Publications by authors named "Chihiro Miyashita"

104 Publications

Hypertensive Disorders during Pregnancy and Anthropometric Measurement of Children up to 7 Years of Age: The Hokkaido Birth Cohort Study in Japan.

Int J Environ Res Public Health 2021 Oct 18;18(20). Epub 2021 Oct 18.

Center for Environmental and Health Sciences, Hokkaido University, North-12, West-7, Kita-ku, Sapporo 060-0812, Japan.

Hypertensive disorders during pregnancy (HDP) increase the risk of offspring with a low birth weight, preterm birth and small-for-gestational age; however, evidence of the anthropometric measurements during early childhood remains limited. We aimed to understand the associations between maternal HDP and anthropometric measurements of children aged up to seven years in a Japanese cohort. In total, 20,926 mother-infant pairs participated in the Hokkaido Study on Environment and Children's Health, Japan, from 2002 to 2013. Medical reports were used to confirm HDP exposure, while weight, height, height z score, and weight z score were the outcomes. The prevalence of HDP in the study population was 1.7%. The birth height of male children born to HDP mothers was smaller as compared to those born to non-HDP mothers. When adjusted with covariates, the linear regressions showed significant changes in birth weight (β: -79.3; 95% confidence interval [CI]: -154.8, -3.8), birth height (-0.67; 95% CI: -1.07, -0.26), weight at seven years (1.21; 95% CI: 0.13, 2.29), and weight gain between four and seven years (1.12; 95% CI: 0.28, 1.96) of male children exposed to HDP. Differences were more significant in male children than female. Our study showed that despite low birth weight, male children exposed to HDP caught up with their growth and gained more weight by seven years of age compared with male children not exposed to HDP, whereas no such differences were observed in female children; however, this finding requires replication.
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http://dx.doi.org/10.3390/ijerph182010951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8536157PMC
October 2021

Association between the Concentrations of Metallic Elements in Maternal Blood during Pregnancy and Prevalence of Abdominal Congenital Malformations: The Japan Environment and Children's Study.

Int J Environ Res Public Health 2021 09 26;18(19). Epub 2021 Sep 26.

Center for Environmental and Health Sciences, Hokkaido University, North-12, West-7, Kita-ku, Sapporo 060-0812, Japan.

Abdominal congenital malformations are responsible for early mortality, inadequate nutrient intake, and infant biological dysfunction. Exposure to metallic elements in utero is reported to be toxic and negatively impacts ontogeny. However, no prior study has sufficiently evaluated the effects of exposure to metallic elements in utero on abdominal congenital malformations. The aim of the present study was to evaluate associations between metallic elements detected in maternal blood during pregnancy and congenital abdominal malformations. Data from participants in the Japan Environment and Children's Study was used in the present study, and contained information on singleton and live birth infants without congenital abnormalities (control: n = 89,134) and abdominal malformations (case: n = 139). Heavy metals such as mercury (Hg), lead (Pb), cadmium (Cd), and trace elements of manganese (Mn) and selenium (Se) were detected in maternal serum samples during mid- and late-gestation. Infant congenital abnormalities were identified from delivery records at birth or one month after birth by medical doctors. In a multivariate analysis adjusted to account for potential confounders, quartiles of heavy metals and trace elements present in maternal blood were not statistically correlated to the prevalence of abdominal congenital malformations at birth. This study is the first to reveal the absence of significant associations between exposure levels to maternal heavy metals and trace elements in utero and the prevalence of abdominal congenital malformations in a large cohort of the Japanese population. Further studies are necessary to investigate the impact of exposure to heavy metals and trace elements via maternal blood in offspring after birth.
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http://dx.doi.org/10.3390/ijerph181910103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507911PMC
September 2021

DNA methylation changes associated with prenatal mercury exposure: A meta-analysis of prospective cohort studies from PACE consortium.

Environ Res 2021 Sep 22;204(Pt B):112093. Epub 2021 Sep 22.

Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Mercury (Hg) is a ubiquitous heavy metal that originates from both natural and anthropogenic sources and is transformed in the environment to its most toxicant form, methylmercury (MeHg). Recent studies suggest that MeHg exposure can alter epigenetic modifications during embryogenesis. In this study, we examined associations between prenatal MeHg exposure and levels of cord blood DNA methylation (DNAm) by meta-analysis in up to seven independent studies (n = 1462) as well as persistence of those relationships in blood from 7 to 8 year-old children (n = 794). In cord blood, we found limited evidence of differential DNAm at cg24184221 in MED31 (β = 2.28 × 10, p-value = 5.87 × 10) in relation to prenatal MeHg exposure. In child blood, we identified differential DNAm at cg15288800 (β = 0.004, p-value = 4.97 × 10), also located in MED31. This repeated link to MED31, a gene involved in lipid metabolism and RNA Polymerase II transcription function, may suggest a DNAm perturbation related to MeHg exposure that persists into early childhood. Further, we found evidence for association between prenatal MeHg exposure and child blood DNAm levels at two additional CpGs: cg12204245 (β = 0.002, p-value = 4.81 × 10) in GRK1 and cg02212000 (β = -0.001, p-value = 8.13 × 10) in GGH. Prenatal MeHg exposure was associated with DNAm modifications that may influence health outcomes, such as cognitive or anthropometric development, in different populations.
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http://dx.doi.org/10.1016/j.envres.2021.112093DOI Listing
September 2021

Associations among maternal perfluoroalkyl substance levels, fetal sex-hormone enzymatic gene polymorphisms, and fetal sex hormone levels in the Hokkaido study.

Reprod Toxicol 2021 Oct 16;105:221-231. Epub 2021 Sep 16.

Center for Environmental and Health Sciences, Hokkaido University, North-12, West-7, Kita-ku, Sapporo, 060-0812, Japan. Electronic address:

Prenatal sex hormones affect fetal growth; for example, prenatal exposure to low levels of androgen accelerates female puberty onset. We assessed the association of perfluoroalkyl substances (PFASs) in maternal sera and infant genotypes of genes encoding enzymes involved in sex steroid hormone biosynthesis on cord sera sex hormone levels in a prospective birth cohort study of healthy pregnant Japanese women (n = 224) recruited in Sapporo between July 2002 and October 2005. We analyzed PFAS and five sex hormone levels using liquid chromatography-tandem mass spectrometry. Cytochrome P450 (CYP) 17A1 (CYP17A1 rs743572), 19A1 (CYP19A1 rs10046, rs700519, and rs727479), 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1 rs6203), type 2 (HSD3B2 rs1819698, rs2854964, and rs4659175), 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1 rs605059, rs676387, and rs2676531), and type 3 (HSD17B3 rs4743709) were analyzed using real-time PCR. Multiple linear regression models were used to establish the influence of log-transformed PFAS levels and infant genotypes on log-transformed sex steroid hormone levels. When the interaction between perfluorooctanesulfonate (PFOS) levels and female infant genotype CYP17A1 (rs743572) on the androstenedione (A-dione) levels was considered, the estimated changes (95 % confidence intervals) in A-dione levels against PFOS levels, female infant genotype CYP17A1 (rs743572)-AG/GG, and interaction between them showed a mean increase of 0.445 (0.102, 0.787), mean increase of 0.392 (0.084, 0.707), and mean reduction of 0.579 (0.161, 0.997) (P = 0.007), respectively. Moreover, a female-specific interaction with testosterone levels was observed. A-dione and T levels showed positive main effects and negative interaction with PFOS levels and the female infant CYP17A1 genotype.
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http://dx.doi.org/10.1016/j.reprotox.2021.09.003DOI Listing
October 2021

Maternal psychological distress, education, household income, and congenital heart defects: a prospective cohort study from the Japan environment and children's study.

BMC Pregnancy Childbirth 2021 Aug 7;21(1):544. Epub 2021 Aug 7.

Center for Environmental and Health Sciences, Hokkaido University, Sapporo, Japan.

Background: The influence of maternal psychological distress on infant congenital heart defects (CHDs) has not been thoroughly investigated. Furthermore, there have been no reports on the combined effect of maternal psychological distress and socioeconomic status on infant CHDs. This study aimed to examine whether maternal psychological distress, socioeconomic status, and their combinations were associated with CHD.

Methods: We conducted a prospective cohort study using data from the Japan Environment and Children's Study, which recruited pregnant women between 2011 and 2014. Maternal psychological distress was evaluated using the Kessler Psychological Distress Scale in the first trimester, while maternal education and household income were evaluated in the second and third trimesters. The outcome of infant CHD was determined using the medical records at 1 month of age and/or at birth. Crude- and confounder-adjusted logistic regression analyses were performed to evaluate the association between maternal psychological distress and education and household income on infant CHD.

Results: A total of 93,643 pairs of mothers and infants were analyzed, with 1.1% of infants having CHDs. Maternal psychological distress had a significantly higher odds ratio in the crude analysis but not in the adjusted analysis, while maternal education and household income were statistically insignificant. In the analysis of the combination variable of lowest education and psychological distress, the P for trend was statistically significant in the crude and multivariate model excluding anti-depressant medication, but the significance disappeared in the full model (P = 0.050).

Conclusions: The combination of maternal psychological distress and lower education may be a possible indicator of infant CHD.
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http://dx.doi.org/10.1186/s12884-021-04001-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348993PMC
August 2021

Association between Early Life Child Development and Family Dog Ownership: A Prospective Birth Cohort Study of the Japan Environment and Children's Study.

Int J Environ Res Public Health 2021 07 2;18(13). Epub 2021 Jul 2.

Center for Environmental and Health Sciences, Hokkaido University, Sapporo 060-0812, Japan.

Pets may play a role in the social-emotional development of children. In particular, some studies have suggested that family dog ownership is associated with better health outcomes. To date, no study has assessed child development in association with dog ownership of different time points. The purpose of the current study was primary to investigate whether "ever" family dog ownership was associated with early child development, and secondary to further examine whether associations between family dog ownership and early child development differ among family dog ownership of status, including "past only", "current only", and "always" groups, using the data of family dog ownership obtained at multiple time points. Associations between family dog ownership and infant development at 3 years of age were examined using data from a nationwide prospective birth cohort study, the Japan Environment and Children's Study ( = 78,941). "Ever" family dog ownership was categorized to "past only", "current only", and "always". We observed that children with "ever" family dog ownership showed a significantly decreased risk of developmental delay in the communication (odds ratio [OR] = 0.87; 95% confidence interval [CI]: 0.78, 0.96), gross motor (OR = 0.83; 95% CI: 0.76, 0.92), problem-solving (OR = 0.89; 95% CI: 0.83, 0.96) and personal-social (OR = 0.86; 95% CI: 0.72, 0.92) domains compared to children with "never" family dog ownership. Furthermore, a significantly decreased risk of developmental delay in gross motor function was observed in association with living with dogs in the "past only" (OR = 0.83; 95% CI: 0.73, 0.95) and "always" (OR = 0.86; 95% CI: 0.75, 0.98). In addition, a decreased risk of developmental delay in the problem-solving domain was associated with "past" family dog ownership (OR = 0.87; 95% CI: 0.79, 0.97) and in the personal-social domain was associated with "always" family dog ownership (OR = 0.81; 95% CI = 0.68, 0.95). Given the possible positive association between early life child development and family dog ownership, living with dogs may be an important factor to be considered when assessing child development.
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http://dx.doi.org/10.3390/ijerph18137082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295854PMC
July 2021

Prenatal alcohol exposure and adverse fetal growth restriction: findings from the Japan Environment and Children's Study.

Pediatr Res 2021 Jun 4. Epub 2021 Jun 4.

Center for Environmental and Health Sciences, Hokkaido University, Sapporo, Japan.

Backgrounds: Japanese studies on the association between maternal alcohol consumption and fetal growth are few. This study assessed the effect of maternal alcohol consumption on fetal growth.

Methods: This prospective birth cohort included 95,761 participants enrolled between January 2011 and March 2014 in the Japan Environment and Children's Study. Adjusted multiple linear and logistic regression models were used to assess the association between prenatal alcohol consumption and infant birth size.

Results: Consumption of a weekly dose of alcohol in the second/third trimester showed a significant negative correlation with standard deviation (SD; Z) scores for body weight, body length, and head circumference at birth, respectively. Consumption of a weekly dose of alcohol during the second/third trimester had a significant positive correlation with incidences of Z-score ≤ -1.5 for birth head circumference. Associations between alcohol consumption in the second/third trimester and Z-score ≤ -1.5 for birth weight or birth length were not significant. Maternal alcohol consumption in the second/third trimester above 5, 20, and 100 g/week affected body weight, body length, and head circumference at birth, respectively.

Conclusion: Low-to-moderate alcohol consumption during pregnancy might affect fetal growth. Public health policies for pregnant women are needed to stop alcohol consumption during pregnancy.

Impact: This study examined the association between maternal alcohol consumption and fetal growth restriction in 95,761 pregnant Japanese women using the prospective birth cohort. Maternal alcohol consumption in the second/third trimester more than 5, 20, and 100 g/week might affect fetal growth in body weight, body length, and head circumference, respectively. The findings are relevant and important for educating pregnant women on the adverse health effects that prenatal alcohol consumptions have on infants.
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http://dx.doi.org/10.1038/s41390-021-01595-3DOI Listing
June 2021

Hokkaido birth cohort study on environment and children's health: cohort profile 2021.

Environ Health Prev Med 2021 May 22;26(1):59. Epub 2021 May 22.

Faculty of Medicine and Graduate School of Medicine, Center for Medical Education and International Relations, Hokkaido University, Sapporo, Japan.

Background: 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 objectives are to (1) examine the effects that low-level environmental chemical exposures have on birth outcomes, including birth defects and growth retardation; (2) follow the development of allergies, infectious diseases, and neurobehavioral developmental disorders, as well as perform a longitudinal observation of child development; (3) identify high-risk groups based on genetic susceptibility to environmental chemicals; and (4) identify the additive effects of various chemicals, including tobacco.

Methods: The purpose of this report is to provide an update on the progress of the Hokkaido Study, summarize recent results, and suggest future directions. In particular, this report provides the latest details from questionnaire surveys, face-to-face examinations, and a collection of biological specimens from children and measurements of their chemical exposures.

Results: The latest findings indicate different risk factors of parental characteristics on birth outcomes and the mediating effect between socioeconomic status and children that are small for the gestational age. Maternal serum folate was not associated with birth defects. Prenatal chemical exposure and smoking were associated with birth size and growth, as well as cord blood biomarkers, such as adiponectin, leptin, thyroid, and reproductive hormones. We also found significant associations between the chemical levels and neuro development, asthma, and allergies.

Conclusions: Chemical exposure to children can occur both before and after birth. Longer follow-up for children is crucial in birth cohort studies to reinforce the Developmental Origins of Health and Disease hypothesis. In contrast, considering shifts in the exposure levels due to regulation is also essential, which may also change the association to health outcomes. This study found that individual susceptibility to adverse health effects depends on the genotype. Epigenome modification of DNA methylation was also discovered, indicating the necessity of examining molecular biology perspectives. International collaborations can add a new dimension to the current knowledge and provide novel discoveries in the future.
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http://dx.doi.org/10.1186/s12199-021-00980-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141139PMC
May 2021

Associations among perfluorooctanesulfonic/perfluorooctanoic acid levels, nuclear receptor gene polymorphisms, and lipid levels in pregnant women in the Hokkaido study.

Sci Rep 2021 05 11;11(1):9994. Epub 2021 May 11.

Center for Environmental and Health Sciences, Hokkaido University, North-12, West-7, Kita-ku, Sapporo, 060-0812, Japan.

The effect of interactions between perfluorooctanesulfonic (PFOS)/perfluorooctanoic acid (PFOA) levels and nuclear receptor genotypes on fatty acid (FA) levels, including those of triglycerides, is not clear understood. Therefore, in the present study, we aimed to analyse the association of PFOS/PFOA levels and single-nucleotide polymorphisms (SNPs) in nuclear receptors with FA levels in pregnant women. We analysed 504 mothers in a birth cohort between 2002 and 2005 in Japan. Serum PFOS/PFOA and FA levels were measured using liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Maternal genotypes in PPARA (rs1800234; rs135561), PPARG (rs3856806), PPARGC1A (rs2970847; rs8192678), PPARD (rs1053049; rs2267668), CAR (rs2307424; rs2501873), LXRA (rs2279238) and LXRB (rs1405655; rs2303044; rs4802703) were analysed. When gene-environment interaction was considered, PFOS exposure (log scale) decreased palmitic, palmitoleic, and oleic acid levels (log scale), with the observed β in the range of - 0.452 to - 0.244; PPARGC1A (rs8192678) and PPARD (rs1053049; rs2267668) genotypes decreased triglyceride, palmitic, palmitoleic, and oleic acid levels, with the observed β in the range of - 0.266 to - 0.176. Interactions between PFOS exposure and SNPs were significant for palmitic acid (P = 0.004 to 0.017). In conclusion, the interactions between maternal PFOS levels and PPARGC1A or PPARD may modify maternal FA levels.
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http://dx.doi.org/10.1038/s41598-021-89285-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113244PMC
May 2021

Effect of prenatal exposure to phthalates on epigenome-wide DNA methylations in cord blood and implications for fetal growth: The Hokkaido Study on Environment and Children's Health.

Sci Total Environ 2021 Aug 17;783:147035. Epub 2021 Apr 17.

Hokkaido University Center for Environmental and Health Sciences, Sapporo, Japan. Electronic address:

Prenatal exposure to phthalates negatively affects the offspring's health. In particular, epigenetic alterations, such as DNA methylation, may connect phthalate exposure with health outcomes. Here, we evaluated the association of di-2-ethylhexyl phthalate (DEHP) exposure in utero with cord blood epigenome-wide DNA methylation in 203 mother-child pairs enrolled in the Hokkaido Study on Environment and Children's Health, using the Illumina HumanMethylation450 BeadChip. Epigenome-wide association analysis demonstrated the predominant positive associations between the levels of the primary metabolite of DEHP, mono(2-ethylhexyl) phthalate (MEHP), in maternal blood and DNA methylation levels in cord blood. The genes annotated to the CpGs positively associated with MEHP levels were enriched for pathways related to metabolism, the endocrine system, and signal transduction. Among them, methylation levels of CpGs involved in metabolism were inversely associated with the offspring's ponderal index (PI). Further, clustering and mediation analyses suggested that multiple increased methylation changes may jointly mediate the association of DEHP exposure in utero with the offspring's PI at birth. Although further studies are required to assess the impact of these changes, this study suggests that differential DNA methylation may link phthalate exposure in utero to fetal growth and further imply that DNA methylation has predictive value for the offspring's obesity.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147035DOI Listing
August 2021

Parental educational level and childhood wheezing and asthma: A prospective cohort study from the Japan Environment and Children's Study.

PLoS One 2021 16;16(4):e0250255. Epub 2021 Apr 16.

Center for Environmental and Health Sciences, Hokkaido University, Sapporo, Japan.

Background: The influence of mothers' and fathers' educational levels in separate evaluations of asthma has not been fully investigated. This study aims to examine the associations of the mother's and fathers' educational levels with childhood wheeze and asthma adjusting for crude and pre-and post-natal modifiable risk factors.

Methods: We conducted a prospective cohort study using data from the Japan Environment and Children's Study, which recruited pregnant women from 2011 to 2014. The mother's and father's educational levels were surveyed by a questionnaire during the pregnancy, and childhood wheezing and doctor-diagnosed asthma were estimated using a 3-year questionnaire. Multilevel logistic regression analysis was performed to evaluate the association between the mother's and father's educational levels and childhood wheezing and asthma, adjusted for pre-and post-natal factors.

Results: A total of 69,607 pairs of parents and their single infants were analyzed. We found 17.3% of children had wheezing and 7.7% had asthma. In crude analyses, lower educational level of parents was associated with an increased risk of childhood wheezing and asthma. After full adjustment, a lower educational level of mothers was associated with an increased risk of childhood asthma (junior high school (reference: high school); odds ratio (OR): 1.17, 95% CI, 1.01-1.36), and higher educational level, especially the mother's, was associated with an increased risk of childhood wheezing (technical junior college, technical/vocational college, or associate degree (ECD3); OR: 1.12, 95% CI, 1.06-1.18, bachelor's degree, or postgraduate degree; OR: 1.10, 95% CI, 1.03-1.18), and asthma (ECD3; OR: 1.13, 95% CI, 1.04-1.21).

Conclusions: Parents' lower educational level was a crude risk factor for childhood wheezing and asthma. However, an increased risk of wheezing due to mothers' higher educational level was found after adjusting for pre-and post-natal factors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250255PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051798PMC
September 2021

DNA methylation of GFI1 as a mediator of the association between prenatal smoking exposure and ADHD symptoms at 6 years: the Hokkaido Study on Environment and Children's Health.

Clin Epigenetics 2021 04 7;13(1):74. Epub 2021 Apr 7.

Center for Environmental and Health Sciences, Hokkaido University, Hokkaido, Japan.

Background: Prenatal smoking exposure has been associated with childhood attention-deficit/hyperactivity disorder (ADHD). However, the mechanism underlying this relationship remains unclear. We assessed whether DNA methylation differences may mediate the association between prenatal smoking exposure and ADHD symptoms at the age of 6 years.

Results: We selected 1150 mother-infant pairs from the Hokkaido Study on the Environment and Children's Health. Mothers were categorized into three groups according to plasma cotinine levels at the third trimester: non-smokers (≤ 0.21 ng/mL), passive smokers (0.21-11.48 ng/mL), and active smokers (≥ 11.49 ng/mL). The children's ADHD symptoms were determined by the ADHD-Rating Scale at the age of 6 years. Maternal active smoking during pregnancy was significantly associated with an increased risk of ADHD symptoms (odds ratio, 1.89; 95% confidence interval, 1.14-3.15) compared to non-smoking after adjusting for covariates. DNA methylation of the growth factor-independent 1 transcriptional repressor (GFI1) region, as determined by bisulfite next-generation sequencing of cord blood samples, mediated 48.4% of the total effect of the association between maternal active smoking during pregnancy and ADHD symptoms. DNA methylation patterns of other genes (aryl-hydrocarbon receptor repressor [AHRR], cytochrome P450 family 1 subfamily A member 1 [CYP1A1], estrogen receptor 1 [ESR1], and myosin IG [MYO1G]) regions did not exert a statistically significant mediation effect.

Conclusions: Our findings demonstrated that DNA methylation of GFI1 mediated the association between maternal active smoking during pregnancy and ADHD symptoms at the age of 6 years.
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http://dx.doi.org/10.1186/s13148-021-01063-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028116PMC
April 2021

Hypertensive Disorders during Pregnancy (HDP), Maternal Characteristics, and Birth Outcomes among Japanese Women: A Hokkaido Study.

Int J Environ Res Public Health 2021 03 24;18(7). Epub 2021 Mar 24.

Center for Environmental and Health Sciences, Hokkaido University, Sapporo 060-0812, Japan.

Hypertension during pregnancy causes a greater risk of adverse birth outcomes worldwide; however, formal evidence of hypertensive disorders during pregnancy (HDP) in Japan is limited. We aimed to understand the association between maternal characteristics, HDP, and birth outcomes. In total, 18,833 mother-infant pairs were enrolled in the Hokkaido study on environment and children's health, Japan, from 2002 to 2013. Medical records were used to identify hypertensive disorders and birth outcomes, namely, small for gestational age (SGA), SGA at full term (term-SGA), preterm birth (PTB), and low birth weight (LBW). The prevalence of HDP was 1.9%. Similarly, the prevalence of SGA, term-SGA, PTB, and LBW were 7.1%, 6.3%, 7.4%, and 10.3%, respectively. The mothers with HDP had increased odds of giving birth to babies with SGA (2.13; 95% Confidence Interval (CI): 1.57, 2.88), PTB (3.48; 95%CI: 2.68, 4.50), LBW (3.57; 95%CI: 2.83, 4.51) than normotensive pregnancy. Elderly pregnancy, low and high body mass index, active and passive smoking exposure, and alcohol consumption were risk factors for different birth outcomes. Therefore, it is crucial for women of reproductive age and their families to be made aware of these risk factors through physician visits, health education, and various community-based health interventions.
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http://dx.doi.org/10.3390/ijerph18073342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038052PMC
March 2021

Lower respiratory tract infections and orofacial clefts: a prospective cohort study from the Japan Environment and Children's Study.

J Epidemiol 2021 Jan 13. Epub 2021 Jan 13.

Center for Environmental and Health Sciences, Hokkaido University.

Background: Lower respiratory tract infections (LRTIs) are a cause of inpatient and outpatient care among children. Although orofacial clefts seem to be associated with LRTIs, epidemiological studies are scarce on this topic. This study aimed to examine whether infants with orofacial clefts were associated with LRTIs.

Methods: This prospective cohort study used data from the Japan Environment and Children's Study, whose baseline recruitment was conducted during 2011-2014. This study included 81,535 participants. The number of infants with cleft lip and palate (CLP), cleft lip (CL), and cleft palate only (CP) was 67, 49, and 36, respectively. We defined history of LRTIs until 12 months' age reported by their mothers as the dependent variable. Accumulated breastfeeding duration was used as potential mediators.

Results: The incidence proportion of LRTIs among the control group was 6.0%. The incidence proportion among infants with CLP, CL, and CP were 11.9%, 14.3%, and 5.6%, respectively. After adjusting for covariates, compared with the control group, infants with CLP and CL were associated with risk of LRTIs (incidence risk ratio [IRR] of CLP = 2.38 [95% confidence interval = 1.30, 4.36] and of CL = 2.73 [1.40, 5.33]) , but not ones with CP (1.08 [0.28, 4.15]). Accumulated breastfeeding duration decreased the IRR of CLP only (IRR of CLP = 2.16 [1.19, 3.93]).

Conclusions: Infants with orofacial clefts aged 1 year have a potentially high incidence proportion of LRTIs. Accumulated breastfeeding duration might mediate the associations of CLP.
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http://dx.doi.org/10.2188/jea.JE20200438DOI Listing
January 2021

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

Matern Child Health J 2021 Apr 3;25(4):645-655. Epub 2021 Jan 3.

Hokkaido University Center for Environmental and Health Sciences, Kita 12, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.

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.
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http://dx.doi.org/10.1007/s10995-020-03035-wDOI Listing
April 2021

Prevalence of childhood wheeze and modified DNA methylation at 7 years of age according to maternal folate levels during pregnancy in the Hokkaido Study.

Pediatr Allergy Immunol 2021 04 15;32(3):514-523. Epub 2020 Dec 15.

Center for Environmental and Health Sciences, Hokkaido University, Sapporo, Japan.

Background: A high dose of folic acid during pregnancy may increase the risk of asthma, wheezing, and respiratory disease in childhood. Folate acid can modify inflammation and immune susceptibility of offspring with some epigenetic differentiation, including DNA methylation. This study evaluated associations between maternal folate levels during pregnancy and childhood wheezing; furthermore, the study assessed whether maternal folate-modified DNA methylation is related to asthma. Methods Participants in the current study were 6651 mother-child pairs who had complete data on characteristics and who had completed at least one of the International Study of Asthma and Allergies in Childhood questionnaires when the child was 1, 2, 4, and 7 years of age. Moreover, a case-control study to assess DNA methylation at 7 years of age was conducted among 136 children who experienced wheezing and a control group of 139 children with no history of allergies. Results The median of maternal serum was 16.76 nmol/L, assayed by chemiluminescent immunoassay. We found significantly increased adjusted odds ratios of childhood wheezing at 2 years age according to maternal folate levels, compared with the lowest folate quartile (odds ratio [95% confidence interval] = highest; 1.27 [1.03, 1.56], and second, 1.27 [1.05, 1.55]); however, no changes were observed at 1, 4, and 7 years of age. In a case-control study, no association of maternal folate levels with DNA methylation was observed. Conclusion Our results suggest that maternal folate did not affect persistent wheezing in school-aged children, or DNA methylation of gasdermin B, orosomucoid-like 3, and Ikaros family zinc finger 3 at 7 years of age.
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http://dx.doi.org/10.1111/pai.13425DOI Listing
April 2021

Associations between prenatal exposure to organochlorine pesticides and thyroid hormone levels in mothers and infants: The Hokkaido study on environment and children's health.

Environ Res 2020 10 16;189:109840. Epub 2020 Jul 16.

Center for Environmental and Health Sciences, Hokkaido University, North 12 West 7, Kita-ku, Sapporo, 060-0812, Japan. Electronic address:

Organochlorine pesticides (OCPs) are environmental contaminants with potentially adverse effects on neurodevelopment. Previous findings on the association between prenatal exposure to OCPs and the maternal or infant thyroid hormone system are inconsistent. Moreover, the influence of exposure to multiple OCPs and other chemical compounds is not clearly understood. Our study therefore aimed to examine the association between OCP exposure and both maternal and infant thyroid hormone systems. We also explored multiple exposure effects of OCPs and the influence of each compound using weighted quantile sum (WQS) methods. The study population included 514 participants in the Hokkaido study, recruited from 2002 to 2005 at one hospital in Sapporo, Japan. To quantify 29 OCPs, maternal blood samples were analyzed using gas chromatography/mass spectrometry. Blood samples for measuring thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were obtained from mothers during the early gestational stage (mean 11.4 weeks), and from infants between 7 and 43 days of age. The data of 333 mother child pairs with OCP and thyroid hormone measurements were included in the final analyses. Multivariate regression models showed a negative association between maternal FT4 and levels of o,p'-dichlorodiphenyldichloroethylene (DDE), o,p'-dichlorodiphenyltrichloroethane (DDT), and dieldrin. The WQS analysis showed that o,p'-DDT (48.6%), cis-heptachlorepoxide (22.8%), dieldrin (15.4%) were the primary contributors to the significant multiple exposure effect of OCPs on maternal FT4. For infants, we found a positive association between FT4 and cis-nonachlor and mirex. The most contributory compounds in the multiple exposure effect were trans-nonachlor (27.1%) and cis-nonachlor (13.8%), while several compounds contributed to the WQS via small weights (0.4-9.1%). These results indicate that OCPs, even at very low levels, may influence maternal and child thyroid hormone levels, which could modulate child development.
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http://dx.doi.org/10.1016/j.envres.2020.109840DOI Listing
October 2020

Trajectories of the Psychological Status of Mothers of Infants With Nonsyndromic Orofacial Clefts: A Prospective Cohort Study From the Japan Environment and Children's Study.

Cleft Palate Craniofac J 2021 03 26;58(3):369-377. Epub 2020 Aug 26.

Center for Environmental and Health Sciences, 12810Hokkaido University, Sapporo, Japan.

Objective: This study examined psychological status trajectories of mothers of infants with nonsyndromic orofacial clefts in Japan.

Design: Prospective cohort study.

Setting: Data from the Japan Environment and Children's Study.

Participants: Infants with a nonsyndromic cleft (N = 148) including cleft lip and palate (CLP; n = 72), cleft lip (CL; n = 46), and cleft palate (CP; n = 30). The control group included unaffected infants (N = 84 454).

Main Outcome Measures: At 15 weeks and 27 weeks of pregnancy and 12 months after birth, the Kessler Psychological Distress Scale (clinical cutoff ≥5) was used. At 1 month and 6 months after birth, the Edinburgh Postnatal Depression Scale (clinical cutoff ≥9) was used.

Results: Prenatal diagnosis rates were unavailable. Mothers of infants with CLP had higher psychological distress than controls at 27 weeks of pregnancy (prevalence ratio [PR] = 1.36, 95% CI: 1.06-1.74) and postnatal depression at 1 month after birth (PR = 2.21, 95% CI: 1.53-3.19). Mothers of infants with CP showed heightened psychological distress at 27 weeks of pregnancy (PR = 1.62, 95% CI: 1.21-2.17) and postnatal depression 6 months after birth (PR = 1.86, 95% CI: 1.01-3.43). There was no significant association between CL and maternal psychological status. At 12 months after birth, no differences in distress were found between mothers of infants with a cleft and controls.

Conclusions: Mothers of infants with orofacial clefts may need psychosocial support, particularly during pregnancy and the first year after birth.
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http://dx.doi.org/10.1177/1055665620951399DOI Listing
March 2021

Effect of prenatal exposure to per- and polyfluoroalkyl substances on childhood allergies and common infectious diseases in children up to age 7 years: The Hokkaido study on environment and children's health.

Environ Int 2020 10 24;143:105979. Epub 2020 Jul 24.

Hokkaido University, Center for Environmental and Health Sciences, Sapporo, Japan. Electronic address:

Per- and polyfluoroalkyl substances (PFAS) are widely used bio-accumulative chemicals in many industrial and household products. Experimental studies reported that exposure to PFAS results in immunotoxicity. We have previously reported that prenatal exposure to PFAS decreased the risk of allergies, while it increased the risk of infectious diseases at ages 2 and 4 years. However, it remains unclear whether the adverse effects of PFAS on allergies and infectious diseases continue until a reliable age of diagnosing allergies. This study aimed at investigating the effects of prenatal exposure to PFAS on the prevalence of allergies and infectious diseases in children up to age 7, from the Hokkaido Study. Among mother-child pairs enrolled in the Hokkaido study and followed up until the age of 7 years, 2689 participants with maternal PFAS, 1st trimester of pregnancy and 7-year-old questionnaire survey data were included in this study. Eleven PFAS in the 3rd-trimester plasma were measured using ultra-performance liquid chromatography coupled to triple quadrupole tandem mass spectrometry. Wheeze, rhino-conjunctivitis, and eczema were defined using the International Study of Asthma and Allergies on Childhood (ISAAC) questionnaire. History childhood infectious diseases diagnosed by a doctor was assessed by a mother-reported questionnaire at child's age 7. The relative risk of childhood allergies was calculated by generalized estimating equation models. The odds ratio of an episode of infectious diseases was calculated by logistic regression analysis, adjusted for potential confounders. The prevalence of various allergies and infectious diseases was: wheeze, 11.9%; rhino-conjunctivitis, 11.3%; eczema, 21.0%; chickenpox, 61.5%; otitis media, 55.7%; pneumonia, 30.6%; and respiratory syncytial virus infection, 16.8%. Prenatal exposure to perfluorooctanoic acid, perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) was inversely associated with rhino-conjunctivitis, while that for perfluorooctanoate (PFOA), perfluorooctane sulfonate, PFUnDA, perfluorododecanoic acid (PFDoDA), and perfluorotridecanoic acid was inversely associated with eczema. For infectious diseases, PFDA and PFDoDA were associated with increased risk of pneumonia and PFOA was associated with increased risk of RSV infection among children not having any siblings (only-one-child). Our results corroborate the hypothesis on immunosuppressive and immunomodulating effects of PFAS on allergies and infectious diseases in children. These effects observed previously at 2 and 4 years continued until the age of 7 years. However, additional studies assessing inflammatory biomarkers along with ISAAC questionnaires, doctor-diagnosed allergies, and longer follow-ups are necessary to better assess the effects of exposure to chemicals on human immune outcomes.
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http://dx.doi.org/10.1016/j.envint.2020.105979DOI Listing
October 2020

Factors correlating with serum birch pollen IgE status in pregnant women in Hokkaido, Japan: The Japan Environment and Children's Study (JECS).

World Allergy Organ J 2020 Jun 3;13(6):100128. Epub 2020 Jul 3.

Center for Environmental and Health Sciences, Hokkaido University, Sapporo, Japan.

Background: Birch pollen allergy affects pregnant women, and such allergy may affect the development of allergic diseases in their children. Using nationwide birth cohort data, this study aimed to investigate the prevalence of birch pollen IgE positivity and to identify correlating factors in pregnant women in Hokkaido, Japan, a high-latitude island.

Methods: Participants included 6856 pregnant women. Participants responded to questionnaires regarding lifestyle factors and history of allergies. Data regarding parity, height, and pre-pregnancy weight were collected from medical records. Blood samples were obtained from participants during the first trimester of pregnancy, and serum allergen-specific IgE titers were determined.

Results: The serum of 30.2% participants was positive for birch pollen IgE (≥0.35 UA/mL). Such positivity significantly correlated with a history of other allergic diseases, particularly food allergy and allergic rhinitis/hay fever. In multivariate logistic regression analysis, pre-pregnancy high body mass index (BMI ≥ 25) significantly correlated with birch pollen IgE positivity [odds ratio (OR), 1.24; 95% CI, 1.05-1.47; reference BMI, 18.5-24.9] and higher income (≥10 million yen per year; OR,0.55; 95% CI, 0.37-0.81; reference, household income < 2 million yen per year), and second quintile level physical activity (OR,0.75; 95% CI, 0.63-0.88; reference, the first quintile of physical activity) had significant protective effects.

Conclusions: Birch pollen IgE positivity in pregnant women was positively associated with food allergy, allergic rhinitis, pre-pregnant high BMI, and was negatively associated with light exercise and high household income in Hokkaido.

Trial Registration: UMIN000030786.
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http://dx.doi.org/10.1016/j.waojou.2020.100128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338638PMC
June 2020

Effect of the occupational environment of parents on cryptorchidism.

Pediatr Int 2020 Nov 10;62(11):1256-1263. Epub 2020 Nov 10.

Hokkaido University Center for Environmental and Health Sciences, Sapporo, Japan.

Background: The early detection and treatment of cryptorchidism are necessary to preserve male fertility. This study aimed to assess the effect of parents' occupational environment on the incidence of cryptorchidism in their sons.

Methods: The study enrolled 51 316 newborn males, whose mothers were recruited in the Japan Environment and Children's Study. We analyzed cryptorchidism incidence in male newborns according to 14 categories of occupation of their parents. We also analyzed the effect of the mother's occupational environment during gestation, including working and night-shift work, on cryptorchidism incidence. Information on occupations was obtained from self-administered questionnaires. Cryptorchidism was identified through a survey at birth or 1 month after birth using medical records.

Results: Cryptorchidism was identified in 305 male infants (0.59%) at birth or 1 month after birth. Weight, height, head circumference, and chest circumference at birth were significantly lower in male infants with cryptorchidism than in those without the condition. Gestational age was also shorter in mothers whose infants developed cryptorchidism. Moreover, maternal age at delivery and smoking during gestation also had an effect on cryptorchidism incidence. However, multivariate analysis of the 14 categories of occupation of parents during gestation showed no significant effect on cryptorchidism incidence in their male infants.

Conclusions: This study revealed that the work environment of parents did not significantly affect the incidence of cryptorchidism in their sons. However, this study might have underestimated mild and transient cases of cryptorchidism. Further studies are necessary to investigate the risk factors of cryptorchidism in relation to parents' occupation.
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http://dx.doi.org/10.1111/ped.14316DOI Listing
November 2020

Risk factors for motor coordination problems in preschool-age children.

Pediatr Int 2020 Oct;62(10):1177-1183

Center for Environmental and Health Sciences, Hokkaido University, Sapporo, Japan.

Background: Motor coordination problems (MCP) in children can sometimes be diagnosed as developmental coordination disorder. Early intervention for developmental coordination disorder is necessary because it often continues into adolescence, causing mental and physical complications. Few studies have investigated the prevalence of childhood MCP in the Japanese population, examining the risk factors for MCP. We therefore investigated the prenatal factors associated with MCP in preschool-age children.

Methods: This study was based on a prospective cohort study, the Hokkaido Study on Environment and Children's Health. Mothers of 4,851 children who reached the age of 5 years within the study-period received questionnaires, including the Japanese version of the Developmental Coordination Disorder Questionnaire (DCDQ-J). We examined the risk factors associated with MCP using logistic regression analysis.

Results: Of 3,402 returned DCDQ-J questionnaires, 3,369 were answered completely. From the 3,369 children, we categorized having MCP by using two cut-off scores: that of the DCDQ'07 and the cut-off at the 5th percentile of a total DCDQ-J score. Comparing children with and without MCP, we found significant differences in the education level of the mothers, annual household income during pregnancy, maternal alcohol consumption and smoking during pregnancy, and sex and age of the children at the time of completing the DCDQ-J by both categorizations. Adjusted logistic regression analysis revealed that maternal smoking during the first trimester of pregnancy and male sex were significantly associated with MCP.

Conclusions: Our results suggest that maternal smoking during pregnancy is the main factor associated with MCP in preschool-age children.
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http://dx.doi.org/10.1111/ped.14275DOI Listing
October 2020

Population Attributable Fractions of Modifiable Risk Factors for Nonsyndromic Orofacial Clefts: A Prospective Cohort Study From the Japan Environment and Children's Study.

J Epidemiol 2021 Apr 25;31(4):272-279. Epub 2020 Apr 25.

Center for Environmental and Health Sciences, Hokkaido University.

Background: Population impact of modifiable risk factors on orofacial clefts is still unknown. This study aimed to estimate population attributable fractions (PAFs) of modifiable risk factors for nonsyndromic cleft lip with or without cleft palate (CL±P) and cleft palate only (CP) in Japan.

Methods: We conducted a prospective cohort study using data from the Japan Environment and Children's Study, which recruited pregnant women from 2011 to 2014. We estimated the PAFs of maternal alcohol consumption, psychological distress, maternal active and passive smoking, abnormal body mass index (BMI) (<18.5 and ≥25 kg/m), and non-use of a folic acid supplement during pregnancy for nonsyndromic CL±P and CP in babies.

Results: A total of 94,174 pairs of pregnant women and their single babies were included. Among them, there were 146 nonsyndromic CL±P cases and 41 nonsyndromic CP cases. The combined adjusted PAF for CL±P of the modifiable risk factors excluding maternal alcohol consumption was 34.3%. Only maternal alcohol consumption was not associated with CL±P risk. The adjusted PAFs for CL±P of psychological distress, maternal active and passive smoking, abnormal BMI, and non-use of a folic acid supplement were 1.4% (95% confidence interval [CI], -10.7 to 15.1%), 9.9% (95% CI, -7.0 to 26.9%), 10.8% (95% CI, -9.9 to 30.3%), 2.4% (95% CI, -7.5 to 14.0%), and 15.1% (95% CI, -17.8 to 41.0%), respectively. We could not obtain PAFs for CP due to the small sample size.

Conclusions: We reported the population impact of the modifiable risk factors on CL±P, but not CP. This study might be useful in planning the primary prevention of CL±P.
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http://dx.doi.org/10.2188/jea.JE20190347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940975PMC
April 2021

Temporal trends and determinants of PFR exposure in the Hokkaido Study.

Int J Hyg Environ Health 2020 07 17;228:113523. Epub 2020 Apr 17.

Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium. Electronic address:

The phase-out of polybrominated diphenyl ethers (PBDE) flame retardants has led to the rapid increase of alternatives such as phosphate flame retardants and plasticizers (PFRs) in many consumer products. Exposure to these additive chemicals is widespread and potentially harmful to humans and the environment. In the present study, we assessed the exposure to PFRs through the analysis of metabolites in urine collected from 7-year old children from Hokkaido, Japan between 2012 and 2017. This allowed us to investigate temporal and seasonal trends for PFR metabolite concentrations and to study determinants of exposure. Thirteen metabolites of seven PFRs were measured in morning spot urine samples (n = 400). Multiple regression models were used to quantify the yearly increase in metabolite concentrations per sampling year. Information on the demographics, indoor environment and dietary habits of the participants were derived from self-administered questionnaires. PFR metabolite concentrations were comparable to our previous study of school children (7-12 years old). Eight PFR metabolites were detected in >50% of the samples. During the study time period, concentrations of three metabolites increased significantly: bis(1,3-dichloro-2-propyl) phosphate (BDCIPP; 13.3% per year), 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP; 12.9% per year), and 2-ethylhexyl phenyl phosphate (EHPHP; 6.7% per year). We also found seasonality as a determinant for several PFR metabolites, with 2-fold higher levels in summer for BCIPHIPP and BDCIPP. Concentrations were also significantly impacted by ventilation habits. More frequent window opening or use of mechanical ventilation was consistently associated with higher levels of PFR metabolites in children's urine. This is the first study to show that human exposure to PFRs has increased in recent years in Japan, which indicates that further research into this class of chemicals is warranted.
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http://dx.doi.org/10.1016/j.ijheh.2020.113523DOI Listing
July 2020

Association of exposure to prenatal phthalate esters and bisphenol A and polymorphisms in the ESR1 gene with the second to fourth digit ratio in school-aged children: Data from the Hokkaido study.

Steroids 2020 07 9;159:108637. Epub 2020 Mar 9.

Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, North-15, West-7, Kita-ku, Sapporo 060-8638, Japan.

Phthalates and bisphenol A (BPA) are estrogenic endocrine disruptors. Polymorphisms in the gene encoding estrogen receptor 1 (ESR1) may contribute to the ratio of the lengths of the second and fourth digits (2D:4D), which is considered an index of prenatal exposure to sex hormones. Thus, we investigated whether ESR1 polymorphisms modify the effects of prenatal exposure to phthalates and BPA on 2D:4D in a birth cohort. Maternal serum in the first trimester was used to determine prenatal exposure to these compounds. Six hundred twenty-three children (7 years of age) provided mean 2D:4D from photocopies and were genotyped for single nucleotide polymorphisms in ESR1, particularly PvuII (T > C, dbSNP: rs2234693), XbaI (A > G, dbSNP: rs9340799), and rs2077647 (A > G). The associations among compound exposure, mean 2D:4D, and ESR1 polymorphisms were assessed by multiple linear regression adjusted for potential cofounding factors. Boys with the AG/GG genotype at rs2077647 in the group exposed to high levels of mono(2-ethylhexyl) phthalate (MEHP) or Σ Di(2-ethylhexyl) phthalate (DEHP) showed feminized 2D:4D compared with boys with the AA genotype at rs2077647 who had low exposure to MEHP or ΣDEHP (MEHP: increase in mean 2D:4D of 1.51%, 95% confidence interval [CI]: 0.40-2.63; ΣDEHP: increase in mean 2D:4D of 1.37%, 95% CI: 0.25-2.49). No significant differences were found among girls. There were no associations between mean 2D:4D and metabolites other than MEHP or BPA. These data suggest that ESR1 polymorphisms modify the effects of prenatal exposure to DEHP on mean 2D:4D among boys.
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http://dx.doi.org/10.1016/j.steroids.2020.108637DOI Listing
July 2020

Combined exposure to phthalate esters and phosphate flame retardants and plasticizers and their associations with wheeze and allergy symptoms among school children.

Environ Res 2020 04 3;183:109212. Epub 2020 Feb 3.

Hokkaido University, Center for Environmental and Health Sciences, Kita 12, Nishi 7, Kita-ku, Sapporo, 060-0812, Japan. Electronic address:

Background: Phthalate esters and phosphate flame retardants and plasticizers (PFRs) are both used as plasticizers and are commonly detected in indoor environments. Although both phthalates and PFRs are known to be associated with children's wheeze and allergic symptoms, there have been no previous studies examining the effects of mixtures of these exposures.

Objectives: To investigate the association between exposure to mixtures of phthalate esters and PFRs, and wheeze and allergic symptoms among school-aged children.

Methods: A total of 128 elementary school-aged children were enrolled. Metabolites of 3 phthalate esters and 7 PFRs were measured in urine samples. Parent-reported symptoms of wheeze, rhinoconjunctivitis, and eczema were evaluated using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. In the primary model, we created a phthalate ester and PFR mixture exposure index, and estimated odds ratios (ORs) using weighted quantile sum (WQS) regression and quantile g (qg)-computation. The two highest chemicals according to qg-computation weight %s were combined to create a combination high × high exposure estimate, with ORs calculated using the "low × low" exposure group as the reference category. Concentrations of each metabolite were corrected by multiplying this value by the sex- and body size-Standardised creatinine concentration and dividing by the observed creatinine value. All models were adjusted for sex, grade, dampness index and annual house income.

Results: The odds ratio of rhinoconjunctivitis for the association between exposure to chemical mixtures according to the WQS index positive models was; OR = 2.60 (95% confidence interval [CI]: 1.38-5.14). However, wheeze and eczema of the WQS index positive model, none of the WQS index negative models or qg-computation result yielded statistically significant results. Combined exposure to the two highest WQS weight %s of "high-high" ΣTCIPP and ΣTPHP was associated with an increased prevalence of rhino-conjunctivitis, OR = 5.78 (1.81-18.43) to the "low × low" group.

Conclusions: Significant associations of mixed exposures to phthalates and PFRs and increased prevalence of rhinoconjunctivitis was found among elementary school-aged children in the WQS positive model. Mixed exposures were not associated with any of allergic symptoms in the WQS negative model or qg-computation approach. However, the combined effects of exposure to two PFRs suggested an additive and/or multiplicative interaction, potentially increasing the prevalence of rhinoconjunctivitis. A further study with a larger sample size is needed to confirm these results.
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http://dx.doi.org/10.1016/j.envres.2020.109212DOI Listing
April 2020

Prenatal exposure to 11 perfluoroalkyl substances and fetal growth: A large-scale, prospective birth cohort study.

Environ Int 2020 03 4;136:105355. Epub 2020 Feb 4.

Center for Environmental and Health Sciences, Hokkaido University, Japan. Electronic address:

Background: Prenatal maternal exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) has been reportedly associated with decreased birth weight. Although a majority of epidemiological studies concerning perfluoroalkyl substances (PFAS) have focused on PFOS and PFOA, epidemiological studies of PFAS with longer carbon chains are scarce. In this study, we investigated whether prenatal maternal exposure to 11 PFAS, in particular those with longer carbon chains, is associated with fetal growth.

Methods: The study included 1985 mother-infant pairs (inclusive of preterm and post-term infants), who enrolled in a large-scale, prospective birth cohort study in any of the 37 hospitals in Hokkaido, Japan between 2003 and 2009. The concentration of 11 PFAS was measured in maternal plasma collected during the third trimester of pregnancy, using ultra-performance liquid chromatography in combination with triple quadrupole mass spectrometry. Associations between the measured PFAS values and weight, length, and head circumference of all newborns at birth were examined using multiple regression analyses with adjustment for potential confounders based on data collected from medical records, questionnaires, and those for maternal plasma samples.

Results: Of the 11 PFAS analyzed, prenatal perfluorononanoic acid (PFNA) [per log10-unit: regression coefficient (β) = -96.2 g, 95% confidence intervals (95% CI), -165.3 to -27.1] and perfluorodecanoic acid (PFDA) (β = -72.2 g, 95% CI, -138.1 to -6.3) concentrations were inversely associated with birth weight. Furthermore, PFNA concentrations were inversely associated with birth length (per Log unit: β = -0.48 cm, 95% CI; - 0.86 to -0.11). Maternal perfluorotridecanoic acid (PFTrDA) exposure showed a significant inverse association with birth weight only for female infants (per Log unit: β = -99.8 g, 95% CI, - 193.7 to -6.0) (P for interaction = 0.04).

Conclusions: Our findings suggest that prenatal, maternal exposure to PFAS with longer carbon chains tends to be inversely associated with birth size of newborn infants, which may indicate that these commercially used compounds have an adverse effect on fetal growth.
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http://dx.doi.org/10.1016/j.envint.2019.105355DOI Listing
March 2020

Cat and Dog Ownership in Early Life and Infant Development: A Prospective Birth Cohort Study of Japan Environment and Children's Study.

Int J Environ Res Public Health 2019 12 27;17(1). Epub 2019 Dec 27.

Hokkaido University Center for Environmental and Health Sciences, Sapporo 060-0812, Japan.

Contact with companion animals has been suggested to have important roles in enhancing child development. However, studies focused on child development and pet ownership at a very early age are limited. The purpose of the current study was to investigate child development in relation to pet ownership at an early age in a nationwide prospective birth cohort study: the Japan Environment and Children's Study. Associations between cat and dog ownership at six months and infant development at 12 months of age were examined in this study. Infant development was assessed using the Ages & Stages Questionnaires (ASQ-3) at 12 months. Among participants of (Japan Environment and Children's Study) JECS, those with available data of cat and dog ownership at six months and data for the ASQ-3 at 12 months were included ( = 78,868). Having dogs showed higher percentages of pass in all five domains measured by ASQ-3 (communication, gross motor, fine motor, problem-solving, and personal-social) compared to those who did not have dogs. Significantly decreased odds ratios (ORs) of developmental delays were observed in association with having dogs in all fix domains (communication: OR = 0.73, gross motor: OR = 0.86, fine motor: OR = 0.84, problem-solving: OR = 0.90, personal-social: OR = 0.83). This study suggested that early life dog ownership may reduce the risks of child developmental delays.
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http://dx.doi.org/10.3390/ijerph17010205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981655PMC
December 2019

Prenatal tobacco exposure and ADHD symptoms at pre-school age: the Hokkaido Study on Environment and Children's Health.

Environ Health Prev Med 2019 Dec 7;24(1):74. Epub 2019 Dec 7.

Center for Environmental and Health Sciences, Hokkaido University, Kita 12, Nishi 7, Kita-ku, Sapporo, 060-0812, Japan.

Background: There have been inconsistent findings reported on maternal passive smoking during pregnancy and child risk of ADHD. In this study, ADHD symptoms at pre-school age children in association with prenatal passive and active tobacco smoke exposure determined by maternal plasma cotinine levels in the third trimester were investigated.

Methods: This was a follow-up study of the birth cohort: the Hokkaido Study on Environment and Children's Health. Children whose parents answered Strengths and Difficulties Questionnaire (SDQ) to identify child ADHD symptoms (hyperactivity/inattention and conduct problems) and total difficulties at age 5 years with available maternal plasma cotinine level at the third trimester were included (n = 3216). Cotinine levels were categorized into 4 groups; ≦ 0.21 ng/ml (non-smoker), 0.22-0.51 ng/ml (low-passive smoker), 0.52-11.48 ng/ml (high-passive smoker), and ≧ 11.49 ng/ml (active smoker).

Results: Maternal cotinine levels of active smokers were significantly associated with an increased risk of total difficulties (OR = 1.67) and maternal low- and high-passive smoking also increased the risk (OR = 1.11, 1.25, respectively) without statistical significance. Similarly, maternal cotinine levels of active smokers were associated with an increased risk of hyperactivity/inattention (OR = 1.49). Maternal low- and high-passive smoking and active smoking increased the risk of hyperactivity/inattention (OR = 1.45, 1.43, and OR = 1.59, respectively) only in boys.

Conclusion: Our findings suggested that maternal active smoking during pregnancy may contribute to the increased risk of child total difficulties and hyperactivity/inattention at pre-school age. Pregnant women should be encouraged to quit smoking and avoid exposure to tobacco smoke.
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http://dx.doi.org/10.1186/s12199-019-0834-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898952PMC
December 2019

Association between perfluoroalkyl substance exposure and thyroid hormone/thyroid antibody levels in maternal and cord blood: The Hokkaido Study.

Environ Int 2019 12 10;133(Pt A):105139. Epub 2019 Sep 10.

Center for Environmental Health and Sciences, Hokkaido University, Sapporo, Japan. Electronic address:

Background: Thyroid antibodies (TAs) are the most common cause of hypothyroidism during gestation. Although previous studies found that prenatal exposure to perfluoroalkyl substances (PFASs) disrupts thyroid hormones (THs) in humans, their effects on TAs during the perinatal period have not been investigated.

Objective: To explore the associations between prenatal exposure to eleven different PFASs from two different groups (carboxylates and sulfonates) and the expression of THs and TAs in maternal and cord blood while considering maternal TA status.

Methods: In a prospective birth cohort (the Hokkaido Study), we included 701 mother‑neonate pairs recruited in 2002-2005 for whom both prenatal maternal and cord blood samples were available. Eleven PFASs were measured in maternal plasma obtained at 28-32 weeks of gestation using ultra-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry. THs and TAs including thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) were measured in maternal blood during early pregnancy (median 11 gestational weeks), and in cord blood at birth.

Results: The median levels of TgAb and TPOAb in maternal serum were 15.0 and 6.0 IU/mL, respectively. The median TgAb level in neonates was 38.0 IU/mL, and TPOAb were detected in only 12.3% of samples. Maternal FT3 level was positively associated with PFAS levels in both TA-positive and TA-negative mothers. Maternal perfluorooctanoate was inversely associated with maternal TPOAb. Among boys, some maternal PFASs were associated with higher TSH and lower FT3 levels in maternal TA-negative group, while perfluorodecanoic acid was associated with lower TSH in maternal TA-positive group. Among girls, some PFAS of mothers showed associations with lower TSH and higher FT3 in maternal TA-negative group, while perfluorododecanoic acid was associated with lower FT4 in maternal TA-positive. Maternal PFASs showed associations with boy's TgAb inversely in maternal TA-negative group and with girl's TgAb positively in maternal TA-positive group.

Conclusions: Our results suggest thyroid disrupting effects of PFAS exposure and susceptibility vary depending on maternal TA levels.
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http://dx.doi.org/10.1016/j.envint.2019.105139DOI Listing
December 2019
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