Association between maternal blood or cord blood metal concentrations and catch-up growth in children born small for gestational age: an analysis by the Japan environment and children's study.

BACKGROUND: Catch-up growth issues among children born small for gestational age (SGA) present a substantial public health challenge. Prenatal exposure to heavy metals can cause adverse effects on birth weight. However, comprehensive studies on the accurate assessment of individual blood concentrations of heavy metals and their effect on the failure to achieve catch-up growth remain unavailable. This study aimed to evaluate the effects of uterine exposure to toxic metals cadmium, lead, and mercury and essential trace metals manganese and selenium at low concentrations on the postnatal growth of children born SGA. METHODS: Data on newborn birth size and other factors were obtained from the medical record transcripts and self-administered questionnaires of participants in the Japan Environment and Children's Study. The blood concentrations of lead, cadmium, mercury, selenium, and manganese in pregnant women in their second or third trimester were determined by inductively coupled plasma mass spectrometry. These heavy metal concentrations were also assessed in pregnant women's cord blood. Furthermore, the relationship between each heavy metal and height measure/catch-up growth in SGA children aged 4 years was analyzed using linear and logistic regression methods. These models were adjusted for confounders. RESULTS: We studied 4683 mother-child pairings from 103,060 pregnancies included in the Japan Environment and Children's Study. Of these, 278 pairs were also analyzed using cord blood. At 3 and 4 years old, 10.7% and 9.0% of children who were born below the 10th percentile of body weight had height standard deviation scores (SDSs) below 2, respectively. Cord blood cadmium concentrations were associated with the inability to catch up in growth by 3 or 4 years old and the height SDS at 3 years old. In maternal blood, only manganese was positively associated with the height SDS of SGA children aged 2 years; however, it was not significantly associated with catch-up growth in these children. CONCLUSION: Cadmium exposure is associated with failed catch-up development in SGA children. These new findings could help identify children highly at risk of failing to catch up in growth, and could motivate the elimination of heavy metal (especially cadmium) pollution to improve SGA children's growth.

Individual and mixed metal maternal blood concentrations in relation to birth size: An analysis of the Japan Environment and Children's Study (JECS).

BACKGROUND: Growth restriction in the prenatal period is a significant public health concern. Metals can negatively affect birth size, and pregnant women may be exposed to metal mixtures. Comprehensive studies analyzing the effects of combined metal exposure with accurate individual blood metal concentrations are limited. The current study investigated the associations between maternal metal exposure and birth size in a large, nationwide Japanese cohort using individual and mixed model approaches. METHODS: Lead, cadmium, mercury, selenium, and manganese blood concentrations were measured in pregnant women in the Japan Environment and Children's Study (JECS). Measurements of infant birth size-including body weight, body length, and head and chest circumference-were collected. Linear and logistic regressions were used for birth size measurements and the odds of an infant being small in size for gestational age, respectively. Associations between combined metal mixtures and measurements at birth were evaluated using quantile g-computation and Bayesian kernel machine regression (BKMR). RESULTS: Of the 103,060 JECS pregnancies, 93,739 mother-infant pairs were analyzed. The linear regression models showed that lead, selenium, cadmium, and manganese-but not mercury-were associated with body weight. Cadmium was associated with length and chest circumference and mercury was associated with head circumference. Quantile g-computation revealed that manganese increased infant birth weight, length, head circumference, and chest circumference. Lead was the strongest negative factor for infant birth weight, length, head circumference, and chest circumference. The BKMR analysis revealed that the metals had an additive, rather than a synergistic effect. CONCLUSION: Metal exposure is associated with infant birth size, with lead and manganese playing a more significant role in Japan. The effects of prenatal combined metal exposure at low levels warrant public health attention.

The relationship of maternal PCB, toxic, and essential trace element exposure levels with birth weight and head circumference in Chiba, Japan.

Maternal exposure to high levels of persistent organic pollutants (POPs) and trace elements is an important concern for fetal growth. In our previous study, we showed the polychlorinated biphenyl (PCB) levels in maternal serum from the Chiba Study of Mother and Child Health (C-MACH) cohort and their relationships between PCB levels in cord serum with birth weight of newborn. Various reports on the relationship between chemical exposure and birth status have been published; however, studies that analyze the effects of both PCB and metal exposure together in one cohort are still limited. In this study, we aimed to determine the relationship of maternal serum levels of PCBs and toxic and essential trace elements [mercury (Hg), manganese (Mn), selenium (Se), and cadmium (Cd)], with birth weight and head circumference, in the C-MACH cohort. The median concentration of total PCBs in maternal serum around 32 gestational weeks (n = 62) was 360 pg g-1 wet wt (41 ng g-1 lipid wt). The levels of Hg, Mn, Se, and Cd in maternal serum were 0.89, 0.84, 100, and 0.024 ng g-1, respectively. In this study, the Bayesian linear model determined the relationships of the birth weight and head circumference with combinations of PCB levels, toxic and essential trace elements, and questionnaire data. We found that PCB concentrations in maternal serum were weakly and negatively related to birth weight, whereas trace elements were not associated with birth weight. Serum PCB and Mn levels were negatively associated with head circumference, whereas other trace elements were not associated with head circumference. These results showed that maternal exposure to PCBs may be related to birth weight and head circumference, while maternal exposure to Mn is related to head circumference, even when adjusted based on the exposure levels of other contaminants, and maternal and fetal characteristics. Therefore, our findings indicate that maternal exposure to PCBs and Mn might be negatively related with birth weight and head circumference.

Association Between Serum Folate Levels and Caffeinated Beverage Consumption in Pregnant Women in Chiba: The Japan Environment and Children's Study.

BACKGROUND: Several studies have reported the adverse effects of caffeine intake during pregnancy on fetal health. However, the effects of caffeine intake from green and oolong teas has not been investigated, despite the considerable consumption of these teas in Japan and the potential inhibitory effects of catechins-chemicals present at relatively high levels in green and oolong teas-on folic acid absorption. The potential associations of serum folate levels with caffeinated beverage consumption and catechin levels remain largely unstudied. The present study aimed to determine these associations in pregnant Japanese women. METHODS: Pregnant women (n = 2,701) not receiving folate supplementation were enrolled at the Chiba Unit Center, a regional site of the Japan Environment and Children's Study (JECS). Serum folate levels were measured using an Access folate assay kit, and nutrient and caffeine intakes were assessed using a self-administered food frequency questionnaire that was previously evaluated in Japanese populations. RESULTS: The low and normal serum folate groups reported caffeine intakes of 42.3 mg/1,000 kcal and 34.4 mg/1,000 kcal, respectively, and tannin intakes of 40.8 mg/1,000 kcal and 36.3 mg/1,000 kcal, respectively. Multiple regression analyses revealed negative associations of serum folate levels with caffeine and tannin intakes and a positive association between serum folate levels and dietary folate intake. CONCLUSIONS: Considering the negative associations of caffeine and tannin levels with serum folate levels, pregnant women should consume caffeinated beverages, such as coffee and green/oolong teas, with caution.

Protective effect of young green barley leaf (Hordeum vulgare L.) on restraint stress-induced decrease in hippocampal brain-derived neurotrophic factor in mice.

BACKGROUND: Many health experts support the hypothesis that stressful lifestyles are the leading cause of illness, like depression. Therefore, from the standpoint of preventive medicine, it is important to reduce stress. Young green barley leaves are a good natural source of vitamins and minerals, and their juice is widely consumed as a functional food for health reasons in Japan. This study investigated the protective effect of young green barley leaves for stress control. MATERIALS AND METHODS: ICR outbred mice were exposed to 3-h sessions of restraint stress. Young green barley leaves (400 and 1,000 mg/kg) were administered orally 1 h before the sessions for 5 days. To analyze voluntary behavior, wheel-running activity was monitored during the dark period. Brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) expression in the whole hippocampus was measured by real-time quantitative polymerase chain reaction. RESULTS: Restraint stress resulted in a significant decrease in voluntary wheel-running behavior, but this decrease was ameliorated by the administration of young green barley leaves. The leaves also enhanced the decreased levels of BDNF mRNA induced by restraint stress; in particular, a significant protective effect was shown in the exon IV variant as compared to vehicle control mice. CONCLUSION: The findings suggest that young green barley leaves have potent anti-stress properties, as evidenced by preventing decreases in the levels of voluntary wheel-running activity and hippocampal BDNF mRNA in response to restraint stress. Our findings support the possibility that supplementation with young green barley leaves might be beneficial for preventing stress-related psychiatric disorders like depression.

Malformation spectrum induced by ketoconazole after single administration to pregnant rats during the critical period - comparison with vitamin A-induced malformation spectrum.

Azole derivatives have teratogenic effects in rodents. In the present study, malformations and their sensitive windows induced by high-dose ketoconazole (KCZ), an azole derivative, without maternal toxicity were investigated. In addition, the malformation spectrum determined was compared with that induced by vitamin A palmitate (VAP). Pregnant rats were administered a single dose of KCZ by oral gavage on specific individual days from gestational days 8 to 15 (GDs 8-15). Maternal animals were subjected to necropsy on GD 20, and the obtained fetuses were examined for external, visceral and skeletal malformations. The malformation spectrum of VAP was identified from available published data (Noda, Sato, and Udaka, 1982) and a complementary study (single administration of VAP at 1 200 000 IU kg(-1) ). Embryonic lethality was observed in dams given KCZ on GDs 9-12 with peak incidence on GDs 10 and 11 with complete resorption. KCZ induced major malformations included cleft palate, digital anomalies, misshapen limbs and unique discontinuous ribs, and the sensitive window for each was identified. Compared with the malformations induced by VAP, unique malformations (e.g. discontinuous ribs by KCZ, neural tube defects by VAP), similar malformations with similar sensitive windows (e.g. digital and limb malformations) and similar malformations with different sensitive windows (e.g. embryonic lethality and cleft palate) were distinguished, suggesting that the mechanisms of several of the types of KCZ-induced malformation are related to excessive vitamin A.

Evaluation of an oral function promotion programme for the independent elderly in Japan.

OBJECTIVES: The purpose of this study was to provide an oral function promotion programme for the independent elderly and evaluate the changes in oral health status and oral function. BACKGROUND: Few studies have scientifically analysed and evaluated the effectiveness of oral function promotion programmes provided for the independent elderly. MATERIALS AND METHODS: The subjects were independent elderly females (mean age: 74.6 +/- 6.3) recruited from senior citizens' centres in Tokyo. The intervention group (n = 79) received a 3-month oral function promotion programme, which included facial muscle and tongue exercises and salivary gland massages. The control group (n = 62) did not receive this programme. RESULTS: In the intervention group, the tongue coating scores decreased and the organoleptic score of oral malodour fell. The amount of food debris in the oral cavity decreased and the tongue dryness improved. Furthermore, the salivary flow rate increased. The length of time for maintaining the tongue in the forward position increased from 11.2 s to 18.7 s, and the number of times for moving the tip of the tongue in a clockwise circular motion, counter-clockwise circular motion and side-to-side motion within 30 s, increased from 14.5 to 20.6, 14.5 to 20.2, and 17.2 to 23.3 respectively. The number of times for movement of the lips significantly improved from 23.0 to 28.8 and the pronunciation of words was observed to be clearer. CONCLUSION: An oral function promotion programme was effective in improving the oral health status and oral function of an independent elderly population.

Neonatal exposure to diethylstilbestrol alters expression of DNA methyltransferases and methylation of genomic DNA in the mouse uterus.

Perinatal exposure to diethylstilbestrol (DES) can have numerous adverse effects on the reproductive organs later in life, such as vaginal clear-cell adenocarcinoma. Epigenetic processes including DNA methylation may be involved in the mechanisms. We subcutaneously injected DES to neonatal C57BL/6 mice. At days 5, 14, and 30, expressions of DNA methyltransferases (Dnmts) Dnmt1, Dnmt3a, and Dnmt3b, and transcription factors Sp1 and Sp3 were examined. We also performed restriction landmark genomic scanning (RLGS) to detect aberrant DNA methylation. Real-time RT-PCR revealed that expressions of Dnmt1, Dnmt3b, and Sp3 were decreased at day 5 in DES-treated mice, and that those of Dnmt1, Dnmt3a, and Sp1 were also decreased at day 14. RLGS analysis revealed that 5 genomic loci were demethylated, and 5 other loci were methylated by DES treatment. Two loci were cloned, and differential DNA methylation was quantified. Our results indicated that DES altered the expression levels of Dnmts and DNA methylation.

Exposure of juvenile female mice to isoflavone causes lowered expression of estrogen-related receptor gamma gene in vagina.

In our previous study, the vaginal opening (VO) day of C57BL/6 mice was accelerated several days by chronic exposure to a 0.05% isoflavone (IF) fortified diet. The purpose of this study was to investigate whether the acceleration of VO by IF (1) has a critical window, (2) is modified by IF exposure combined with 17beta-estradiol (E2), and (3) has any relation with gene expressions of estrogen-related receptors (ERRs). As a result, we determined that the critical window for the acceleration of VO was between 15 and 21 days postnatal. The combined effect of E2 and IF was thought to be additional in the acceleration of VO. The gene expression of ERRgamma was significantly decreased in vagina by IF. The reduction of ERRgamma may have two possible sequelae: disarrangement of vaginal development and high risk of vaginal cancer. In conclusion, IF exposure has a critical window for acceleration of VO and may have adverse effect on mouse vagina.

Fetal exposure to phytoestrogens--the difference in phytoestrogen status between mother and fetus.

The goal of this study was to investigate fetal exposure to phytoestrogens, estrogenic compounds derived from plants, by measuring serum concentrations of phytoestrogens in maternal and cord blood. This study included 51 mothers scheduled for cesarean section (C-section), to obtain the serum of mother and fetus at almost the same time. Serum concentrations of phytoestrogens, including genistein (Gen), daidzein (Dai), coumestrol (Cou), equol (Equ; a metabolite of Dai), and sulfate-conjugated Gen, were measured in maternal and cord blood samples by LC-MS/MS and HPLC. It was found that phytoestrogens were transferred from mother to fetus. The detection rates of Gen, Dai, Equ, and Cou in cord serum were 100%, 80%, 35%, and 0%, respectively. Levels of Gen and Dai were higher in cord than in maternal serum (mean=19.4 ng/ml vs.7.2 ng/ml and 4.3 ng/ml vs.1.8 ng/ml for Gen and Dai, respectively). However, a reverse pattern was seen for Equ (cord mean=0.9 ng/ml, maternal mean=2.0 ng/ml). The correlations were significant between the concentration levels of Gen and Dai, Gen and Equ, and Gen and Dai plus Equ in cord serum. However, in maternal serum, the correlations were weak. Also, in 8 of 10 cord serum samples, sulfate-conjugated Gen was detected (mean=5.2 ng/ml, standard deviation=4.7), but it was detected from only one maternal serum (8.7 ng/ml). This study demonstrates placental transfer of phytoestrogens from mother to fetus. It is suggested that the metabolic and/or excretion rates of phytoestrogens are different between mother and fetus and once phytoestrogens are transferred to the fetus, they tend to stay in the fetal side longer than in the maternal side. While the implications for the health and development of the newborn are not known, these data suggest that the effects of fetal exposure to phytoestrogens should be studied further.

Comprehensive analysis of the effect of phytoestrogen, daidzein, on a testicular cell line, using mRNA and protein expression profile.

In this study, we examined the effects of exposure to phytoestrogen (daidzein), 17beta-estradiol (E2), diethylstilbestrol (DES) and staurosporin on the TM4 testicular cell line, using comprehensive analysis, such as cDNA microarray and two-dimension polyacrylamide gel electropholesis (2D-PAGE) analysis, and we demonstrated if these toxicogenomic analyses could classify the chemical compounds. First, RNA was extracted from TM4 cells that had been treated with daidzein (80 microM), DES, E2 (40 microM) and stauroporin (100 nM) for 30 min. We performed cDNA microarray analysis, and the expression ratio data thus obtained were then analyzed using hierarchical clustering. This hierarchical clustering showed that daidzein exposure induced a different effect on gene expression change from that of E2, DES and staurosporin. Next, protein extracted from TM4 cells also underwent cDNA microarray analysis for 3 h. We performed 2D-PAGE analysis, and the spot intensity ratio data thus obtained were analyzed using hierarchical clustering. As with cDNA microarray, the hierarchical clustering of protein spot ratios showed that daidzein exposure induced a different effect on gene expression change from that of the other substances. In conclusion, we have demonstrated for the first time that classification of these chemicals can be performed by clustering analysis, using data from cDNA microarray and 2D-PAGE analyses, and that exposure to daidzein induces effects different from those of E2, DES and staurosporin.