Blood persistent organochlorine pesticides in pregnant women in relation to physical and environmental variables in The Hokkaido Study on Environment and Children's Health.

The aim of this study was to document the exposure levels of pregnant women in Hokkaido to persistent organochlorine (POC) pesticides and the relationship between the body burdens of these pesticides and the study population's characteristics, such as age, pre-pregnancy body weight and calendar year in which blood was collected. From 2002 to 2005, whole blood samples were obtained from 186 pregnant women (aged 17 to 47 years) from the population of 514 women registered with the Sapporo Toho hospital cohort of the Hokkaido Study. Blood samples were analyzed by GC/NCIMS and GC/HRMS to quantify 29 POC pesticides. The subjects' demographic details were obtained from medical records and self-administered questionnaires. The Jonckheere-Terpstra test was used to determine relevant trends in the chemical concentrations of these pesticides and their relationship to the subjects' demographic details. Twenty-one of the 29 targeted compounds (including pesticides that have never been used in Japan, such as Mirex, Parlar-26 and Parlar-50) were detected in whole blood samples, and their log-transformed concentrations were found to significantly correlate with each other. The concentrations of p,p'-DDD, o,p'-DDE, p,p'-DDE, Parlar-26 and Parlar-50 declined from 2002 to 2005 (p<0.05). The pesticide concentrations appeared to have stronger associations with past conception than with parity, with most pesticide concentrations declining in a manner that appeared inversely related to past conceptions (p<0.05). Maternal age was positively associated with the following pesticide concentrations: p,p'-DDE, chlordanes group, cis-heptachlorepoxide, ß-HCH and mirex. Maternal pre-pregnancy body weight was positively associated with the concentrations of dieldrin, HCB, ß-HCH, Parlar-26 and Parlar-50, and appeared to be more strongly related to the body burdens of POC pesticides when compared with BMI associations. Further studies are required to evaluate the effects of POC pesticides on human health with regard to reproductive outcomes and child development.

Prenatal exposure to perfluorinated chemicals and relationship with allergies and infectious diseases in infants.

BACKGROUND: Recent studies have shown effects of prenatal exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) on infants in the general environmental levels. Laboratory animal studies have shown that exposure to PFOS and PFOA is associated with immunotoxic effects. OBJECTIVES: To investigate the relationship between maternal PFOS and PFOA levels and infant allergies and infectious diseases during the first 18 months of life. Cord blood immunoglobulin (Ig) E levels were also evaluated. METHODS: We conducted a prospective cohort study of pregnant women from 2002 to 2005 in Sapporo, Japan. Maternal PFOS and PFOA levels were measured in relation to cord blood IgE concentrations (n=231) and infant allergies and infectious diseases (n=343). Characteristics of mothers and their infants were obtained from self-administered questionnaires and medical records. Development of infant allergies and infectious diseases was determined from self-administered questionnaires at 18 months of age. Concentrations of PFOS and PFOA in maternal serum and concentrations of IgE in umbilical cord serum at birth were measured. RESULTS: Cord blood IgE levels decreased significantly with high maternal PFOA concentration among female infants. However, there were no significant associations among maternal PFOS and PFOA levels and food allergy, eczema, wheezing, or otitis media in the 18 month-old infants (adjusted for confounders). CONCLUSIONS: Although cord blood IgE level decreased significantly with high maternal PFOA levels among female infants, no relationship was found between maternal PFOS and PFOA levels and infant allergies and infectious diseases at age in 18 months.

[Concentrations of persistent organochlorine pesticides in whole blood of pregnant women in Hokkaido study on environment and children's health].

OBJECTIVES: This study was performed to evaluate the levels of exposure to persistent organochlorine pesticides in pregnant women in Hokkaido. METHODS: Whole-blood samples were obtained from 70 pregnant women aged 17 to 39 years in Hokkaido and analyzed to quantify 29 organochlorine pesticides by gas chromatography/negative ion chemical ionization mass spectrometry and gas chromatography/high-resolution mass spectrometry. RESULTS: Among 29 target compounds, 20 were detected in the whole-blood samples. Mirex, Parlar-26, and Parlar-50, which have never been used in Japan, were identified in all samples, as well as 11 compounds that have been used in Japan. Log-transformed concentrations of compounds with detection rates above 60% linearly correlated with each other (p<0.01). p,p'-DDE exhibited the highest concentration, with a geometric mean of 730 pg/g wet weight. From the results of the Jonckheere-Terpstra trend test, body weight or age was positively associated with the concentrations of several compounds. CONCLUSIONS: We detected 22 organochlorine pesticides including pesticides with no history of use in Japan in the whole-blood samples from pregnant women in Hokkaido. Through long-distance transport mechanisms, these pollutants may distribute widely, and further surveillance of human blood, in addition to foods and the environment, should be conducted.

Effects of prenatal exposure to dioxin-like compounds on allergies and infections during infancy.

Dioxin-like compounds are endocrine disruptors. The effects of prenatal exposure to environmental levels of dioxins on immune function during infancy have not been clarified, although dioxins induce immunosuppression in offspring of animals. Moreover, human studies have not assessed the effects of gender- or congener-specific differences. The purpose of this study was to investigate the association between dioxin levels in maternal blood and the risk of infection and allergies in infancy. We examined 364 mothers and their infants enrolled in a Hokkaido Study on Environment and Children's Health between 2002 and 2005 in Sapporo, Japan. Relevant information was collected from a baseline questionnaire during pregnancy, medical records at delivery, and a follow-up questionnaire when the child was 18 months of age that assessed development of allergies and infections in infancy. Dioxin-like compound levels in maternal blood were measured with high-resolution gas chromatography/high-resolution mass spectrometry. Relatively higher levels of polychlorinated dibenzofuran were associated with a significantly increased risk of otitis media, especially among male infants (odds ratio=2.5, 95% confidence interval=1.1-5.9). Relatively higher levels of 2,3,4,7,8-pentachlorodibenzofuran were also associated with a significantly increased risk of otitis media (odds ratio=5.3, 95% confidence interval=1.5-19). However, we observed a weak association between dioxin-like compound levels and allergic symptoms in infancy. At environmental levels, prenatal exposure to dioxin-like compounds may alter immune function and increase the risk of infections in infancy, especially among males. The compound 2,3,4,7,8-pentachlorodibenzofuran may be responsible for this.

Prenatal exposure to PCDDs/PCDFs and dioxin-like PCBs in relation to birth weight.

Several human studies have shown that low-level exposure to environmental contaminants, such as polychlorinated biphenyls (PCBs) and organochlorine pesticides, negatively influences birth outcomes. However, the effects of low-level exposure to polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like PCBs (DL-PCBs) on birth outcomes have not been clarified in human studies. A prospective cohort study was established to investigate the possible adverse effects of PCDDs/PCDFs and DL-PCBs on fetal growth and neurodevelopment. We recruited 514 pregnant women between July 2002 and October 2005 in Sapporo, Japan. We measured 29 congener levels of PCDDs/PCDFs and DL-PCBs in maternal blood. Using multiple liner regression analysis of the association between birth weight and the levels of PCDDs/PCDFs and DL-PCBs with full adjustments for potential confounders, a significant adverse effect was observed regarding total PCDDs toxic equivalents (TEQ) levels (adjusted beta=-231.5g, 95% CI: -417.4 to -45.6) and total PCDFs TEQ levels (adjusted beta=-258.8g, 95% CI: -445.7 to -71.8). Among male infants, significant adverse associations with birth weight were found for total PCDDs TEQ level, total PCDDs/PCDFs TEQ level, and total TEQ level. However, among female infants, these significant adverse associations were not found. With regard to individual congeners of PCDDs/PCDFs and DL-PCBs, we found significantly negative association with the levels of 2,3,4,7,8-PeCDF (adjusted beta=-24.5g, 95% CI: -387.4 to -61.5). Our findings suggest that prenatal low-level exposure to PCDDs and PCDFs, especially 2,3,4,7,8-PeCDF, may accumulate in the placenta and retard important placental functions, which result in lower birth weight.

Correlations between prenatal exposure to perfluorinated chemicals and reduced fetal growth.

BACKGROUND: Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are man-made, ubiquitous, and persistent contaminants in the environment, wildlife, and humans. Although recent studies have shown that these chemicals interfere with fetal growth in humans, the results are inconsistent. OBJECTIVES: Our goal was to investigate the correlation between relatively low levels of PFOS and PFOA in maternal serum and birth weight and birth size. METHODS: We conducted a hospital-based prospective cohort study between July 2002 and October 2005 in Sapporo, Japan. A total of 428 women and their infants were involved in the study. We obtained characteristics of the mothers and infants from self-administered questionnaire surveys and from medical records. We analyzed maternal serum samples for PFOS and PFOA by liquid chromatography-tandem mass spectrometry (LC/MS/MS). RESULTS: After adjusting for confounding factors, PFOS levels negatively correlated with birth weight [per log10 unit: beta = -148.8 g; 95% confidence interval (CI), -297.0 to -0.5 g]. In addition, analyses stratified by sex revealed that PFOS levels negatively correlated with birth weight only in female infants (per log10 unit: beta = -269.4 g; 95% CI, -465.7 to -73.0 g). However, we observed no correlation between PFOA levels and birth weight. CONCLUSION: Our results indicate that in utero exposure to relatively low levels of PFOS was negatively correlated with birth weight.

Adverse birth outcomes associated with maternal smoking and polymorphisms in the N-Nitrosamine-metabolizing enzyme genes NQO1 and CYP2E1.

Maternal smoking during pregnancy can result in both pregnancy complications and reduced size of the fetus and neonate. Among women who smoke, genetic susceptibility to tobacco smoke also is a likely causative factor in adverse pregnancy outcomes. A prospective cohort study was conducted among 460 pregnant women who delivered live singletons in Sapporo, Japan, from 2002 to 2005. Multiple linear regression models were used to estimate associations of maternal smoking and polymorphisms in two genes encoding N-nitrosamine-metabolizing enzymes-NAD(P)H: quinone oxidoreductase 1 (NQO1) and cytochrome P-450 2E1 (CYP2E1)-with birth size. Among infants born to smokers with the NQO1 homozygous wild-type allele, birth weight, birth length, and birth head circumference were significantly reduced (p < 0.01 for each factor). For the homozygous wild-type CYP2E1 allele, birth weight was lower by an estimated 195 g (standard error, 55; p < 0.001) among smokers. These genotypes did not confer adverse effects among women who had never smoked or who quit smoking during the first trimester. The adverse effects of maternal smoking on infant birth size may be modified by maternal genetic polymorphisms in N-nitrosamine-metabolizing enzymes among Japanese subjects. These results may help in directing smoking cessation interventions during pregnancy, especially among susceptible women.

Exploiting gene-environment interaction to detect adverse health effects of environmental chemicals on the next generation.

There is increasing evidence from epidemiological studies that genetic susceptibilities may modify the teratogenic effects of toxic chemicals. However, in contrast to tobacco smoke, few epidemiological studies have addressed environmental chemicals, such as polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans and polychlorinated biphenyls in regard to genetic susceptibility. Recent studies, including the Hokkaido Study of Environments and Children's Health, have investigated the impacts of both environmental and genetic factors on children's development. Several xenobiotic-metabolizing genes have been reported to confer genetic susceptibility to low birth weight. These genes seem to be influenced functionally by maternal smoking during pregnancy, itself a significant risk factor. In our study, we found that birth weight was significantly lower among infants born to smoking women having the specific AHR, CYP1A1, GSTM1, CYP2E1 and NQO1 genotypes. When combinations of these genotypes were considered, birth weight was even lower. On the other hand, congenital anomalies such as hypospadias seemed to be caused by environmental factors in conjunction with genetic predisposition as suggested by linkage in several case-control studies reported to low birth weight. We have found an association between maternal CYP1A1 genotype or low birth weight and the risk of hypospadias irrespective of smoking. At the same time, birth weight was negatively correlated with maternal blood concentrations of polychlorinated dibenzofurans. Further studies should elucidate the impact of genetic factors on adverse effects of exposures to dioxin-related chemicals.

Using microarray analysis to evaluate genetic polymorphisms involved in the metabolism of environmental chemicals.

The field of molecular biology currently faces the need for a comprehensive method of evaluating individual differences derived from genetic variation in the form of single nucleotide polymorphisms (SNPs). SNPs in human genes are generally considered to be very useful in determining inherited genetic disorders, susceptibility to certain diseases, and cancer predisposition. Quick and accurate discrimination of SNPs is the key characteristic of technology used in DNA diagnostics. For this study, we first developed a DNA microarray and then evaluated its efficacy by determining the detection ability and validity of this method. Using DNA obtained from 380 pregnant Japanese women, we examined 13 polymorphisms of 9 genes, which are associated with the metabolism of environmental chemical compounds found in high frequency among Japanese populations. The ability to detect CYP1A1 I462V, CYP1B1 L432V, GSTP1 I105V and AhR R554K gene polymorphisms was above 98%, and agreement rates when compared with real time PCR analysis methods (kappa values) showed high validity: 0.98 (0.96), 0.97 (0.93), 0.90 (0.81), 0.90 (0.91), respectively. While this DNA microarray analysis should prove important as a method for initial screening, it is still necessary that we find better methods for improving the detection of other gene polymorphisms not part of this study.

Good outcome for infant of mother treated with chemotherapy for ewing sarcoma at 25 to 30 weeks' gestation.

There have been only three previous reports of women with Ewing sarcoma who received chemotherapy while pregnant. A 17-year-old woman with Ewing sarcoma was treated with a combination of doxorubicin (Adriamycin) and ifosfamide during the 25th to 30th week of gestation, and the baby was delivered at the 32nd week. The baby was developing normally at follow-up at 8 months of age. This case report supports the idea that in this situation, the pregnancy can be continued to await fetal growth, and second-trimester chemotherapy may not have a deleterious effect on the fetus.