Correlation between Conjugated Bisphenol A Concentrations and Efflux Transporter Expression in Human Fetal Livers.

Because of its widespread use in the manufacturing of consumer products over several decades, human exposure to bisphenol A (BPA) has been pervasive. Fetuses are particularly sensitive to BPA exposure, with a number of negative developmental and reproductive outcomes observed in rodent perinatal models. Xenobiotic transporters are one mechanism to extrude conjugated and unconjugated BPA from the liver. In this study, the mRNA expression of xenobiotic transporters and relationships with total, conjugated, and free BPA levels were explored utilizing human fetal liver samples. The mRNA expression of breast cancer resistance protein (BCRP) and multidrug resistance-associated transporter (MRP)4, as well as BCRP and multidrug resistance transporter 1 exhibited the highest degree of correlation, with r(2) values of 0.941 and 0.816 (P < 0.001 for both), respectively. Increasing concentrations of conjugated BPA significantly correlated with high expression of MRP1 (P < 0.001), MRP2 (P < 0.05), and MRP3 (P < 0.05) transporters, in addition to the NF-E2-related factor 2 transcription factor (P < 0.001) and its prototypical target gene, NAD(P)H quinone oxidoreductase 1 (P < 0.001). These data demonstrate that xenobiotic transporters may be coordinately expressed in the human fetal liver. This is also the first report of a relationship between environmentally relevant fetal BPA levels and differences in the expression of transporters that can excrete the parent compound and its metabolites.

Developmental pesticide exposure reproduces features of attention deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is estimated to affect 8-12% of school-age children worldwide. ADHD is a complex disorder with significant genetic contributions. However, no single gene has been linked to a significant percentage of cases, suggesting that environmental factors may contribute to ADHD. Here, we used behavioral, molecular, and neurochemical techniques to characterize the effects of developmental exposure to the pyrethroid pesticide deltamethrin. We also used epidemiologic methods to determine whether there is an association between pyrethroid exposure and diagnosis of ADHD. Mice exposed to the pyrethroid pesticide deltamethrin during development exhibit several features reminiscent of ADHD, including elevated dopamine transporter (DAT) levels, hyperactivity, working memory and attention deficits, and impulsive-like behavior. Increased DAT and D1 dopamine receptor levels appear to be responsible for the behavioral deficits. Epidemiologic data reveal that children aged 6-15 with detectable levels of pyrethroid metabolites in their urine were more than twice as likely to be diagnosed with ADHD. Our epidemiologic finding, combined with the recapitulation of ADHD behavior in pesticide-treated mice, provides a mechanistic basis to suggest that developmental pyrethroid exposure is a risk factor for ADHD.

Evaluation of particle resuspension in young children's breathing zone using stationary and robotic (PIPER) aerosol samplers.

Development of asthma in young children may be associated with high exposure to particulate matter (PM). However, typical stationary samplers may not represent the personal exposure of children ages 3 and younger since they may not detect particles resuspended from the floor as children play, thus reducing our ability to correlate exposure and disease etiology. To address this, an autonomous robot, the Pretoddler Inhalable Particulate Environmental Robotic (PIPER) sampler, was developed to simulate the movements of children as they play on the floor. PIPER and a stationary sampler took simultaneous measurements of particle number concentration in six size channels using an optical particle counter and inhalable PM on filters in 65 homes in New Jersey, USA. To study particle resuspension, for each sampler we calculated the ratio of particle concentration measured while PIPER was moving to the average concentration of particles measured during a reference period when PIPER remained still. For all investigated particle sizes, higher particle resuspension was observed by PIPER compared to the stationary sampler. In 71% of carpeted homes a more significant (at the α = 0.05 level) resuspension of particles larger than 2.5 µm was observed by PIPER compared to the stationary sampler. Typically, particles larger than 2.5 µm were resuspended more efficiently than smaller particles, over both carpeted and bare floors. Additionally, in carpeted homes estimations of PM10 mass from the particle number concentrations measured on PIPER while it was moving were on average a factor of 1.54 higher compared to reference period when PIPER was not moving. For comparison, the stationary sampler measured an increase of PM2.5 mass by a factor of only 1.08 when PIPER was moving compared to a reference period. This demonstrates that PIPER is able to resuspend particles through movement, and provide a better characterization of the resuspended particles than stationary samplers. Accurate measurement of resuspended PM will improve estimates of children's total PM exposure.

Physician-led, hospital-linked, birth care centers can decrease cesarean section rates without increasing rates of adverse events.

BACKGROUND: This study compares outcomes at a hospital-linked, physician-led, birthing center to a traditional hospital labor and delivery service. METHODS: Using de-identified electronic medical records, a retrospective cohort design was employed to evaluate 32,174 singleton births during 1998-2005. RESULTS: Compared with hospital service, birth care center delivery was associated with a lower rate of cesarean sections (adjusted Relative Risk = 0.73, 95% confidence interval 0.59-0.91; p < 0.001) without an increased rate of operative vaginal delivery (adjusted Relative Risk = 1.04, 95% confidence interval 0.97-1.13; p = 0.25) and a higher initiation of breastfeeding (adjusted Relative Risk = 1.28, 95% confidence interval 1.25-1.30; p ≤ 0.001). A maternal length of stay greater than 72 hours occurred less frequently in the birth care center (adjusted Relative Risk = 0.60, 95% confidence interval 0.55-0.66; p < 0.001). Comparing only women without major obstetrical risk factors, the differences in outcomes were reduced but not eliminated. Adverse maternal and infant outcomes were not increased at the birth care center. CONCLUSION: A hospital-linked, physician-led, birth care center has the potential to lower rates of cesarean sections without increasing rates of operative vaginal delivery or other adverse maternal and infant outcomes.

Development and in-home testing of the Pretoddler Inhalable Particulate Environmental Robotic (PIPER Mk IV) sampler.

Exposure and dose estimation are essential to understanding the etiology of environmentally linked childhood diseases. The behavior of resuspended particulate matter (PM) suggests that stationary measurements may underestimate household exposures in young children (ages 6-36 months). Because of the size and weight of the sampling equipment, use of personal samplers in this age group is either difficult or impossible. The Pretoddler Inhalable Particulate Environmental Robotic (PIPER Mk IV) sampler has been developed to provide a surrogate method to ascertain personal exposures to PM for this age group. As part of a study of childhood asthma, 55 homes in central New Jersey were tested. Simultaneous sampling for inhalable PM using stationary (110 cm height) and PIPER mobile sampler were carried out. In homes with bare floors (N=21), the absolute difference was 3.9 µg/m3 (SE=3.01; p=0.217) and relative difference (PIPER/Stationary) was 1.12 (linearized SE=0.11). On carpets (N=34), the absolute difference was 54.1 µg/m3 (SE=13.50; p=0.0003), and the relative difference was 2.30 (linearized SE=0.34). The results confirm the importance of understanding the personal dust cloud caused by children's activity in a room, particularly when rugs or carpets are present.

Analysis of six pyrethroid insecticide metabolites in cord serum using a novel gas chromatography-ion trap mass spectrometry method.

Pyrethroid insecticides are commonly used for residential and commercial pest control in the US. Pregnant women and their fetuses are vulnerable to pesticide exposures during critical windows of neurodevelopment. Biomonitoring for exposure requires accurate and sensitive methods to assess exposures during pregnancy. The objective of this study was to develop a sensitive analytical method to measure pyrethroid metabolite concentrations in cord serum. Six pyrethroid metabolites, cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropanecarboxylic acid (c/t-DCCA), trans-chrysanthemum dicarboxylic acid (t-CDCA), cis-3-(2,2-dibromovinyl)-2,2-dimethyl-cyclopropane carboxylic acid (c-DBCA), 4-fluoro-3-phenoxybenzoic acid (FPBA), and 3-phenoxybenzoic acid (3PBA) were extracted from cord serum by a dichloromethane liquid-liquid extraction, derivatized by 1,1,1,3,3,3-hexafluoro-2-propanol carboxylic acid esterification, and then measured by gas chromatography/ion trap mass spectrometry. Limits of detection ranged from 0.02 to 0.6 ng/mL. Sixty-three cord serum samples were collected from maternal-fetal dyads in central New Jersey to test for pyrethroid metabolites. Non-specific metabolites, 3PBA, t-DCCA, and t-CDCA, were detected most frequently, present in 29%, 6.3% and 6.3% of samples, respectively. Sensitivities were comparable or greater than other published studies assessing pyrethroid metabolites in cord blood. Comparisons with other literature-reported studies emphasize the importance of method sensitivity when assessing exposures at biologically relevant concentrations.

Improving estimation of indoor exposure to inhalable particles for children in the first year of life.

There is growing scientific evidence linking early childhood exposure to environmental agents with asthma and other illnesses that may not appear until later in life. Unfortunately the direct measurement of personal exposures of children in the first year of life is not possible by existing methodologies. This study developed and evaluated a new methodology to better assess exposure of children to inhalable particles in the first year of life while involved in floor play in the home. We constructed the Pre-Toddler Inhalable Particulate Environmental Robotic (PIPER) sampler. Two series of measurements of inhalable particles were carried out. One collected filter samples of airborne inhalable particles and a second used a real-time total particle mass concentration monitor. Samples were collected for seven residential locations. Duplicate samples were collected with PIPER 20 cm above the floor and from an identical stationary monitor positioned at a height of 110 cm. The mean observed airborne inhalable particle concentrations measured by PIPER was 98.6 microg/ m3, whereas simultaneously collected stationary samples mean concentration was 49.8 microg/m3. The average observed ratio of PIPER samples to stationary samples was 2.4. A paired t test comparison of the two sampling methods indicated a statistically significant higher level of inhalable particle concentration measured by PIPER in comparison with the fixed sampler (P < 0.0001). Peak concentrations as measured by a real-time monitor were in excess of 3600 microg/m3. The results suggest that children playing on the floor are exposed to a higher concentration of total inhalable particles than previous methodologies estimate.

Comparison of particulate matter exposure estimates in young children from personal sampling equipment and a robotic sampler.

Accurate characterization of particulate matter (PM) exposure in young children is difficult, because personal samplers are often too heavy, bulky or impractical to be used. The Pretoddler Inhalable Particulate Environmental Robotic (PIPER) sampler was developed to help address this problem. In this study, we measured inhalable PM exposures in 2-year-olds via a lightweight personal sampler worn in a small backpack and evaluated the use of a robotic sampler with an identical sampling train for estimating PM exposure in this age group. PM mass concentrations measured by the personal sampler ranged from 100 to almost 1,200 µg/m3, with a median value of 331 µg/m3. PM concentrations measured by PIPER were considerably lower, ranging from 14 to 513 µg/m3 with a median value of 56 µg/m3. Floor cleaning habits and activity patterns of the 2-year-olds varied widely by home; vigorous play and recent floor cleaning were most associated with higher personal exposure. Our findings highlight the need for additional characterization of children's activity patterns and their effect on personal exposures.

Use of a Robotic Sampler (PIPER) for Evaluation of Particulate Matter Exposure and Eczema in Preschoolers.

While the association of eczema with asthma is well recognized, little research has focused on the potential role of inhalable exposures and eczema. While indoor air quality is important in the development of respiratory disease as children in the U.S. spend the majority of their time indoors, relatively little research has focused on correlated non-respiratory conditions. This study examined the relationship between particulate matter (PM) exposures in preschool age children and major correlates of asthma, such as wheeze and eczema. Air sampling was carried out using a robotic (PIPER) child-sampling surrogate. This study enrolled 128 participants, 57 male and 71 female children. Ages ranged from 3 to 58 months with the mean age of 29.3 months. A comparison of subjects with and without eczema showed a difference in the natural log (ln) of PM collected from the PIPER air sampling (p = 0.049). PIPER's sampling observed an association between the ln PM concentrations and eczema, but not an association with wheezing history in pre-school children. Our findings are consistent with the hypothesis of the role of the microenvironment in mediating atopic dermatitis, which is one of the predictors of persistent asthma. Our findings also support the use of PIPER in its ability to model and sample the microenvironment of young children.

Children's mouthing and food-handling behavior in an agricultural community on the US/Mexico border.

Children's mouthing and food-handling activities were measured during a study of nondietary ingestion of pesticides in a south Texas community. Mouthing data on 52 children, ranging in age from 7 to 53 months, were collected using questionnaires and videotaping. Data on children's play and hand-washing habits were also collected. Children were grouped into four age categories: infants (7-12 months), 1-year-olds (13-24 months), 2-year-olds (25-36 months) and preschoolers (37-53 months). The frequency and type of events prompting hand washing did not vary by age category except for hand washing after using the bathroom; this increased with increasing age category. Reported contact with grass and dirt also increased with increasing age category. The median hourly hand-to-mouth frequency for the four age groups ranged from 9.9 to 19.4, with 2-year-olds having the lowest frequency and preschoolers having the highest. The median hourly object to mouth frequency ranged from 5.5 to 18.1 across the four age categories; the frequency decreased as age increased (adjusted R(2)=0.179; P=0.003). The median hourly hand-to-food frequency for the four age groups ranged from 10.0 to 16.1, with the highest frequency being observed in the 1-year-olds. Hand-to-mouth frequency was associated with food contact frequency, particularly for children over 12 months of age (adjusted R(2)=0.291; P=0.002). The frequency and duration of hand-to-mouth, object-to-mouth and food-handling behaviors were all greater indoors than outdoors. Infants were more likely to remain indoors than children in other age groups. The time children spent playing on the floor decreased with increasing age (adjusted R(2)=0.096; P=0.031). Parental assessment was correlated with hand-to-mouth activity but not with object-to-mouth activity. The highest combined (hand and object) mouthing rates were observed among infants, suggesting that this age group has the greatest potential for exposure to environmental toxins.

Seasonal pesticide use in a rural community on the US/Mexico border.

An environmental measurement and correlation study of infant and toddler exposure to pesticides was carried out in a colonia south of the city of Laredo, Texas. As part of the study, homes were visited during the late spring or summer, and during the winter of 2000-2001. At each visit, families reported on their use of pesticides in and around the home and floor wipe samples were collected and analyzed for 14 organophosphate and triazine pesticides. Selection of homes was based on the presence of infants and toddlers. A total of 27 homes participated in both seasonal visits. The interval between visits was 6 +/- 1.4 months. Univariate and multivariate nonparametric analyses were carried out using SPSS statistical software. Pesticide use within the home was more often reported than outside use and showed seasonal variation in use patterns. Indoor use was primarily associated with ants and cockroaches, and secondarily with rodents. The primary room treated was the kitchen, and the primary structures treated were the floors, lower walls, and dish cupboards. Seasonal variations were not found in the use of pesticides used outside the home and outdoor use was primarily associated with ant control. Based on parent reports, most pesticides used in the homes were pyrethroids. Several of the pesticides measured in floor wipe samples, Azinphos methyl, Fonofos, and Simazine, also showed seasonal variations. However, these pesticides are used in agriculture and were not associated with reported house and yard use patterns.

Nondietary ingestion of pesticides by children in an agricultural community on the US/Mexico border: preliminary results.

An environmental measurement and correlation study of nondietary ingestion of pesticides was carried out in a colonia in south Texas. The purpose of the study was to evaluate young children's exposure to environmental levels of organophosphate (OP) pesticides in the household. Samples were collected to measure levels of OP pesticides in housedust and on children's hands. These, in turn, were compared to levels of OP pesticide metabolites in urine. A total of 52 children, 25 boys and 27 girls, participated in the spring and summer of 2000. The children were 7-53 months of age at the time of recruitment. Univariate and multivariate regression analyses were carried out using SAS statistical software. Seventy-six percent of housedust samples and 50% of hand rinse samples contained OP pesticides. All urine samples had at least one metabolite and over 95% had at least two metabolites above the limit of detection (LOD). Total OP loadings in the housedust ranged from nondetectable (nd) to 78.03 nmol/100 cm(2) (mean=0.15 nmol/100 cm(2); median=0.07 nmol/100 cm(2)); total OP loadings on the children's hands ranged from nd to 13.40 nmol/100 cm(2) (mean=1.21 nmol/100 cm(2); median=1.41 nmol/100 cm(2)), and creatinine corrected urinary levels (nmol/mol creatinine) of total OP metabolites ranged from 3.2 to 257 nmol/mol creatinine (mean=42.6; median 27.4 nmol/mol creatinine). Urinary metabolites were inversely associated with the age of the child (in months) with the parameter estimate (pe)=-2.11, P=0.0070, and 95% confidence interval -3.60 to -0.61. The multivariate analysis observed a weak association between concentrations of OP pesticides in housedust, loadings in housedust, and concentration on hands, hand surface area, and urinary levels of OP metabolites. However, hand loadings of OP pesticides were more strongly associated (r(2)=0.28; P=0.0156) with urinary levels of OP metabolites (pe=6.39; 95% CI 0.98-11.80). This study's preliminary findings suggest that surface loadings of pesticides, on hands, are more highly correlated with urinary bioassays and, therefore, may be more useful for estimation of exposure in epidemiologic studies than levels of pesticides in housedust.

Elevated serum pesticide levels and risk for Alzheimer disease.

IMPORTANCE: The causes of late-onset Alzheimer disease (AD) are not yet understood but likely include a combination of genetic, environmental, and lifestyle factors. Limited epidemiological studies suggest that occupational pesticide exposures are associated with AD. Previously, we reported that serum levels of dichlorodiphenyldichloroethylene (DDE), the metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), were elevated in a small number of patients with AD (n=20). OBJECTIVE: To evaluate the association between serum levels of DDE and AD and whether the apolipoprotein E (APOE) genotype modifies the association. DESIGN, SETTING, AND PARTICIPANTS: A case-control study consisting of existing samples from patients with AD and control participants from the Emory University Alzheimer's Disease Research Center and the University of Texas Southwestern Medical School's Alzheimer's Disease Center. Serum levels of DDE were measured in 79 control and 86 AD cases. MAIN OUTCOMES AND MEASURES: Serum DDE levels, AD diagnosis, severity of AD measured by the Mini-Mental State Examination score, and interaction with APOE4 status. RESULTS: Levels of DDE were 3.8-fold higher in the serum of those with AD (mean [SEM], 2.64 [0.35] ng/mg cholesterol) when compared with control participants (mean [SEM], 0.69 [0.1] ng/mg cholesterol; P < .001). The highest tertile of DDE levels was associated with an odds ratio of 4.18 for increased risk for AD (95% CI, 2.54-5.82; P < .001) and lower Mini-Mental State Examination scores (-1.605; range, -3.095 to -0.114; P < .0001). The Mini-Mental State Examination scores in the highest tertile of DDE were -1.753 points lower in the subpopulation carrying an APOE ε4 allele compared with those carrying an APOE ε3 allele (P interaction = .04). Serum levels of DDE were highly correlated with brain levels of DDE (ρ = 0.95). Exposure of human neuroblastoma cells to DDT or DDE increased levels of amyloid precursor protein. CONCLUSIONS AND RELEVANCE: Elevated serum DDE levels are associated with an increased risk for AD and carriers of an APOE4 ε4 allele may be more susceptible to the effects of DDE. Both DDT and DDE increase amyloid precursor protein levels, providing mechanistic plausibility for the association of DDE exposure with AD. Identifying people who have elevated levels of DDE and carry an APOE ε4 allele may lead to early identification of some cases of AD.

Improved exposure characterization with robotic (PIPER) sampling and association with children's respiratory symptoms, asthma and eczema.

Particulate matter (PM) and its constituents are recognized risk factors for the development of respiratory symptoms and illness in children. Most measurements of exposure have relied upon stationary indoor monitors (SIMs), overlooking the role of resuspended PM. To improve exposure characterization to resuspended aerosol PM, a recently developed methodology has been employed. The goal of this study was to characterize the resuspendable fraction of house dust and early childhood exposures to PM and its constituents in the child's home and compare conventional SIM and the Pre-toddler Inhalable Particulate Environmental Robotic (PIPER), an innovative mobile sampler. The study seeks to demonstrate that PIPER provides a more relevant estimate of exposure from inhalable particulate matter through improved correlation with respiratory symptoms in young children. Seventy-five households with children between 3 and 59 months of age were recruited from clinics in central New Jersey. Demographic information, and responses to a health questionnaire based upon that used by the International Study of Allergies and Asthma in Childhood (ISAAC), and household data were collected. Household exposures to inhalable PM (PM100) and endotoxin were determined with simultaneous SIM and mobile (PIPER) sampling. Univariate and multivariate analyses were carried out. History of wheeze ("recent" (<1 year) and "ever"), cough, asthma and eczema was evaluated. Multivariate analysis models included PM100 and endotoxin levels by tertiles of exposure. Risk of asthma for the highest tertile of PM100, as measured by PIPER (odds ratio=4.2; 95% confidence interval 0.7-24.0), was compared with measurements by SIM (odds ratio=0.7; 95% confidence interval 0.2-2.6). Measurements of PM and its constituents with PIPER are more strongly associated with asthma, eczema and wheeze compared with measurements using SIMs. Application of this methodology may provide useful insights into early childhood exposures related to the etiology of childhood illnesses associated with inhalation exposures.

ß-Hexachlorocyclohexane levels in serum and risk of Parkinson's disease.

Pesticide exposure has been implicated as an environmental risk factor for the development of Parkinson's disease (PD). However, few studies have identified specific pesticides. Previously, we identified elevated serum levels of the organochlorine pesticide ß-hexachlorocyclohexane (ß-HCH) in PD patients from a small clinical sample. Here, we conducted a case-control study to confirm the association between ß-HCH and PD in a larger sample size (n=283) with serum samples of PD patients and controls obtained from UT Southwestern Medical Center and Emory University. Samples were obtained from two discrete periods at both sites, 2001-2003 and 2006-2008, and were analyzed for ß-HCH levels. Adjusted odds ratios (ORs) for PD were estimated using logistic regression and generalized estimating equations. The mean serum ß-HCH level across all cohorts in this study was 22.3 ng/mg cholesterol (range: 0-376.7), and the levels were significantly higher and samples collected in 2001-2003 vs. 2006-2008. After controlling for age and gender, the OR for increased risk of PD for every 1 ng/mg increase in serum ß-HCH ranged from 1.02 to 1.12 across the four different cohorts, and 1.03 (95% CI: 1.00-1.07, p value=0.031) in the pooled analysis. Furthermore, the OR for increased risk of PD of subjects having serum ß-HCH levels above the inter-quartile range of 39.08 ng/mg cholesterol was 2.85 (95% CI: 1.8, 4.48; p value<0.001). These data are consistent with environmental decreases in ß-HCH levels between 2001 and 2008, but they indicate that elevated levels of serum ß-HCH are still associated with heightened risk for PD.

Elevated serum pesticide levels and risk of Parkinson disease.

BACKGROUND: Exposure to pesticides has been reported to increase the risk of Parkinson disease (PD), but identification of the specific pesticides is lacking. Three studies have found elevated levels of organochlorine pesticides in postmortem PD brains. OBJECTIVE: To determine whether elevated levels of organochlorine pesticides are present in the serum of patients with PD. DESIGN: Case-control study. SETTING: An academic medical center. PARTICIPANTS: Fifty patients with PD, 43 controls, and 20 patients with Alzheimer disease. MAIN OUTCOME MEASURES: Levels of 16 organochlorine pesticides in serum samples. RESULTS: beta-Hexachlorocyclohexane (beta-HCH) was more often detectable in patients with PD (76%) compared with controls (40%) and patients with Alzheimer disease (30%). The median level of beta-HCH was higher in patients with PD compared with controls and patients with Alzheimer disease. There were no marked differences in detection between controls and patients with PD concerning any of the other 15 organochlorine pesticides. Finally, we observed a significant odds ratio for the presence of beta-HCH in serum to predict a diagnosis of PD vs control (odds ratio, 4.39; 95% confidence interval, 1.67-11.6) and PD vs Alzheimer disease (odds ratio, 5.20), which provides further evidence for the apparent association between serum beta-HCH and PD. CONCLUSIONS: These data suggest that beta-HCH is associated with a diagnosis of PD. Further research is warranted regarding the potential role of beta-HCH as a etiologic agent for some cases of PD.