Mediating Factors Between Parental Socioeconomic Status and Small for Gestational Age in Infants: Results from the Hokkaido Study on Environment and Children's Health.

OBJECTIVES: Previous studies indicated a significant association between small for gestational age (SGA) in infants and their parents' socioeconomic status (SES). Thus, this study aimed to examine if parental factors, such as maternal smoking, and the pre-pregnancy body mass index (BMI) could mediate the associations between parental SES and SGA. METHODS: The participants of this study were pregnant women who enrolled in an ongoing birth cohort study, the Hokkaido study, during the first trimester of their pregnancies. A total of 14,593 live singleton births were included in the statistical analysis, of which 1011 (6.9%) were SGA. Two structural equation models were employed to evaluate the associations between parental SES, parental characteristics, and SGA. RESULTS: The effect of low SES on SGA was directly mediated by maternal pre-pregnancy BMI, smoking during the third trimester, and alcohol consumption during the first trimester in the first model, which was based the assumption of independent associations between mediating factors. In the second model, which additionally considered the mediating factors from the first model, smoking during pregnancy mediated decline in parental SES, consequently increased SGA. Moreover, an increase in pregnancy smoking status increased the prevalence of lower maternal pre-pregnancy BMI and its effect on SGA. CONCLUSIONS FOR PRACTICE: In this study, we observed the independent mediating effect of maternal pre-pregnancy BMI, smoking, and alcohol consumption during pregnancy on low SES and, consequently, SGA, with the additional mediating pathway of SES to smoking to low BMI on SGA.

Association Between Maternal Serum Folate Concentrations in the First Trimester and the Risk of Birth Defects: The Hokkaido Study of Environment and Children's Health.

BACKGROUND: Low red blood cell folate concentrations during early pregnancy might cause neural tube defects. However, the association between folate concentrations and birth defects of other neural crest cell-derived organs remains unknown. We investigated the associations between birth defects and first-trimester serum folate concentrations in a birth-cohort study in Japan. METHODS: In total, 14,896 women who were prior to 13 weeks of gestation were enrolled from 2003 through 2012. Birth defect information was obtained from medical records and questionnaires. The association between folate levels in the first trimester and birth defects categorized as ICD-10 cord defects and neural crest cell-derived organ defects was examined. The crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) per log-transformed folate concentration were calculated using logistic regression. RESULTS: Blood samples were obtained at a mean of 10.8 weeks of gestation. Median serum folate level was 16.5 (interquartile range, 13.4-21.5) nmol/L, and the deficiency level (less than 6.8 nmol/L) was 0.7%. There were 358 infants with birth defects. The adjusted odds ratio for any birth defect, ventricular septal defects, and cleft lip was 0.99 (95% CI, 0.74-1.32), 0.63 (95% CI, 0.30-1.33), and 4.10 (95% CI, 0.96-17.58), respectively. There were no significant associations between first-trimester maternal serum folate and the risk of birth defects. CONCLUSIONS: We were unable to demonstrate a relationship between maternal serum folate in the first trimester and birth defects. Potential confounding factors may have influenced our results.

Prevalence and Risk of Birth Defects Observed in a Prospective Cohort Study: The Hokkaido Study on Environment and Children's Health.

BACKGROUND: Prevalence rates of all anomalies classified as birth defects, including those identified before the 22nd gestational week, are limited in published reports, including those from the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). In our birth cohort study, we collected the data for all birth defects after 12 weeks of gestation. METHODS: Subjects in this study comprised 19,244 pregnant women who visited one of 37 associated hospitals in the Hokkaido Prefecture from 2003 through 2012, and completed follow-up. All birth defects after 12 weeks of gestation, including 55 marker anomalies associated with environmental chemical exposures, were recorded. We examined parental risk factors for birth defects and the association between birth defects and risk of growth retardation. RESULTS: Prevalence of all birth defects was 18.9/1,000 births. The proportion of patients with birth defects delivered between 12 and 21 weeks of gestation was approximately one-tenth of all patients with birth defects. Among those with congenital malformation of the nerve system, 39% were delivered before 22 weeks of gestation. All patients with anencephaly and encephalocele were delivered before 22 weeks of gestation. We observed different patterns of parental risk factors between birth defect cases included in ISBDSR and cases not included. Cases included in ISBDSR were associated with an increased risk of preterm birth. Cases not included in ISBDSR were associated with an increased risk of being small for gestational age at term. CONCLUSIONS: Data from our study complemented the data from ICBDSR. We recommend that birth defects not included in ICBDSR also be analyzed to elucidate the etiology of birth defects.

The Hokkaido Birth Cohort Study on Environment and Children's Health: cohort profile-updated 2017.

The Hokkaido Study on Environment and Children's Health is an ongoing study consisting of two birth cohorts of different population sizes: the Sapporo cohort and the Hokkaido cohort. Our primary study goals are (1) to examine the effects of low-level environmental chemical exposures on birth outcomes, including birth defects and growth retardation; (2) to follow the development of allergies, infectious diseases, and neurobehavioral developmental disorders and perform a longitudinal observation of child development; (3) to identify high-risk groups based on genetic susceptibility to environmental chemicals; and (4) to identify the additive effects of various chemicals, including tobacco smoking. The purpose of this report is to update the progress of the Hokkaido Study, to summarize the recent results, and to suggest future directions. In particular, this report provides the basic characteristics of the cohort populations, discusses the population remaining in the cohorts and those who were lost to follow-up at birth, and introduces the newly added follow-up studies and case-cohort study design. In the Sapporo cohort of 514 enrolled pregnant women, various specimens, including maternal and cord blood, maternal hair, and breast milk, were collected for the assessment of exposures to dioxins, polychlorinated biphenyls, organochlorine pesticides, perfluoroalkyl substances, phthalates, bisphenol A, and methylmercury. As follow-ups, face-to-face neurobehavioral developmental tests were conducted at several different ages. In the Hokkaido cohort of 20,926 enrolled pregnant women, the prevalence of complicated pregnancies and birth outcomes, such as miscarriage, stillbirth, low birth weight, preterm birth, and small for gestational age were examined. The levels of exposure to environmental chemicals were relatively low in these study populations compared to those reported previously. We also studied environmental chemical exposure in association with health outcomes, including birth size, neonatal hormone levels, neurobehavioral development, asthma, allergies, and infectious diseases. In addition, genetic and epigenetic analyses were conducted. The results of this study demonstrate the effects of environmental chemical exposures on genetically susceptible populations and on DNA methylation. Further study and continuous follow-up are necessary to elucidate the combined effects of chemical exposure on health outcomes.

Immunogenicity and Efficacy of A/H1N1pdm Vaccine Among Subjects With Severe Motor and Intellectual Disability in the 2010/11 Influenza Season.

BACKGROUND: While the immunogenicity and effectiveness of seasonal influenza vaccines among subjects with severe motor and intellectual disability (SMID) are known to be diminished, the efficacy of the A/H1N1pdm vaccine has not been evaluated. METHODS: We prospectively evaluated 103 subjects with SMID (mean age, 41.7 years) who received trivalent inactivated influenza vaccine during the 2010/11 influenza season. The hemagglutination inhibition (HI) antibody titer was measured in serum samples collected pre-vaccination (S0), post-vaccination (S1), and end-of-season (S2) to evaluate subjects' immunogenicity capacity. Vaccine efficacy was assessed based on antibody efficacy and achievement proportion. RESULTS: The proportions of seroprotection and seroconversion, and the geometric mean titer (GMT) ratio (GMT at S1/GMT at S0) for A/H1N1pdm were 46.0%, 16.0%, and 1.8, respectively-values which did not meet the European Medicines Evaluation Agency criteria. The achievement proportion was 26%. During follow-up, 11 of 43 subjects with acute respiratory illness were diagnosed with type A influenza according to a rapid influenza diagnostic test (RIDT), and A/H1N1pdm strains were isolated from the throat swabs of 5 of those 11 subjects. When either or both RIDT-diagnosed influenza or serologically diagnosed influenza (HI titer at S2/HI titer at S1 ≥2) were defined as probable influenza, subjects with A/H1N1pdm seroprotection were found to have a lower incidence of probable influenza (odds ratio, 0.31; antibody efficacy, 69%; vaccine efficacy, 18%). CONCLUSIONS: In the present seasonal assessment, antibody efficacy was moderate against A/H1N1pdm among SMID subjects, but vaccine efficacy was low due to the reduced immunogenicity of SMID subjects.

Urinary 1-hydroxypyrene as a comprehensive carcinogenic biomarker of exposure to polycyclic aromatic hydrocarbons: a cross-sectional study of coke oven workers in China.

PURPOSE: Polycyclic aromatic hydrocarbons (PAHs) are multiple compounds that include many carcinogens. We conducted a cross-sectional study in steel plant workers in Anshan, China, to identify biomarkers that reflect the carcinogenicity of PAHs. METHODS: Subjects were 57 workers and 20 controls. Level of personal exposure to PAHs was measured using GC-MS. In accordance with the assessment methods defined by the United States Environmental Protection Agency (US EPA), 15 PAHs were selected for the analysis. For the measurement of urinary metabolites, urine samples were treated with ß-glucuronidase and analyzed using HPLC with a fluorescence detector. RESULTS: The mean range of personal exposure to 15 PAHs (total PAHs) was 178.85, 47.08-1,329.45 (geometric mean, 5th and 95th percentile) µg/m(3). Ten known urinary metabolites (1-hydroxynaphthalene, 2-hydroxynaphthalene, 2-hydroxyfluorene, 1-hydroxyphenanthrene, 3-hydroxyphenanthrene, 9-hydroxyphenanthrene, 1-hydroxypyrene, 3-hydroxybenz[a]anthracene, 6-hydroxychrysene, and 3-hydroxybenzo[a]pyrene) and four unknown peaks were detected. The highest correlation was between total PAHs and urinary 2-hydroxynaphthalene (Spearman r = 0.716, P < 0.01). Among the detected urinary metabolites, 2-hydroxyfluorene, 1-hydroxyphenanthrene, 3-hydroxyphenanthrene, and 1-hydroxypyrene were found to correlate significantly with the "Σ carcinogenic potency of PAHs" (sum of seven carcinogenic PAHs calculated from the levels of personal PAHs and relative potency factors), and with the greatest correlation found for 1-hydroxypyrene (Spearman r = 0.630, P < 0.01). CONCLUSIONS: The analysis of personal exposure to 15 PAHs and 10 urinary metabolites, and calculation of Σ carcinogenic potency, indicated that urinary 1-hydroxypyrene was the most comprehensive carcinogenic biomarker of exposure to PAHs.

Dietary isoflavone intake, polymorphisms in the CYP17, CYP19, 17beta-HSD1, and SHBG genes, and risk of breast cancer in case-control studies in Japanese, Japanese Brazilians, and non-Japanese Brazilians.

We tested the hypothesis that polymorphisms in cytochrome P450c17alpha (CYP17), aromatase (CYP19), 17beta-hydroxysteroid dehydrogenase type I (17beta-HSD1) and sex hormone-binding globulin (SHBG) genes may modify the association between isoflavone intake and breast cancer risk. We conducted hospital-based, case-control studies in Nagano, Japan and Sao Paulo, Brazil. A total of 846 pairs (388 Japanese, 79 Japanese Brazilians, and 379 non-Japanese Brazilians) completed validated food frequency questionnaires. Four single nucleotide polymorphisms (SNPs) in CYP17 (rs743572), CYP19 (rs10046), 17beta-HSD1 (rs605059), and SHBG (rs6259) genes were genotyped. We found no association between the 4 SNPs and breast cancer risk. In combination analyses of isoflavone intake and SNPs, an inverse association between intake and risk was limited to women with at least one A allele of the rs605059 polymorphism for all 3 populations, albeit without statistical significance. For the rs6259 polymorphism, the inverse association was limited to postmenopausal Japanese with the GG genotype (odds ratio [OR] for highest vs. lowest tertile = 0.50, 95% confidence interval [CI] = 0.29-0.87; P for trend < 0.01), and to non-Japanese Brazilians with at least one A allele (OR for consumers vs. nonconsumer = 0.21, 95% CI = 0.06-0.77). We found no remarkable difference for the rs743572 and rs10046 polymorphisms. Our findings suggest that polymorphisms in the 17beta-HSD1 and SHBG genes may modify the association between isoflavone intake and breast cancer risk.

Survival prognosis of Japanese with severe motor and intellectual disabilities living in public and private institutions between 1961 and 2003.

BACKGROUND: Although the prognosis for survival in people with severe functional disabilities is a serious concern for their families and health care practitioners, there have been few reports on survival rates for this population. Every year, the Japanese Association of Welfare for Persons with Severe Motor and Intellectual Disability collects anonymous records of individual registrations and deaths from all private and public institutions, excepting national institutions. We used these data to estimate the prognosis for survival. METHODS: We reviewed the records of 3221 people with severe motor and intellectual disabilities (SMID); all subjects had lived in one of 119 public or private institutions in Japan between 1961 and 2003. Kaplan-Meier survival estimates were calculated according to disability type and birth year range. RESULTS: Of the 3221 persons, 2645 were alive and 576 had died. The survival rate at the age of 20 for all subjects was 79% (95% confidence interval, 78%-81%). Among people who were unable to sit, those with lower intelligence quotients had lower survival rates. CONCLUSIONS: The survival rate among people with SMID housed in public and private institutions in Japan was much worse than that of the general population, and has not improved since the 1960s.

Isoflavone, polymorphisms in estrogen receptor genes and breast cancer risk in case-control studies in Japanese, Japanese Brazilians and non-Japanese Brazilians.

Epidemiologic studies have shown an inverse association between isoflavones and breast cancer risk. Because isoflavones bind estrogen receptors, we hypothesized that polymorphisms in the estrogen receptor genes might modify the association between isoflavone intake and breast cancer risk. We conducted hospital-based case-control studies of patients aged 20-74 years with primary, incident, histologically confirmed invasive breast cancer, and matched controls from among medical checkup examinees in Nagano, Japan, and from cancer-free patients in São Paulo, Brazil. A total of 846 pairs (388 Japanese, 79 Japanese Brazilians and 379 non-Japanese Brazilians) completed validated food frequency questionnaires, and provided blood samples. Five single nucleotide polymorphisms in the estrogen receptor alpha (rs9340799, rs1913474, and rs2234693) and beta (rs4986938 and rs1256049) genes were genotyped. We found no consistent association between the five single nucleotide polymorphisms and breast cancer risk among the three populations. In analyses of combinations of isoflavone intake and single nucleotide polymorphisms, an inverse association between intake and risk was limited to women with the GG genotype of the rs4986938 polymorphism for postmenopausal Japanese (odds ratio for highest versus lowest tertile = 0.47; P for trend = 0.01), Japanese Brazilians (odds ratio for highest versus lowest median = 0.31) and non-Japanese Brazilians (odds ratio for consumers versus non-consumers = 0.37) (P for interaction = 0.11, 0.08, and 0.21, respectively). We found no remarkable difference for the other four polymorphisms. Our findings suggest that polymorphisms in the estrogen receptor beta gene may modify the association between isoflavone intake and breast cancer risk.

Dietary isoflavone intake and breast cancer risk in case-control studies in Japanese, Japanese Brazilians, and non-Japanese Brazilians.

Although epidemiologic studies have shown an inverse association between isoflavones and breast cancer risk, little evidence for a dose-response relation is available. We conducted hospital-based case-control studies of patients aged 20-74 years with primary, incident, histologically confirmed invasive breast cancer, and matched controls from medical checkup examinees in Nagano, Japan and from cancer-free patients in São Paulo, Brazil. A total of 850 pairs (390 Japanese, 81 Japanese Brazilians and 379 non-Japanese Brazilians) completed validated food frequency questionnaires. The odds ratio of breast cancer according to isoflavone intake was estimated using a conditional logistic regression model. We found a statistically significant inverse association between isoflavone intake and the risk of breast cancer for Japanese Brazilians and non-Japanese Brazilians. For Japanese, a non-significant inverse association was limited to postmenopausal women. In the three populations combined, breast cancer risk linearly decreased from 'no' to 'moderate' isoflavone intake and thereafter leveled off. Compared to non-consumers, adjusted odds ratios (95% confidence interval) for consumers in increasing quintile intake categories (median intake in each category: 8.7, 23.1, 33.8, 45.7, and 71.3 mg/day) were 0.69 (0.44-1.09), 0.54 (0.31-0.94), 0.45 (0.26-0.77), 0.34 (0.19-0.62), and 0.43 (0.24-0.76), respectively. Overall, we found an inverse association between dietary isoflavone intake and risk of breast cancer. Our finding suggests a risk-reducing rather than risk-enhancing effect of isoflavones on breast cancer within the range achievable from dietary intake alone. In addition, women may benefit from risk reduction if they consume at least moderate amounts of isoflavones.

Serum organochlorines and breast cancer risk in Japanese women: a case-control study.

OBJECTIVE: Most epidemiological studies of the association between breast cancer risk and exposure to organochlorine pesticides or polychlorinated biphenyls (PCBs), which are suspected endocrine disrupters and potential risk factors for human breast cancer, have been conducted in western countries, and the majority of results have been null and the rest inconsistent. Here, we examined these associations in Japanese women in the largest study in Asian women to date. METHODS: The study was a matched case-control study of breast cancer with 403 eligible matched pairs from May 2001 to September 2005 at four hospitals in Nagano Prefecture, Japan. MEASUREMENTS: Serum samples were measured for PCBs and nine pesticide-related organochlorines, including dichlorodiphenyltrichloroethane (DDT). Odds ratios of breast cancer or its hormone-receptor-defined subtypes according to serum organochlorines were calculated. RESULTS: No increase in the risk of breast cancer was seen among women with higher serum concentrations of any organochlorine: o,p'-DDT, p,p'-DDT, p,p'-dichlorodiphenyldichloroethylene, hexachlorobenzene, beta-hexachlorocyclohexane, trans-nonachlor, cis-nonachlor, oxychlordane, mirex, or PCBs. Rather, higher serum levels of cis-nonachlor, mirex, or total PCBs were associated with a decreased risk of breast cancer CONCLUSIONS: Overall, these results suggest that breast cancer risk in Japan, a low-incidence country, is similar to that in western countries in terms of organochlorine exposure.

Association between maternal passive smoking and increased risk of delivering small-for-gestational-age infants at full-term using plasma cotinine levels from The Hokkaido Study: a prospective birth cohort.

OBJECTIVES: To investigate the association between plasma cotinine level measured at the 8th gestational month and the delivery of small-for-gestational-age (SGA) infants, using a highly sensitive ELISA method. DESIGN: Prospective birth cohort study from The Hokkaido Study on Environment and Children's Health. SETTING: Hokkaido, Japan. PARTICIPANTS: Our sample included 15 198 mother-infant pairs enrolled in 2003-2012. MAIN OUTCOME MEASURES: SGA, defined as a gestational age-specific weight Z-score below -2. RESULTS: The number of SGA infants was 192 (1.3%). The cotinine cut-off level that differentiated SGA infants from other infants was 3.03 ng/mL for both the total population and the full-term births subgroup (sensitivity 0.307; positive predictive value 2.3%). Compared with infants of mothers with a plasma cotinine level of <3.03 ng/mL, infants of mothers with a plasma cotinine level of ≥3.03 ng/mL showed an increased OR for SGA in the total population and the full-term infant group (2.02(95% CI 1.45 to 2.83) and 2.44(95% CI 1.73 to 3.44), respectively). CONCLUSION: A plasma cotinine level of ≥3.03 ng/mL, which included both passive and active smokers, was associated with an increased risk of SGA. This finding is of important relevance when educating pregnant women about avoiding prenatal passive and active smoking due to the adverse effects on their infants, even those born at full-term.

A case-control study of the association between urinary cadmium concentration and endometriosis in infertile Japanese women.

Cadmium may act like an estrogen and be a potential risk factor for estrogen-related diseases such as breast cancer and endometriosis. Here, we tested the hypothesis that higher cadmium exposure is associated with endometriosis among infertile Japanese women in a hospital-based case-control study. We recruited consecutive female patients aged 20-45 years who had complained of infertility and presented to a university hospital in Tokyo. The subjects were interviewed and provided a urine sample prior to a laparoscopic diagnosis of endometriosis between January 2000 and December 2001. The severity of endometriosis was then dichotomized into controls (stage 0 and I) and cases (stage II-IV). We finally measured urinary total cadmium concentration in 54 cases and 74 controls as a biomarker of long-term cumulative exposure. Odds ratios were adjusted for average menstrual cycle length, body-mass index and smoking status using unconditional logistic regression. Results showed no association between endometriosis and urinary cadmium concentration. Medians (interquartile ranges) of urinary cadmium concentration in cases and controls were 0.53 (0.40-0.73) and 0.54 (0.34-0.76) microg/g creatinine, respectively (P for difference=0.88). Adjusted odds ratio (95% confidence interval) for the highest versus lowest tertile of urinary creatinine-adjusted cadmium concentration was 0.86 (0.30 to 2.49, P for trend=0.79). Our results do not support the hypothesis that higher urinary cadmium concentration is associated with the risk of endometriosis.

Different Risk Factors for Very Low Birth Weight, Term-Small-for-Gestational-Age, or Preterm Birth in Japan.

From 1985 to 2013, the mean birth weight of infants in Japan decreased from 3120 g to 3000 g, and the low-birth-weight rate among live births increased from 6.3% to 9.6%. No prospective study has elucidated the risk factors for poor fetal growth and preterm birth in recent Japanese parents, such as increased parental age, maternal body figure, assisted reproductive technology (ART), and socioeconomic status. Participants were mother-infant pairs (n = 18,059) enrolled in a prospective birth cohort in Hokkaido, Japan from 2002 to 2013. Parental characteristics were obtained via self-reported questionnaires during pregnancy. Medical records helped identify very-low-birth-weight (VLBW; <1500g), term-small-for-gestational-age (term-SGA), and preterm-birth (PTB; <37 weeks) infants. We calculated relative risks (RRs) for PTB, VLBW, and term-SGA birth based on parental characteristics. The prevalence of PTB, VLBW, and term-SGA was 4.5%, 0.4%, and 6.5%, respectively. Aged parents and ART were risk factors for PTB and VLBW. Maternal alcohol drinking during pregnancy increased the risk; a parental educational level of ≥16 years reduced risk of term-SGA. Maternal pre-pregnancy BMI of <18.5 kg/m² increased the risk of PTB and term-SGA. The RR for low BMI was highest among mothers who have low educational level. Among various factors, appropriate nutritional education to maintain normal BMI is important to prevent PTB and term-SGA in Japan.

Validity of a self-administered food frequency questionnaire in the assessment of heterocyclic amine intake using 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) levels in hair.

Several case-control studies have reported possible associations between heterocyclic amine (HCA) intake and the risk of cancer. The validity of questionnaires used to assess HCA intake has hardly been examined, however; in particular, no biomarker able to serve as an independent measure of habitual HCA intake has been established. In this study, we examined the validity of HCA intake estimated from a food frequency questionnaire (FFQ) using 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) level in hair as a reference method. Study subjects were 20 volunteers (7 men and 13 women) aged 25-57 years residing in Tokyo or neighboring cities in Japan. The subjects completed the FFQ, and gave 3-5g of hair twice at an interval of 1-3 months for use in establishing validity. Results showed that intakes of PhIP, MeIQ, Trp-P-1, and total HCA by the FFQ were significantly correlated with PhIP levels in hair when adjustment was made for melanin content (r=0.47, r=0.50, r=0.55, and r=0.51, respectively). The present study indicates that HCA intake estimated from this FFQ provides a reasonable ranking of individuals to allow the analysis of associations between HCA intake and risk of cancer in large-scale epidemiological studies.

Application of the adductome approach to assess intertissue DNA damage variations in human lung and esophagus.

Methods for determining the differential susceptibility of human organs to DNA damage have not yet been explored to any large extent due to technical constraints. The development of comprehensive analytical approaches by which to detect intertissue variations in DNA damage susceptibility may advance our understanding of the roles of DNA adducts in cancer etiology and as exposure biomarkers at least. A strategy designed for the detection and comparison of multiple DNA adducts from different tissue samples was applied to assess esophageal and peripherally- and centrally-located lung tissue DNA obtained from the same person. This adductome approach utilized LC/ESI-MS/MS analysis methods designed to detect the neutral loss of 2'-deoxyribose from positively ionized 2'-deoxynucleoside adducts transmitting the [M+H](+)>[M+H-116](+) transition over 374 transitions. In the final analyses, adductome maps were produced which facilitated the visualization of putative DNA adducts and their relative levels of occurrence and allowed for comprehensive comparisons between samples, including a calf thymus DNA negative control. The largest putative adducts were distributed similarly across the samples, however, differences in the relative amounts of putative adducts in lung and esophagus tissue were also revealed. The largest-occurring lung tissue DNA putative adducts were 90% similar (n=50), while putative adducts in esophagus tissue DNA were shown to be 80 and 84% similar to central and peripheral lung tissue DNA respectively. Seven DNA adducts, N(2)-ethyl-2'-deoxyguanosine (N(2)-ethyl-dG), 1,N(6)-etheno-2'-deoxyadenosine (varepsilondA), alpha-S- and alpha-R-methyl-gamma-hydroxy-1,N(2)-propano-2'-deoxyguanosine (1,N(2)-PdG(1), 1,N(2)-PdG(2)), 3-(2'-deoxyribosyl)-5,6,7,8-tetrahydro-8-hydroxy-pyrimido[1,2-a]purine-(3H)-one (8-OH-PdG) and the two stereoisomers of 3-(2'-deoxyribosyl)-5,6,7,8-tetrahydro-6-hydroxypyrimido[1,2-a]purine-(3H)-one (6-OH-PdG) were unambiguously detected in all tissue DNA samples by comparison to authentic adduct standards and stable isotope dilution and their identities were matched to putative adducts detected in the adductome maps.

Development of the adductome approach to detect DNA damage in humans.

The development of new strategies designed to detect DNA damage caused by oxidative stress and other means may advance our understanding of the roles of such types of damage in the etiology of cancers, in aging processes, and as biomarkers of exposure. A DNA adduct detection method that uses liquid chromatography coupled with electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) to detect multiple DNA adducts in human lung tissue is reported herein. This adductome analysis strategy is designed to detect the neutral loss of 2 -deoxyribose from positively ionized 2 -deoxynucleoside adducts in multiple reaction ion monitoring mode (MRM) transmitting the [M + H](+) > [M + H - 116](+) transition over a total of 374 transitions in the mass range from m/z 228.8 to m/z 602.8. Data analysis is optimized and coupled with a comprehensive manual screening process designed to minimize the number of artifactual adducts appearing in the final analysis. In the final analysis, putative adducts were organized into an adductome map and unambiguous confirmation of selected oxidative adducts were made by stable isotope dilution and comparison to authentic standards. The future applications of this method are discussed.

Effect of Helicobacter pylori infection combined with CagA and pepsinogen status on gastric cancer development among Japanese men and women: a nested case-control study.

BACKGROUND: Although accumulating evidence suggests that Helicobacter pylori plays a role in gastric carcinogenesis, the magnitude of the risk remains uncertain. AIM: We aimed to estimate the magnitude of the risk of gastric cancer associated with H. pylori infection by a large case-control study nested within a prospective cohort. Possible effect modification by CagA status, and serum pepsinogen status, as a marker of atrophic gastritis, was also considered to see its effect on developing gastric cancer. SUBJECTS AND METHODS: Subjects (n = 123,576) were followed up from 1990 to 2004; 511 gastric cancer cases matched to 511 controls were used in the analysis. Plasma immunoglobulin G antibody to H. pylori, CagA, and pepsinogen I and II were measured. RESULTS: The adjusted odds ratio (95% confidence interval) of gastric cancer associated with H. pylori infection was 5.1 (3.2-8.0). Assuming all CagA-positive subjects are true H. pylori positives doubled this risk. Atrophic gastritis was also associated with an elevated risk of gastric cancer and the risk increased further with pepsinogen levels. CONCLUSIONS: Subjects with pepsinogen levels indicative of severe atrophic gastritis may need careful examination regularly regardless of H. pylori infection. Those who have other pepsinogen levels but who are H. pylori seropositive are likely to benefit from H. pylori eradication therapy. Considering both the cost and the potential for misclassification that may occur using multiple serologic tests, caution is needed in interpreting or extrapolating these findings into a screening strategy.

Decreased serum free testosterone in workers exposed to high levels of di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP): a cross-sectional study in China.

BACKGROUND: Observations of adverse developmental and reproductive effects in laboratory animals and wildlife have fueled increasing public concern regarding the potential for various chemicals to impair human fertility. OBJECTIVE: Our objective in this study was to assess the effect of occupational exposure to high levels of phthalate esters on the balance of gonadotropin and gonadal hormones including luteinizing hormone, follicle-stimulating hormone, free testosterone (fT), and estradiol. METHODS: We examined urine and blood samples of 74 male workers at a factory producing unfoamed polyvinyl chloride flooring exposed to di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP) and compared them with samples from 63 male workers from a construction company, group matched for age and smoking status. RESULTS: Compared to the unexposed workers, the exposed workers had substantially and significantly elevated concentrations of mono-n-butyl phthalate (MBP; 644.3 vs. 129.6 microg/g creatinine, p < 0.001) and mono-2-ethylhexyl phthalate (MEHP; 565.7 vs. 5.7 microg/g creatinine, p < 0.001). fT was significantly lower (8.4 vs. 9.7 microg/g creatinine, p = 0.019) in exposed workers than in unexposed workers. fT was negatively correlated to MBP (r = -0.25, p = 0.03) and MEHP (r = -0.19, p = 0.095) in the exposed worker group. Regression analyses revealed that fT decreases significantly with increasing total phthalate ester score (the sum of quartiles of MBP and MEHP; r = -0.26, p = 0.002). CONCLUSION: We observed a modest and significant reduction of serum fT in workers with higher levels of urinary MBP and MEHP compared with unexposed workers.

Mortality of iron-steel workers in Anshan, China: a retrospective cohort study.

Foundry workers have increased mortality and morbidity risks from numerous causes, including various cancers. A retrospective Chinese iron-steel cohort study was conducted to examine the mortality effects of exposure to foundry work. Standardized mortality ratios (SMRs) and standardized rate ratios (SRRs) were calculated to evaluate mortality risks among male workers with exposure to 15 hazardous factors, adjusting for confounders. During 14 years of follow-up, 13,363 of 121,846 male workers died. SMR analysis showed a healthy-worker effect in comparison with the general population. SRR analysis showed increased risks for all causes, all neoplasms, and others among the exposed workers compared with non-exposed blue-collar workers. Combined exposure to polycyclic aromatic hydrocarbons and two or more dusts increased the risks of lung cancer (SRR = 654; 95% CI: 113-3,780) and other malignancies. Foundry work has adverse health effects, including carcinogenic risks.