a Peroxisome Proliferator‐activated Receptor α‐independent Pathway: Yuki Ito, et al. Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine—Di(2ethylhexyl)phthalate (DEHP), a commonly used industrial plasticizer, causes liver tumorigenesis presumably via activation of peroxisome proliferator‐activated receptor alpha (PPARα). The mechanism of DEHP tumorigenesis has not been fully elucidated, and to clarify whether DEHP tumorigenesis is induced via PPARα, we compared DEHP‐induced tumorigenesis in wild‐type and Pparα‐null mice. Mice of each genotype were divided into three groups, and treated for 22 months with diets containing 0, 0.01 or 0.05% DEHP. Surprisingly, the incidence of liver tumors was higher in Pparα‐null mice exposed to 0.05% DEHP (25.8%) than in similarly exposed wild‐type mice (10.0%). These results suggest the existence of pathways for DEHP‐induced hepatic tumorigenesis that are independent of PPARα. The levels of 8‐OHdG increased dose‐dependently in mice of both genotypes, but the degree of increase was higher in Pparα‐null than in wild‐type mice. NFκB levels also significantly increased in a dose‐dependent manner in Pparα‐null mice. The protooncogene c‐jun‐mRNA was induced, and c‐fos‐mRNA tended to be induced only in Pparα‐null mice fed a 0.05% DEHP‐containing diet. These results suggest that increases in oxidative stress induced by DEHP exposure may lead to the induction of inflammation and/or the expression of protooncogenes, resulting in a high incidence of tumorigenesis in Pparα‐null mice.

Epicondylitis among cooks in nursery schools

OBJECTIVES: To investigate the prevalence and risk factors of epicondylitis among cooks in nursery schools in a cross sectional study because they are suspected to have strenuous workloads on the hands and arms. METHODS: Prevalence of epicondylitis among 209 nursery school cooks and 366 control workers aged 40-59 were studied. Both groups consisted of women workers chosen from 1299 subjects who agreed to participate from 1329 social welfare employees in a city. All workers were interviewed with a questionnaire and had a clinical examination of the tenderness to palpation of epicondyles and epicondylar pain provoked by resisted extension and flexion of the wrist. RESULTS: Nursery school cooks had a significantly higher prevalence of epicondylitis (11.5%) than the controls (2.5%). In a logistic regression model, job title of the cook was also found to have a strong association with epicondylitis (odds ratio (OR) 5.4, 95% confidence interval (95% CI) 2.4 to 11.9) after adjustment for age, body length, and body mass index. Weaker associations were also found between epicondylitis and suspected job stress or workload scores for mechanical workload and psychosocial stressors based on factor analysis. CONCLUSIONS: This study supported the hypothesis that nursery school cooks had a higher prevalence of epicondylitis than other workers with less strenuous hand and arm tasks. It was suggested that risk factors of epicondylitis would be multifactorial, including mechanical workload and psychosocial factors.

A survey of semen indices in insecticide sprayers.

A Survey of Semen Indices in Insecticide Sprayers: Michihiro Kamijima, et al. Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine—This study aims at clarifying the semen indices of insecticide sprayers who are exposed mainly to organophosphorus and pyrethroid insecticides. Eighteen male sprayers out of 54 working for 9 companies in central Japan and 18 age‐matched students or medical doctors as unexposed controls participated in detailed reproductive check‐ups conducted in summer and the following winter. The sprayers were exposed to insecticides more in summer, the busiest season, than winter, the off‐season (p<0.05). Erythrocyte true cholinesterase activities in the sprayers were lower than in the controls in summer (p<0.05), and decreased in significant association with the increase in exposure frequency. Testicular volumes in the sprayers tended to be smaller than in the controls (p=0.06). The serum testosterone concentration in winter in the sprayers was higher than in the controls (p<0.05), though luteinizing hormone and follicle stimulating hormone concentrations were not significantly different. The sperm counts and vitality were comparable between the groups, but detailed sperm motility analysis in summer revealed that the percentages of slow progressive and nonprogressive motile sperm were twice as high in the sprayers (p<0.05), and that of rapid progressive sperm tended to be lower (p=0.06). Such differences were not observed in winter. Differential sperm morphology counts showed that interaction of group and abstinence effects were significant in sperm with normal morphology and with head deformity only in the summer check‐up. Despite possible inherent differences between the groups, the above season‐dependent differences suggested that the observed lower semen quality in the sprayers was associated with pesticide spraying work.

Testicular and Hematopoietic Toxicity of 2-Bromopropane, a Substitute for Ozone Layer-Depleting Chlorofluorocarbons

Testicular and Hematopoietic Toxicity of 2‐Bromopropane, a Substitute for Ozone Layer‐Depleting Chlorofluorocarbons: Gaku Ichihara, et al. Department of Hygiene, Nagoya University School of Medicine—In 1995r unexpected amenorrhea, oligozoospermia and anemia were discovered in Korean workers exposed to solvents containing 2‐bromopropane which was a substitute for chlorofluorocarbon. We aimed to determine experimentally the testicular and hematopoietic toxicity of 2‐bromopropane in male rats. Thirty‐six Wistar male rats were divided into four groups of nine each. The rats were exposed to 300r 1,000 and 3,000 ppm 2‐bromopropane or only fresh air, respectively, 8 hr a day, 7 days per week. The 300 ppm and 1,000 ppm groups were exposed for 9 weeks, but the 3,000 ppm groups exposure was discontinued and three rats in this group were dissected after 9‐11 days’ exposure because of serious illness. The others were dissected at the end of the experiment. At 300 ppm or over, the testicular and epididymal weights per body weight, epididymal sperm count, motile sperm percentage and the number of erythrocytes and platelets had decreased compared to the control. Histopathologically, all types of germ cells decreased in the 300 ppm group. Germ cells were absent but Sertoli cells still remained in the 1,000 ppm and 3,000 ppm groups at the end of the experiment. Spermatogonia were absent and the number of spermatocytes decreased in the 3,000 ppm group rats sacrificed after 1 1 days’ exposure. Sertoli cell vacuolations were marked in two of these three rats. Bone marrow was hypocellular in the 1,000 ppm group and in all the rats in the 3,000 ppm group. These results clearly showed that 2‐bromopropane had a testicular and hematopoietic toxicity in male rats.

Permethrin may induce adult male mouse reproductive toxicity due to cis isomer not trans isomer.

Permethrin, the most popular insecticide among the synthetic pyrethroids, has been used worldwide to control a wide range of insects in agriculture, forestry, public health, and homes. Humans may have suffered potential exposure to this compound. The commercial formulation of permethrin contains trans and cis isomers. Here, at the same dosage, we made a comparison of the reproductive effects between these two isomers. Male adult ICR mice were orally administered trans- or cis-permethrin daily for 6 weeks at a dose of 0 or 70 mg/(kg day). In the cis-permethrin exposure group, the caudal epididymal sperm count and sperm motility were significantly reduced, and testosterone levels in testes and plasma also fell. Moreover, cis-permethrin induced abnormal seminiferous tubules in testes and suppressed testicular mRNA expression levels of peripheral benzodiazepine receptor, steroidogenic acute regulatory protein, and the cytochrome P450 side-chain cleavage enzyme. Although such adverse effects were not observed in the trans-permethrin exposure group, testicular and urinary metabolite 3-phenoxybenzoic acid levels in trans-permethrin-exposed mice were about three- and sevenfold higher than those in cis-permethrin-exposed mice, respectively. Furthermore, in vitro, hepatic microsomal hydrolase activity for trans-permethrin was nearly 62-fold higher than that for cis-permethrin. Taken together, the difference in metabolic activity between cis- and trans-permethrin might contribute to the difference in the reproductive toxicity between both isomers.

Neurologic Abnormalities in Workers of a 1-Bromopropane Factory

We reported recently that 1-bromopropane (1-BP; n-propylbromide, CAS Registry no. 106-94-5), an alternative to ozone-depleting solvents, is neurotoxic and exhibits reproductive toxicity in rats. The four most recent case reports suggested possible neurotoxicity of 1-BP in workers. The aim of the present study was to establish the neurologic effects of 1-BP in workers and examine the relationship with exposure levels. We surveyed 27 female workers in a 1-BP production factory and compared 23 of them with 23 age-matched workers in a beer factory as controls. The workers were interviewed and examined by neurologic, electrophysiologic, hematologic, biochemical, neurobehavioral, and postural sway tests. 1-BP exposure levels were estimated with passive samplers. Tests with a tuning fork showed diminished vibration sensation of the foot in 15 workers exposed to 1-BP but in none of the controls. 1-BP factory workers showed significantly longer distal latency in the tibial nerve than did the controls but no significant changes in motor nerve conduction velocity. Workers also displayed lower values in sensory nerve conduction velocity in the sural nerve, backward recalled digits, Benton visual memory test scores, pursuit aiming test scores, and five items of the Profile of Mood States (POMS) test (tension, depression, anxiety, fatigue, and confusion) compared with controls matched for age and education. Workers hired after May 1999, who were exposed to 1-BP only (workers hired before 1999 could have also been exposed to 2-BP), showed similar changes in vibration sense, distal latency, Benton test scores, and depression and fatigue in the POMS test. Time-weighted average exposure levels in the workers were 0.34–49.19 ppm. Exposure to 1-BP could adversely affect peripheral nerves or/and the central nervous system.

Pyrethroid pesticide exposure and risk of childhood acute lymphocytic leukemia in Shanghai.

Significant amounts of pyrethroid pesticides are used throughout China. Previous studies have suggested that exposure to pesticides may increase the risk of childhood cancer; however, few studies have focused on pyrethroid metabolites. We investigated five nonspecific metabolites of pyrethroid pesticides found in childrens urine and examined the correlation with childhood leukemia. We conducted a hospital-based case-control study of childhood acute lymphocytic leukemia (ALL) in Shanghai between 2010 and 2011. The study included 176 children aged 0-14 years and 180 controls matched for age and sex. Compared with those in the lowest quartiles of total and individual metabolites, the highest quartiles were associated with an approximate 2-fold increased risk of ALL [total metabolites: odds ratio (OR) = 2.75, 95% confidence interval (CI), 1.43-5.29; cis-DCCA: OR = 2.21, 95% CI, 1.16-4.19; trans-DCCA: OR = 2.33, 95% CI, 1.23-4.41; and 3-PBA: OR = 1.84, 95% CI, 1.00-3.38], and most of the positive trends were significant (p < 0.05). Our findings suggest that urinary levels of pyrethroid metabolites may be associated with an elevated risk of childhood ALL and represent a previously unreported quantitative exposure assessment for childhood leukemia.

2-Ethyl-1-hexanol in Indoor Air as a Possible Cause of Sick Building Symptoms.

Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya City Public Health Research Institute, Department of Medical Technology, Nagoya University School of Health Sciences, Department of Environmental Dermatology, Nagoya University School of Medicine, Second Department of Internal Medicine, Nagoya University School of Medicine and Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, Japan