Chikako Kiyohara

Influence of antibiotic exposure in the early postnatal period on the development of intestinal microbiota

The influence of antibiotic exposure in the early postnatal period on the development of intestinal microbiota was monitored in 26 infants including five antibiotic-treated (AT) subjects orally administered a broad-spectrum antibiotic for the first 4 days of life and three caesarean-delivered (CD) subjects whose mothers were intravenously injected by the similar type of antibiotics in the same period. The faecal bacterial composition was analysed daily for the first 5 days and monthly for the first 2 months. Terminal restriction fragment length polymorphisms in the AT subjects showed less diversity with the attenuation of the colonization of some bacterial groups, especially in Bifidobacterium and unusual colonization of Enterococcus in the first week than the control antibiotic-free infants (AF, n=18). Quantitative real-time PCR showed overgrowth of enterococci (day 3, P=0.01; day 5, P=0.003; month 1, P=0.01) and arrested growth of Bifidobacterium (day 3, P=0.03) in the AT group. Furthermore, after 1 month, the Enterobacteriaceae population was markedly higher in the AT group than in the AF group (month 1, P=0.02; month 2, P=0.02). CD infants sustained similar, although relatively weaker, alteration in the developing microbiota. These results indicate that antibiotic exposure at the beginning of life greatly influences the development of neonatal intestinal microbiota.

Genetic polymorphisms and lung cancer susceptibility: a review.

Lung cancer is a major cause of cancer-related death in the developed countries and the overall survival rate has still an extremely poor. Cigarette smoking is an established risk factor for lung cancer although a possible role for genetic susceptibility in the development of lung cancer has been inferred from familial clustering of the disease and segregation analyzes. Everyone may have a unique combination of polymorphic traits that modify genetic susceptibility and response to drugs, chemicals and carcinogens. Developments in molecular biology have led to growing interest in investigation of biological markers, which may increase predisposition to lung carcinogenesis. Therefore, the high-risk genotype of an individual could be determined easily. As there are the great number of carcinogen-activating and -detoxifying enzymes, the variation in their expression and the complexity of exposures to tobacco carcinogens, the existence of multiple alleles at loci of those enzymes may result in differential susceptibilities of individuals. This review summarize data addressing the relationships of lung cancer to markers of genetic susceptibility genes, including metabolic polymorphisms other than well-investigated cytochrome P450s or glutathione S-transferases, DNA repair genes and the p53 tumor suppressor gene. Among genetic polymorphisms reviewed here, myeloperoxidase gene (a G to A mutation) and microsomal epoxide hydrolase exon 4 polymorphism (substitution of Arg for His) were significantly associated with lung cancer risk. As lung cancer is a multifactorial disease, an improved understanding of the interplay of environmental and genetic polymorphisms at multiple loci may help identify individuals who are at increased risk for lung cancer. Hopefully, in the future we will be able to screen for lung cancer susceptibility by using specific biomarkers.

Obesity, Weight Gain and Risk of Colon Adenomas in Japanese Men

Obesity has been related to increased risk of colon cancer or adenomas, but the epidemiologic findings are not entirely consistent. We examined the relation of not only body mass index (BMI) but also waist‐to‐hip ratio (WHR) and weight gain to colon adenoma risk in men who received a preretirement health examination at the Japan Self Defense Forces (SDF) Fukuoka and Kumamoto Hospitals during the period from 995 to 1996. In the series of 803 men at age 47–55 years, 189 cases of colon adenomas and 226 controls with normal total colonoscopy were identified. Weight at 10 years before was ascertained by referring to the recorded data. After allowance for hospital, rank in the SDF, smoking and alcohol use, weight gain over the past 10 years was significantly associated with increased risk of colon adenomas (odds ratio for ≥ 6 kg versus ≤−2 kg = 2.2; 95% confidence interval 1.0–4.8). High BMI and high WHR were each associated with increased risk, but only WHR was related to the risk independently of weight gain. In particular, weight gain accompanied with a high WHR was associated with a significant increase in the risk. Men with high physical activity tended to have lower risk. Associations with obesity‐related variables and physical activity were not materially differential as regards the location and size of adenoma. The findings indicate that weight gain in middle age leading to abdominal obesity increases the risk of colon adenomas, and consequently of colon cancer.

The Relationship between Aryl Hydrocarbon Hydroxylase and Polymorphisms of the CYP1A1 Gene

We examined the relationship between aryl hydrocarbon hydroxylase (AHH) and the frequency of a Msp I mutation in the 3′‐flanking region of cytochrome P450 (CYP) 1A1 (Mspl polymorphism) and another mutation in exon 7 (Ile‐Val polymorphism) in 84 healthy male subjects in Fukuoka, Japan. AHH inducibility (3‐methylcholanthrene (MC)‐induced AHH activity/non‐induced AHH activity) was correlated with the MspI polymorphism (P<0.0001) and age class (P=0.015), whereas no correlation was found for the Ile‐Val polymorphism (P=0.509). Age‐adjusted AHH inducibility (mean±SE) of the predominant homozygote (genotype A), the heterozygote (genotype B) and a homozygote rare allele (genotype C) genotypes was 4.89±0.36, 4.82±0.29 and 13.61±1.44, respectively. The genotype C showed much higher AHH inducibility than genotypes A and B (P<0.001), while no significant difference was observed between genotypes A and B. Non‐induced AHH activity was also correlated with these polymorphisms. The AHH activity of a homozygous mutant Val/Val genotype (0.076±0.010 pmol/min/106 cells) was significantly higher (P<0.05) than that of the wild‐type homozygous Ile/Ile (0.044±0.004 pmol/min/106 cells) and heterozygous Ile/Val (0.047±0.007 pmol/min/106 cells) genotypes. Our study suggests that the genotypes C and Val/Val, which are more frequent in smoking‐related lung cancer, are closely related with high AHH inducibility and high non‐induced AHH activity, respectively. Thus, the positive relationship between AHH inducibility and lung cancer is supported by our study. If our results are confirmed and the assessment of genotype becomes feasible on a population basis, identification of smokers who have genetically high susceptibility to lung cancer (genotype C or Val/Val) may become important for the prevention of lung cancer.

CYP1A1 T3801 C polymorphism and lung cancer: A pooled analysis of 2,451 cases and 3,358 controls

CYP1A1 is involved in the metabolism of benzopyrene, a suspected lung carcinogen; it is therefore conceivable that genetically determined variations in its activity modify individual susceptibility to lung cancer. The role of the CYP1A1 MspI polymorphism in lung cancer has been widely studied but has not been fully clarified. We have included 2,451 cases and 3,358 controls in a pooled analysis of 22 case‐control studies on CYP1A1 and lung cancer risk. We found a clear association between the CYP1A1 homozygous MspI restriction fragment length polymorphism (RFLP) and lung cancer risk in Caucasians (age‐ and gender‐adjusted odds ratio = 2.36; 95% confidence interval 1.16–4.81); other associations were weaker or not statistically significant. The association with the homozygous variant was equally strong for squamous cell carcinomas and adenocarcinomas among Caucasians. We analyzed the risk by duration of smoking: for Caucasian subjects with the MspI RFLP combined variants (homozygotes plus heterozygotes), the increase in the risk of lung cancer was steeper than among the individuals with the homozygous reference allele. Our analysis suggests that Caucasians with homozygous variant CYP1A1 polymorphism have a higher risk of lung cancer. The data were more consistent among Caucasians, with a strong association between the homozygous variant in both squamous cell carcinomas and adenocarcinomas, and a stronger association in men than in women. The analyses were more inconsistent and failed to reach statistical significance in Asians. This observation might be due to design specificities or unknown effect modifiers in the Asian studies.

Sex differences in lung cancer susceptibility: a review.

BACKGROUND Several epidemiologic and molecular epidemiologic studies have indicated that, for a given number of cigarettes smoked, women may be at higher risk of lung cancer compared with men. OBJECTIVE The objective of this article was to address sex differences in lung cancer susceptibility, with special emphasis on genetic, biological, and sex-related hormonal factors. METHODS Using the search terms gender or sex difference in combination with lung cancer, susceptibility, survival, polymorphism, biomarker, and smoking, we conducted a review of the available literature in the MEDLINE, Current Contents, and Web of Science biomedical databases. Relevant English-language publications (January 1966-December 2009) on sex differences in lung cancer were identified. RESULTS Higher levels of polycyclic aromatic hydrocarbon DNA adducts were observed in female lung cancer patients compared with their male counterparts, even though the level of tobacco carcinogens was lower among women than among men. DNA repair capacity was found to be lower in female lung cancer patients than in their male counterparts. A higher frequency of G-to-T transversion mutations in the tumor suppressor protein p53 gene has been observed in women compared with men. Non-small cell lung tumors in women appeared to be more likely than those in men to harbor K-ras, c-erbB-2, or epidermal growth factor receptor mutations. Sex differences have been identified in the expression of the cytochrome P4501A1 gene and gastrin-releasing peptide receptor gene, with women exhibiting higher gene expression than men for both of these genes. Evidence supporting a possible association between estrogen and lung cancer risk based on epidemiologic studies has not been consistent, but sex hormones may influence susceptibility to lung carcinogenesis. CONCLUSIONS Women may be more susceptible to tobacco smoke and potentially more vulnerable to lung cancer development. If additional studies yield supporting evidence, researchers, the public, and policy makers should focus on ways to reduce the risk of lung cancer for women.

International Lung Cancer Consortium: Pooled Analysis of Sequence Variants in DNA Repair and Cell Cycle Pathways

Background: The International Lung Cancer Consortium was established in 2004. To clarify the role of DNA repair genes in lung cancer susceptibility, we conducted a pooled analysis of genetic variants in DNA repair pathways, whose associations have been investigated by at least 3 individual studies. Methods: Data from 14 studies were pooled for 18 sequence variants in 12 DNA repair genes, including APEX1, OGG1, XRCC1, XRCC2, XRCC3, ERCC1, XPD, XPF, XPG, XPA, MGMT, and TP53. The total number of subjects included in the analysis for each variant ranged from 2,073 to 13,955 subjects. Results: Four of the variants were found to be weakly associated with lung cancer risk with borderline significance: these were XRCC3 T241M [heterozygote odds ratio (OR), 0.89; 95% confidence interval (95% CI), 0.79-0.99 and homozygote OR, 0.84; 95% CI, 0.71-1.00] based on 3,467 cases and 5,021 controls from 8 studies, XPD K751Q (heterozygote OR, 0.99; 95% CI, 0.89-1.10 and homozygote OR, 1.19; 95% CI, 1.02-1.39) based on 6,463 cases and 6,603 controls from 9 studies, and TP53 R72P (heterozygote OR, 1.14; 95% CI, 1.00-1.29 and homozygote OR, 1.20; 95% CI, 1.02-1.42) based on 3,610 cases and 5,293 controls from 6 studies. OGG1 S326C homozygote was suggested to be associated with lung cancer risk in Caucasians (homozygote OR, 1.34; 95% CI, 1.01-1.79) based on 2,569 cases and 4,178 controls from 4 studies but not in Asians. The other 14 variants did not exhibit main effects on lung cancer risk. Discussion: In addition to data pooling, future priorities of International Lung Cancer Consortium include coordinated genotyping and multistage validation for ongoing genome-wide association studies. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3081–9)

Risk of postpartum depression in relation to dietary fish and fat intake in Japan: The Osaka Maternal and Child Health Study

BACKGROUND An ecological analysis found that the docosahexaenoic acid content in mothers milk and seafood intake were inversely correlated with postpartum depression. This prospective study investigated the relationship of consumption of selected high-fat foods and specific types of fatty acids with the risk of postpartum depression. METHOD The subjects were 865 Japanese women. Dietary data were obtained from a self-administered diet history questionnaire during pregnancy. The Edinburgh Postnatal Depression Scale (EPDS) was used for the evaluation of postpartum depression. Adjustment was made for age, gestation, parity, cigarette smoking, family structure, family income, education, changes in diet in the previous month, season when data at baseline were collected, body mass index, time of delivery before the second survey, medical problems in pregnancy, babys sex and babys birthweight. RESULTS The percentage of women with high depression scores was 14.0%. No evident dose-response associations were observed between intake of fish, meat, eggs, dairy products, total fat, saturated fatty acids, monounsaturated fatty acids, n-3 polyunsaturated fatty acids, n-6 polyunsaturated fatty acids, linoleic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid and the ratio of n-3 to n-6 polyunsaturated fatty acids and the risk of postpartum depression. However, there was an inverted J-shaped relationship between intake of n-3 polyunsaturated fatty acids and docosahexaenoic acid and the risk of postpartum depression. CONCLUSIONS This study failed to substantiate a clear inverse relationship between fish and n-3 polyunsaturated fatty acid intake and postpartum depression. Further investigations are needed to determine whether fish and n-3 polyunsaturated fatty acid consumption is preventive against postpartum depression.

Polymorphisms of human Ah receptor gene are not involved in lung cancer.

The Ah receptor (Ahr) is a ligand-dependent transcription factor that positively regulates inducible expression of the CYP1A1 gene. Based on the sequence information of the human Ahr and the intron-exon junctions of the mouse counterpart, an analysis of single-strand conformational polymorphism (SSCP) was carried out to detect subtle base differences in the coding region of the gene among individuals. We found that the Ahr protein has at least two forms of variants in a Japanese gene pool, and that these variants can be ascribed to one amino acid replacement of Arg by Lys at codon 554. The frequencies of Arg-coded and Lys-coded alleles were 0.57 and 0.43, respectively. We found, however, that this germ line polymorphism of the Ahr gene did not show a significant association with aryl hydrocarbon hydroxylase (AHH) inducibility nor with lung cancer incidence.

Diversity in gut bacterial community of school-age children in Asia

Asia differs substantially among and within its regions populated by diverse ethnic groups, which maintain their own respective cultures and dietary habits. To address the diversity in their gut microbiota, we characterized the bacterial community in fecal samples obtained from 303 school-age children living in urban or rural regions in five countries spanning temperate and tropical areas of Asia. The microbiota profiled for the 303 subjects were classified into two enterotype-like clusters, each driven by Prevotella (P-type) or Bifidobacterium/Bacteroides (BB-type), respectively. Majority in China, Japan and Taiwan harbored BB-type, whereas those from Indonesia and Khon Kaen in Thailand mainly harbored P-type. The P-type microbiota was characterized by a more conserved bacterial community sharing a greater number of type-specific phylotypes. Predictive metagenomics suggests higher and lower activity of carbohydrate digestion and bile acid biosynthesis, respectively, in P-type subjects, reflecting their high intake of diets rich in resistant starch. Random-forest analysis classified their fecal species community as mirroring location of resident country, suggesting eco-geographical factors shaping gut microbiota. In particular, children living in Japan harbored a less diversified microbiota with high abundance of Bifidobacterium and less number of potentially pathogenic bacteria, which may reflect their living environment and unique diet.