Sachiko Ito

Prenatal exposure to perfluorinated chemicals and neurodevelopment in early infancy: The Hokkaido Study.

Perfluorinated chemicals (PFCs) are ubiquitous and persistent pollutants widely detected in blood samples of animals and humans across the globe. Although animal studies have shown the potential neurotoxicity of PFCs, there are few epidemiological studies regarding neurological effects of PFCs in humans, and those studies have had inconclusive results. In this study, we conducted a hospital-based prospective birth cohort study between 2002 and 2005 (n=514) to examine the associations between prenatal perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) exposures and the neurodevelopment of infants at 6 (n=173) and 18 (n=133) months of age. Using the second edition of the Bayley Scales of Infant Development (BSID II), the Mental and Psychomotor Developmental Indices (MDI and PDI, respectively) were assessed. PFOS and PFOA were measured in maternal serum samples by liquid chromatography-tandem mass spectrometry. After controlling for confounders, prenatal PFOA concentrations were associated with the MDI of female (but not male) infants at 6 months of age (β=-0.296; 95% confidence interval (CI): -11.96, -0.682). Furthermore, females born to mothers with prenatal concentrations of PFOA in the fourth quartile had MDI scores -5.05 (95% CI: -10.66 to 0.55) lower than females born to mothers with concentrations of PFOA in the first quartile (p for trend=0.045). However, PFOA concentrations were not significantly associated with neurodevelopmental indices at 18 months of age. In addition, we did not observe any significant association between PFOS concentrations and neurodevelopmental outcomes in early infancy. In conclusion, our results suggest that prenatal PFOA exposure may affect female mental scales of neurodevelopment at 6 months of age. Further studies with larger sample sizes and longer observation periods are required to clarify sex difference of the neurodevelopmental effects.

Effects of in utero exposure to polychlorinated biphenyls, methylmercury, and polyunsaturated fatty acids on birth size

The adverse effects of in utero exposure to polychlorinated biphenyls (PCBs) or methylmercury (MeHg), and the beneficial effects of nutrients from maternal fish intake might have opposing influences on fetal growth. In this study, we assessed the effects of in utero exposure to PCBs and MeHg on birth size in the Japanese population, which is known to have a high frequency of fish consumption. The concentrations of PCBs and polyunsaturated fatty acids in maternal blood, and the total mercury in hair (as a biomarker of MeHg exposure) were measured during pregnancy and at delivery. Maternal intakes of fish (subtypes: fatty and lean) and shellfishes were calculated from a food frequency questionnaire administered at delivery. Newborn anthropometric measurement data were obtained from birth records. The associations between chemical exposures and birth size were analyzed by using multiple regression analysis with adjustment for confounding factors among 367 mother-newborn pairs. The birth weight was 3073±37 g (mean±SD). The incidence of babies small for gestational age (SGA) by weight was 4.9%. The median concentrations of total PCBs and hair mercury were 108 ng/g lipid and 1.41 μg/g, respectively. There was no overall association between mercury concentrations and birth weight, birth length, chest circumference, and head circumference. We observed that the risk of SGA by weight decreased with increasing mercury concentration in regression analyses with adjustment for polyunsaturated fatty acids. Our results suggest that the beneficial effect of essential nutrition may mask the adverse effects of MeHg on birth size. The concentrations of PCBs had no association with birth size.

The Relationship between the Second-to-Fourth Digit Ratio and Behavioral Sexual Dimorphism in School-Aged Children

Sexually dimorphic brain development and behavior are known to be influenced by sex hormones exposure in prenatal periods. On the other hand, second-to forth digit ratio (2D/4D) has been used as an indirect method to investigate the putative effects of prenatal exposure to androgen. In the present study, we herein investigated the relationship between gender-role play behavior and the second-to-fourth digit ratio (2D/4D), which has been used as an indirect method to investigate the putative effects of prenatal exposure to androgens, in school-aged children. Among 4981 children who became 8 years old by November 2014 and were contactable for this survey by The Hokkaido Study of Environment and Childrens Health, 1631 (32.7%), who had data for 2D/4D and Pre-school Activities Inventory (PSAI) as well as data for the survey at baseline, were available for analysis. Parents sent reports of PSAI on the sex-typical characteristics, preferred toys, and play activities of children, and black and white photocopies of the left and right hand palms via mail. PSAI consisted of 12 masculine items and 12 feminine items, and a composite score was created by subtracting the feminine score from the masculine score, with higher scores representing masculine-typical behavior. While composite scores in PSAI were significantly higher in boys than in girls, 2D/4D was significantly lower in boys than in girls. Although the presence or absence of brothers or sisters affected the composite, masculine, and feminine scored of PSAI, a multivariate regression model revealed that 2D/4D negatively correlated with the composite scores of PSAI in boys, whereas no correlation was found in girls. Although 2D/4D negatively correlated with the masculine score in boys and girls, no correlation was observed between 2D/4D and the feminine score. In conclusion, although social factors, such as the existence of brother or sisters, affect dimorphic brain development and behavior in childhood, the present study revealed that the prenatal hormonal environment was an important factor influencing masculine-typical dimorphic brain development and behavior in school-aged children.

Effects of prenatal exposure to perfluoroalkyl acids on prevalence ofallergic diseases among 4-year-old children

Perfluoroalkyl acids (PFAAs) are ubiquitous chemicals extremely resistant and widespread throughout the environment, frequently being detected in human blood samples. Animal studies have revealed that exposure to PFAAs results in immunotoxicity. However, the association between PFAAs, especially long-chain PFAAs, and allergies in humans is not well established. We examined whether prenatal exposure to PFAAs is associated with allergic diseases among 4-year-old children in a large-scale prospective birth cohort in Hokkaido, Japan. In total, 1558 mother-child pairs were included in this study and prenatal levels of eleven PFAAs were measured in maternal plasma samples obtained between 28 and 32weeks of pregnancy by using ultra-performance liquid chromatography-tandem mass spectrometry. Participant demographic and characteristic information were obtained from self-administered pre- and postnatal questionnaires and medical birth records. Infant allergies were assessed using the Japanese version of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three questionnaire, which was administered 4years post-delivery. Symptoms included eczema, wheezing and rhinoconjunctivitis with a prevalence of 19.0%, 18.7%, and 5.4%, respectively. Associations of PFAA quartiles with allergic outcomes were examined using logistic models. Adjusted odds ratios (ORs) in the 4th quartile vs. 1st quartile (Q4 vs. Q1) for total allergic diseases (including at least one allergic outcome) significantly decreased for perfluorododecanoic acid (PFDoDa) (Q4 vs. Q1 OR: 0.621; 95% confidence interval (CI): 0.454, 0.847) and perfluorotridecanoic acid (PFTrDA) (Q4 vs. Q1 OR: 0.712; 95% CI: 0.524, 0.966) in all children. We obtained similar results when examining the association between PFAAs and eczema. The adjusted OR (Q4 vs. Q1) for wheezing in relation to higher maternal PFHxS levels was 0.728 (95% CI: 0.497, 1.06) in all children. In conclusion, prenatal exposure to long-chain PFAAs, such as PFDoDa and PFTrDA may have an immunosuppressive effect on allergic diseases in 4-year-old children.

Effects of prenatal Leydig cell function on the ratio of the second to fourth digit lengths in school-aged children.

Prenatal sex hormones can induce abnormalities in the reproductive system and adversely impact on genital development. We investigated whether sex hormones in cord blood influenced the ratio of the second to fourth digit lengths (2D/4D) in school-aged children. Of the 514 children who participated in a prospective cohort study on birth in Sapporo between 2002 and 2005, the following sex hormone levels were measured in 294 stored cord blood samples (135 boys and 159 girls); testosterone (T), estradiol (E), progesterone, LH, FSH, inhibin B, and insulin-like factor 3 (INSL3). A total of 350 children, who were of school age and could be contacted for this survey, were then requested via mail to send black-and-white photocopies of the palms of both the left and right hands. 2D/4D was calculated in 190 children (88 boys and 102 girls) using photocopies and derived from participants with the characteristics of older mothers, a higher annual household income, higher educational level, and fewer smokers among family members. 2D/4D was significantly lower in males than in females (p<0.01). In the 294 stored cord blood samples, T, T/E, LH, FSH, Inhibin B, and INSL3 levels were significantly higher in samples collected from males than those from females. A multivariate regression model revealed that 2D/4D negatively correlated with INSL3 in males and was significantly higher in males with <0.32 ng/mL of INSL3 (p<0.01). No correlations were observed between other hormones and 2D/4D. In conclusion, 2D/4D in school-aged children, which was significantly lower in males than in females, was affected by prenatal Leydig cell function.

Effects of adrenal androgens during the prenatal period on the second to fourth digit ratio in school-aged children

OBJECTIVES We investigated the relationship between the levels of adrenal steroid hormones in cord blood and the second to fourth digit ratio (2D/4D), which is regarded as an indirect method to investigate the putative effects of prenatal exposure to androgens, in school-aged children. MATERIALS AND METHODS Of the 514 mother-child pairs who participated in the prospective cohort study of birth in Sapporo between 2002 and 2005, the following adrenal steroid hormone levels in 294 stored cord blood samples (135 males and 159 females) were measured; cortisol, cortisone, androstenedione and dehydroepiandrosterone (DHEA). A total of 190 out of 350 children who were currently school-aged and contactable for this survey sent back photocopies of their palms for 2D/4D measurements. RESULTS 2D/4D in all right hands, left hands, and mean values was significantly lower in males than in females (p<0.01). DHEA levels were significantly higher in females. A multivariate regression model showed that 2D/4D negatively correlated with DHEA in males only (p<0.01). No correlations were observed in the other adrenal steroid hormones tested in males or in any adrenal steroid hormones in females. CONCLUSION DHEA is mainly secreted in large amounts by the adrenal gland and is transformed into active sex-steroid hormones in peripheral tissues. The present study demonstrated that sex differences in digits were influenced by adrenal androgens during the prenatal period, possibly through intracrinological processes for androgen receptors located in fetal cartilaginous tissues.

A Radiologic Reporting System for Computer-Aided Diagnosis with Associated Database: Hokkaido University Diagnostic Information Processing System — HDIPS

A reporting system which assists radiologists reporting on medical images and calculates alternatives of probable diseases was developed with proven applicability for CT and ultrasonography. The diagnostic information found by radiologists in various types of images is managed as a database in the reporting system and is also transferred to a medical record database, the HIS (Hospital Information System) of Hokkaido University Hospital. The reporting system supports both data conversion and transfer to the host computer of the HIS. The system has processed about 20 000 reports over the last 5 years. Here we present the efficiency of producing reports, the structure of the database, and the hit ratio of calculated diagnoses in this system.

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

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

Association of prenatal exposure to PCDD/Fs and PCBs with maternal and infant thyroid hormones: The Hokkaido Study on Environment and Children's Health☆

Polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs) are persistent organic pollutants that are universally detected. Some congeners of PCDDs, PCDFs or PCBs have dioxin-like toxicity, whereas non-dioxin-like PCBs are considered to have different toxicity. Reports of the relationships between prenatal exposure to PCDDs, PCDFs or PCBs and thyroid homeostasis in pregnant women and infants have been inconsistent. The aim of this study was to investigate the effect of maternal serum PCDD/F or PCB levels on maternal and neonatal thyroid hormone (TH) levels in a prospective cohort. Of the 514 subjects in the prospective cohort, 386 mothers and 410 infants were included for analysis. Fifteen dioxins and seventy PCBs in maternal blood collected between 23 and 41weeks of gestation were measured using high-resolution gas chromatography and high-resolution mass spectrometry. Blood samples to measure thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were obtained from mothers at an early gestational stage (median ten weeks), and from infants between four and seven days of age, respectively. Multiple linear regression analysis was conducted. Median concentration of total PCBs, PCB 153 were 104,700, and 20,500pg/g lipid, respectively. Median total dioxin-TEQ was 13.8pg/g lipid. Total dioxin-TEQ, coplanar PCBs were positively associated with neonatal FT4 (beta=0.224, 0.206, respectively). The association was stronger in boys (beta=0.299, 0.282, respectively). Several PCDD/F and PCB isomers were also positively associated with neonatal FT4. Total PCBs or non-dioxin-like PCBs were not associated with any maternal or neonatal THs. No DLC grouping or congeners were associated with neonatal TSH. Non-ortho PCBs were positively associated with maternal FT4. Three PCB congeners had significant positive association(s) with maternal THs. In conclusion, the results of our study suggest that perinatal exposure to background-level DLCs increases neonatal FT4, especially in boys.

Relationship between adrenal steroid hormones in cord blood and birth weight: The Sapporo Cohort, Hokkaido Study on Environment and Children's Health

We investigated the relationship between steroid hormone levels in cord blood and birth weight.