パラベン類曝露とヒト生殖機能との関連

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 吉田 好邦, 東京大学教授 多部田 茂, 東京大学准教授 布浦 鉄兵, 東京大学准教授 梅崎 昌裕, 東洋大学教授 吉永 淳University of Tokyo(東京大学

Identification of the sex-determining factor in the liverwort Marchantia polymorpha reveals unique evolution of sex chromosomes in a haploid system

半数体生物の性染色体上の性決定遺伝子を解明 --コケがもつ現生生物最古の起源の性染色体--. 京都大学プレスリリース. 2021-11-08.Sex determination is a central process for sexual reproduction and is often regulated by a sex determinant encoded on a sex chromosome. Rules that govern the evolution of sex chromosomes via specialization and degeneration following the evolution of a sex determinant have been well studied in diploid organisms. However, distinct predictions apply to sex chromosomes in organisms where sex is determined in the haploid phase of the life cycle: both sex chromosomes, female U and male V, are expected to maintain their gene functions, even though both are non-recombining. This is in contrast to the X-Y (or Z-W) asymmetry and Y (W) chromosome degeneration in XY (ZW) systems of diploids. Here, we provide evidence that sex chromosomes diverged early during the evolution of haploid liverworts and identify the sex determinant on the Marchantia polymorpha U chromosome. This gene, Feminizer, encodes a member of the plant-specific BASIC PENTACYSTEINE transcription factor family. It triggers female differentiation via regulation of the autosomal sex-determining locus of FEMALE GAMETOPHYTE MYB and SUPPRESSOR OF FEMINIZATION. Phylogenetic analyses of Feminizer and other sex chromosome genes indicate dimorphic sex chromosomes had already been established 430 mya in the ancestral liverwort. Feminizer also plays a role in reproductive induction that is shared with its gametolog on the V chromosome, suggesting an ancestral function, distinct from sex determination, was retained by the gametologs. This implies ancestral functions can be preserved after the acquisition of a sex determination mechanism during the evolution of a dominant haploid sex chromosome system

Population attributable fraction of risk factors for low birth weight in the Japan Environment and Children’s Study

Background: Low birth weight (LBW), which is considered a birth weight of <2500  g, poses significant health problems for children. However, population attributable fraction (PAF) of risk factors for LBW have not been well studied. Objective: We aimed to re-evaluate associations between risk factors for LBW reported in previous studies that used the Japan Environment and Children’s Study (JECS) data, and to estimate the magnitude of risk using PAF. Methods: Data including 91,559 mother–child dyads were obtained from JECS. Risk factors identified by previous studies that used JECS data were used to calculate odds ratios for LBW using a Bayesian logistic regression model. Based on calculated odds ratios, the PAF was calculated. Results: Parity, history of adenomyosis, hypertension disorder of pregnancy, maternal age at birth, prepregnancy body mass index, gestational weight gain (GWG), maternal smoking and lead (Pb) exposure were all significantly associated with LBW. The sum of the PAF of all factors was 79.4 %, with the largest PAF among single risk factors being GWG (16.5 %); the environmental portion of the PAF (Pb exposure, 14.6 % + maternal smoking, 12.1 %) surpassed the PAF of GWG. Conclusion: Our findings suggest that the number of births classified as LBW can be reduced by approximately 27% if Pb exposure is reduced to the lowest quartile and maternal smoking is eliminated. Further investigations are needed to identify unknown risk factors for LBW

Optimal method for determining the intraclass correlation coefficients of urinary biomarkers such as dialkylphosphates from imputed data

Urinary biomarkers are commonly used in epidemiological studies as surrogates or indicators of exposure to chemical substances. Evaluating the reliability of a biomarker is highly important because use of an unreliable marker may lead to misclassification and attenuation bias, resulting in flawed interpretations and conclusions. Although intraclass correlation coefficient (ICC) is regarded as a typical index of test reliability, methods for determining the ICCs of urinary biomarkers have not been standardised, and different methods have been used. This study evaluated different imputation methods for left-censored data, i.e., four imputation or one substitution methods, before calculating ICCs, and at the same time mathematically assessed the impact of the left-censoring proportion on the estimated ICCs. Biomarkers of exposure to organophosphate pesticides, i.e., dialkylphosphates, were used as an example. The Gibbs sampler-based left-censored missing value imputation approach had the best performance for imputation of values below reporting limits, with lower values on Kolmogorov–Smirnov test statistics than other imputation/substitution methods, i.e., a univariate distribution fitting approach, multiple imputation by chained equation, a bootstrap expectation–maximisation algorithm approach, and a single value substitution. In all imputation methods, however, ICCs decreased as censoring rates increased. We propose a method to estimate true ICCs based on mathematical estimation

Urinary concentrations of environmental phenol among pregnant women in the Japan Environment and Children’s Study

Humans are exposed to various bisphenols, alkylphenols and nitrophenols through dietary intake, food packaging and container materials, indoor and outdoor air/dust. This study aimed to evaluate exposure of Japanese pregnant women to environmental phenols by measuring target compounds in urine samples. From a cohort of the Japan Environment and Children’s Study, 4577 pregnant women were selected. Bisphenol A (BPA), bisphenol S (BPS), bisphenol F (BPF), bisphenol AF (BPAF), para-nitrophenol (PNP), 3-methyl-4-nitrophenol (PNMC), branched 4-nonylphenol (4-NP), linear 4-nonylphenol and 4-tert-octylphenol (4-t-OP) were analysed using a high-performance liquid chromatograph coupled to a triple-quadrupole mass spectrometer. The urinary metabolite data were combined with a questionnaire to examine the determinants of phenol exposure by machine learning. The estimated daily intake (EDI) and hazard quotient (HQ) of BPA were calculated. PNP (68.2%) and BPA (71.5%) had the highest detection frequencies, with median concentrations of 0.76 and 0.46 μg/g creatinine, respectively. PNMC, BPS, BPF and 4-NP were determined in 24.9%, 11.9%, 1.3% and 0.4% of samples, respectively, whereas BPAF (0.02%) and 4-t-OP (0.02%) were only determined in a few samples. The PNP concentrations measured in this study were comparable with those reported in previous studies, whereas the BPA concentrations were lower than those reported previously worldwide. The EDI of BPA was 0.014 μg/kg body weight/day. Compared with the tolerable daily intake set by the German Federal Institute for Risk Assessment, the median (95th percentile) HQ was 0.044 (0.2). This indicates that the observed levels of BPA exposure pose a negligible health risk to Japanese pregnant women. Determinants of bisphenol and nitrophenol exposure could not be identified by analysing the questionnaire solely, suggesting that biological measurement is necessary to assess exposure of pregnant women to bisphenols and nitrophenols. This is the first study to report environmental phenol exposure of Japanese pregnant women on a nationwide scale

Urinary 8-Hydroxy-2′-deoxyguanosine (8-OHdG) Concentrations and Menstrual Cycle Characteristics in Female University Students

Higher concentrations of oxidative stress biomarkers are found in women with polycystic ovary syndrome (PCOS) and endometriosis, conditions linked to irregular menstrual cycles and menstrual pain. The aim of the present study was to test whether women with higher oxidative stress are more likely to show irregular menstrual cycles and severe menstrual pain compared with women with lower oxidative stress. A cross-sectional study was conducted targeting female university students with a mean (SD) age of 20.5 (1.8) years (n = 188). Participants completed a questionnaire on reproductive characteristics and anthropometry and kept a menstrual cycle diary for 5 consecutive months. Urinary 8-hydroxy-2&prime;-deoxyguanosine (8-OHdG), cotinine, and creatinine concentrations were measured once during the study period. The mean (SD) value of the urinary 8-OHdG concentration was 4.7 (2.0) &mu;g/g of creatinine. A total of 1021 menstrual cycles were recorded. The participants were categorized as either having regular (68%) or irregular (18%) cycles or oligomenorrhea (13%) or polymenorrhea (1%). The urinary 8-OHdG concentration did not significantly differ across menstrual cycle regularity or pain categories. Even after adjusting for age, body mass index (BMI), and urinary cotinine concentrations, having irregular cycles or more severe menstrual pain was not associated with urinary 8-OHdG concentration

Health Risk Assessment and Source Apportionment of Mercury, Lead, Cadmium, Selenium, and Manganese in Japanese Women: An Adjunct Study to the Japan Environment and Children’s Study

Toxic element pollution is a serious global health concern that has been attracting considerable research. In this study, we elucidated the major routes of exposure to three toxic elements (mercury, cadmium, and lead) and two essential elements (manganese and selenium) through diet, soil, house dust, and indoor air and assessed the potential health risks from these elements on women from the coastal area of Miyagi prefecture, Japan. Twenty-four-hour duplicate diet, house dust, soil, and indoor air samples were collected from 37 participants. Cd, Pb, Mn, and Se concentrations were measured using inductively coupled plasma mass spectrometry, and Hg concentrations using cold vapor atomic absorption spectrometry. We found that soil and house dust were the primary reservoirs of these elements. Diet contributed most strongly to the daily intake of these elements, with mean values of 0.72, 0.25, 0.054, 47, and 0.94 &mu;g/kg/day for Hg, Cd, Pb, Mn, and Se, respectively. The mean hazard quotient of Hg was 1.53, indicating a high potential health risk from Hg exposure in daily lives. The intakes of other elements were below the tolerable limits. Future studies with a larger sample size are warranted to confirm our findings