Guang-Wen Lien

Perfluorinated Compounds in Umbilical Cord Blood and Adverse Birth Outcomes

Background Previous animal studies have shown that perfluorinated compounds (PFCs) have adverse impacts on birth outcomes, but the results have been inconclusive in humans. We investigated associations between prenatal exposure to perfluorooctanoic acid (PFOA), perfluorooctyl sulfonate (PFOS), perfluorononanoic acid (PFNA), and perfluoroundecanoic acid (PFUA) and birth outcomes. Methods In total, 429 mother-infant pairs were recruited from the Taiwan Birth Panel Study (TBPS). Demographic data were obtained by interviewing mothers using a structured questionnaire and birth outcomes were extracted from medical records. Cord blood was collected for PFOA, PFOS, PFNA, and PFUA analysis by ultra-high-performance liquid chromatography/tandem mass spectrometry. Results The geometric mean (standard deviation) levels of PFOA, PFOS, PFNA, and PFUA in cord blood plasma were 1.84 (2.23), 5.94 (1.95), 2.36(4.74), and 10.26 (3.07) ng/mL, respectively. Only PFOS levels were found to be inversely associated with gestational age, birth weight, and head circumference [per ln unit: adjusted β (95% confidence interval, CI) = −0.37 (−0.60, −0.13) wks, −110.2 (−176.0, −44.5) gm and −0.25 (−0.46, −0.05) cm]. Additionally, the odds ratio of preterm birth, low birth weight, and small for gestational age increased with PFOS exposure [per ln unit: adjusted odds ratio (OR) (95%CI) = 2.45 (1.47, 4.08), 2.61(0.85, 8.03) and 2.27 (1.25, 4.15)]. When PFOS levels were divided into quartiles, a dose-response relation was observed. However, PFOA, PFNA, and PFUA were not observed to have any convincing impact on birth outcomes. Conclusions An adverse dose-dependent association was observed between prenatal PFOS exposure and birth outcomes. However, no associations were found for the other examined PFCs.

The effect of prenatal perfluorinated chemicals exposures on pediatric atopy

BACKGROUND The role of perfluorinated compounds (PFCs) in the immune system and allergic diseases is not well-known. This study examined the effects of pre-natal exposure to PFCs on immunoglobulin E (IgE) levels and atopic dermatitis (AD). METHODS In Taiwan Birth Panel cohort study, newborns with cord blood and peri-natal factors (i.e. birth body weight, weeks of gestation, and type of delivery) gathered at birth were evaluated. At the age of 2 years, information on the development of AD, environmental exposures, and serum total IgE were collected. The AD and non-AD children were compared for the concentration of cord blood serum PFCs measured by Ultra-performance liquid chromatography/triple-quadrupole mass (UPLC-MS/MS). Correlations among cord blood IgE, serum total IgE at 2 years of age, and cord blood PFC levels were made. RESULTS Of 244 children who completed the follow-up and specimen collections, 43 (17.6%) developed AD. Concentrations of cord blood serum perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS) were median (range) 1.71 (0.75-17.40), 5.50 (0.11-48.36), 2.30 (0.38-63.87), and 0.035 (0.035-0.420)ng/mL, respectively. PFOA and PFOS levels positively correlated with cord blood IgE levels (per ln-unit: β=0.134 KU/l, p=0.047 for PFOA; β=0.161 KU/l, p=0.017 for PFOS). Analyses stratified by gender revealed that PFOA and PFOS levels positively correlated with cord blood IgE levels only in boys (per ln-unit: β=0.206 KU/l, p=0.025 for PFOA; β=0.175 KU/l, p=0.053 for PFOS). When dividing cord blood serum PFCs into quartiles in the fully adjusted models, AD had no significant association with PFOS. CONCLUSIONS Pre-natal PFOA and PFOS exposures positively correlated with cord blood IgE levels.

Comparison of electrospray ionization, atmospheric pressure chemical ionization and atmospheric pressure photoionization for determining estrogenic chemicals in water by liquid chromatography tandem mass spectrometry with chemical derivatizations

This study compared the sensitivities and matrix effects of four ionization modes and four reversed-phase liquid chromatographic (LC) systems on analyzing estrone (E1), 17beta-estradiol (E2), estriol (E3), 17alpha-ethinylestradiol (EE2), 4-nonylphenol (NP), 4-tert-octylphenol (OP), bisphenol A (BPA) and their derivatives of dansyl chloride or pentafluorobenzyl bromide (PFBBr) in water matrixes using a triple-quadrupole mass spectrometer with selected reaction monitoring (SRM). The four probes were electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), atmospheric pressure photoionization (APPI) and APCI/APPI; the four LC systems were ultra-performance liquid chromatography (UPLC) with or without post-column split, a mixed-mode column and two-dimensional LC (2D-LC). Dansylated compounds with ESI at UPLC condition had the most intense signals and less matrix effects of the various combinations of ionization and LC systems. The on-column limits of detection (LODs) of dansylated estrogens by SRM were 0.05-0.20 pg, and the LODs in sewage treatment plant effluent and in river water were 0.23-0.52 and 0.56-0.91 ng/L, respectively. The LODs using selected ion monitoring (SIM) reached low ng/L levels in real samples and measured concentrations were comparable with those of SRM.

Association between Maternal Serum Perfluoroalkyl Substances during Pregnancy and Maternal and Cord Thyroid Hormones: Taiwan Maternal and Infant Cohort Study

Background: Perfluoroalkyl substances (PFASs) are synthetic compounds that are widely used in industry and are often detectable in humans. In pregnant rats and their pups, PFASs can interfere with thyroid hormone homeostasis. In humans, maternal thyroid hormones supply the fetus throughout pregnancy, and thyroid hormones play a critical role in fetal growth and neurodevelopment. Objectives: We investigated the association between maternal PFAS exposure and thyroid hormone status in pregnant women and neonates. Methods: In a study of environmental exposure and health in Taiwan, we measured serum concentrations of nine PFASs and four thyroid hormones for 285 pregnant women in their third trimester, and also measured cord serum thyroid hormones for 116 neonates. Associations between maternal PFASs and maternal and cord thyroid hormones were examined in multiple linear regression models. Results: Perfluorohexanesulfonic acid concentrations were positively associated with maternal thyroid-stimulating hormone (TSH) levels. Pregnant women with higher levels of perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUnDA), and perfluorododecanoic acid (PFDoDA) had lower free thyroxine (T4) and total T4 levels. For example, we estimated that maternal free T4 levels decreased 0.019 ng/dL (95% CI: –0.028, –0.009) with each nanogram per milliliter increase in maternal PFNA. Finally, maternal PFNA, PFUnDA, and PFDoDA levels were associated with lower cord total triiodothyronine (T3) and total T4 levels, and maternal perfluorodecanoic acid (PFDeA) was associated with lower cord total T3. Conclusions: Our results suggest that exposure to some PFASs during pregnancy may interfere with thyroid hormone homeostasis in pregnant women and fetuses. Citation: Wang Y, Rogan WJ, Chen PC, Lien GW, Chen HY, Tseng YC, Longnecker MP, Wang SL. 2014. Association between maternal serum perfluoroalkyl substances during pregnancy and maternal and cord thyroid hormones: Taiwan Maternal and Infant Cohort Study. Environ Health Perspect 122:529–534; http://dx.doi.org/10.1289/ehp.1306925

Analysis of perfluorinated chemicals in umbilical cord blood by ultra-high performance liquid chromatography/tandem mass spectrometry

Perfluorinated compounds (PFCs) can cross the placental barrier and enter fetal circulation. This study aimed at developing a fast and sensitive ultra-high performance liquid chromatography/tandem mass spectrometry method for the determination of twelve perfluorinated compounds in cord blood. Samples were processed with protein precipitation using formic acid and methanol, mixed with stable isotope labeled standard, followed by sonication and centrifugation, and were analyzed using a Waters ACQUITY UPLC coupled with a Waters Quattro Premier XE triple-quadrupole mass spectrometer. The instrument was operated in selected reaction monitoring (SRM) with negative electrospray ionization. Using BEH C(18) column (2.1 mm×50 mm, 1.7 μm) with 10-mM N-methylmorpholine/methanol gradient elution provided a fast chromatographic separation (5.5 min) and sharp peaks. Intra- and inter-day calibration bias was less than 7% and intra- and inter-day calibration of relative standard deviations were within 0.02-8.22% for all the analytes and concentrations. The recoveries of PFCs spiked into bovine serum ranged from 85 to 104% with relative standard deviations from 0.02 to 6.37%. The limits of quantitation (LOQs), defined as a signal-to-noise ratio of ten, ranged from 0.15 to 3.1 ng/mL for the twelve PFCs. Perfluorooctanoic acid (PFOA), perfluorooctyl sulfonate (PFOS), perfluoroundecanoic acid (PFUA) and perfluorononanoic acid (PFNA) were detected in up to 68% of umbilical cord plasma (n=444) in Taiwan Birth Panel Study and the health effect of these chemicals on children developmental deserves further investigation.

Perfluorinated compound levels in cord blood and neurodevelopment at 2 years of age.

Background: Epidemiologic data regarding the potential neurotoxicity of perfluorinated compounds (PFCs) are inconclusive. We investigated the associations between in utero exposure to perfluorooctanoic acid (PFOA) and perfluorooctyl sulfonate (PFOS) and early childhood neurodevelopment. Methods: We recruited 239 mother–infant pairs in northern Taiwan from the Taiwan Birth Panel Study, which was established in 2004. We examined the association between PFCs in cord blood and children’s neurodevelopment at 2 years of age, using the Comprehensive Developmental Inventory for Infants and Toddlers. This tool contains cognitive, language, motor, social, and self-help domains; test scores were further transformed into developmental quotients according to standardized norms. All multivariate regression models were adjusted for infant sex and gestational age, maternal education, family income, cord blood cotinine levels, postnatal environmental tobacco smoke exposure, and breastfeeding. Results: Prenatal PFOS concentrations in both untransformed and natural log (Ln)-transformed values were associated with adverse performance on the whole test and the domains related to development. A dose–response relationship was observed when PFOS levels were categorized into four groups. This association was most obvious in relation to the gross-motor subdomain. Across the PFOS interquartile range, the quotients of the gross-motor subdomain decreased by 3.7 points (95% confidence interval [CI] = −6.0 to −1.5), with an increasing odds ratio of poor performance (2.4; 95% CI = 1.3 to 4.2). In contrast, measures of association between PFOA concentrations and test scores were close to null. Conclusions: Prenatal exposure to PFOS, but not PFOA, may affect children’s development, especially gross-motor development at 2 years of age.

Associations between Levels of Serum Perfluorinated Chemicals and Adiponectin in a Young Hypertension Cohort in Taiwan

In animals, perfluorinated chemicals (PFCs), specifically perfluorooctanoic acid (PFOA) and perfluorooctane sulfate (PFOS), function as peroxisome proliferator-activated receptor (PPAR) alpha agonists. However, the relevance of animal (primarily rodent) data to humans is unresolved. While plasma adiponectin level is very responsive to PPAR gamma agonist drugs, it has not been determined whether adiponectin level is related to serum PFCs concentrations. In the present study, 287 subjects (12-30 years of age) were recruited to determine the relationship between serum level of PFCs and serum level of adiponectin. The results showed males had higher serum PFOS concentrations than females and that those with metabolic syndrome had lower serum PFOA than controls. Besides, it showed regional elevations of the perfluoroundecanoic acid (PFUA) (median concentration: 7.11 ng/mL) in the study subjects. No relationship of PFOA, PFOS, PFUA, and the sum of all four PFCs was found to glucose homeostasis, adiponectin level, lipid profile, and inflammatory markers. The median and the range of perfluorononanoic acid (PFNA) concentration (in ng/mL; for four categories corresponding to the <50, 50-74, 75-89, and ≥90th percentiles) were 0.38 (0.38-1.68), 3.22 (1.73-4.65), 5.85 (4.75-8.29), 10.56 (8.40-25.40), respectively. After controlling for confounding factors, multiple linear regression analysis revealed that the mean natural log-transformed level of adiponectin increased significantly across categories of PFNA (in ng/mL; 8.78, 8.73, 9.06, 9.36; P for trend = 0.010 in the full model). In conclusion, higher serum PFNA concentration is associated with elevated serum adiponectin concentration.

Neonatal–maternal factors and perfluoroalkyl substances in cord blood

Perfluoroalkyl substances (PFASs) can cross the placenta, enter fetal circulation, and were found to correlate with adverse fetal growth. However, determinants of cord blood PFASs are not fully characterized. The study aimed to explore the association between PFASs and neonatal-maternal factors within a Taiwanese birth cohort. We selected subjects from Taiwan Birth Panel Study, which enrolled 486 infant-mother pairs in 2004-2005. We collected cord blood and analyzed perfluorooctanoic acid (PFOA), perfluorooctanyl sulfonate (PFOS), perfluorononanoic acid (PFNA) and perfluoroundecanoic acid (PFUA) using a simple protein precipitation and an ultra-high performance liquid chromatography/tandem mass spectrometry. We retrieved information pertaining to maternal socio-demographics, lifestyle- and dietary-related factors through structured questionnaires during the postpartum hospital stay. A total of 439 subjects, with 90% response rate, have completed serum analysis and questionnaire survey. The median concentrations for PFOA, PFOS, PFNA, and PFUA in cord blood were 1.86, 5.67, 3.00, and 13.5ngmL(-1), respectively. After adjusting for potential confounders, multiple linear regression models revealed that log10-PFOA was positively associated with maternal age (β=0.011) and negatively associated with multiparity (β=-0.044). Log10-PFOS was negatively correlated with birth weight (β=-0.011) and higher maternal education (senior high school: β=-0.067; university: β=-0.088). Log10-PFUA tended to negatively associate with gender, male infants (β=-0.075), and using cosmetics during pregnancy (β=-0.065). Interestingly, presence of cockroaches in the home was positively associated with log10-PFOA (β=0.041) and 1og10-PFNA (β=0.123). In conclusion, this study demonstrated several factors to correlate with cord blood PFASs and further investigation are still needed for confirmation of exposure routes.

Serum perfluorinated chemicals, glucose homeostasis and the risk of diabetes in working-aged Taiwanese adults ☆

BACKGROUND The link among perfluoroalkyl and polyfluoroalkyl substances (PFASs), abnormal glucose homeostasis and the risk of diabetes has been intensively debated with conflicting evidence. OBJECTIVES We evaluated the associations among PFASs, oral glucose tolerance testing (OGTT) curves and diabetes prevalence in 571 working-aged Taiwanese participants. METHODS Exposure measures included serum perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluoroundecanoic acid (PFUA). Outcomes were OGTT curves and prevalent diabetes defined by fasting blood glucose (FBG) ≥126mg/dL, 2-h glucose ≥200mg/dL, or glycated hemoglobin ≥6.5%. Analyses were performed with multiple logistic regression and functional data analysis. RESULTS A total of 39 participants (6.8%) had diabetes in this study. After full adjustment, the increase in the geometric means of FBG, 2-h glucose concentrations, and area under the OGTT curve (AUC120) with a doubling increase in PFOS was 3% (95% CI 1-4), 8% (5-12), and 6% (4-9), respectively. Compared to the lowest-quartile of PFOS concentrations (<2.4ng/ml), the OGTT trajectories were significantly steeper in participants of the highest-quartile PFOS exposure (>4.8ng/ml) and the vertical shifting of the mean curve for each PFOS quartile showed a dose-response pattern. The adjusted odds ratio for diabetes comparing the highest to lowest quartile was 3.37 (95% CI 1.18-9.65). For PFOA, PFNA, and PFUA, the opposite pattern of OGTT trajectory and the opposite risk profile for diabetes were observed. CONCLUSIONS Chronic PFOS exposure was associated with impaired glucose homeostasis and the increased prevalence of diabetes. However, PFOA, PFNA, and PFUA showed a potential protective effect against glucose intolerance and the risk of diabetes. Future research focusing on clarifying possible differential effects of different species of PFASs on glucose homeostasis and establishing the prospective associations between PFASs and diabetes is needed.

Perfluoroalkyl substances in cord blood and attention deficit/hyperactivity disorder symptoms in seven-year-old children.

OBJECTIVE The effect of perfluoroalkyl substances (PFASs) on the development of neurotoxicity in children is still controversial. This study aimed to evaluate the association between in utero exposure to four PFASs and the development of neurobehavioral symptoms related to attention deficit hyperactivity disorder (ADHD) in early childhood. METHODS Eligible study subjects were selected from the Taiwan Birth Panel Study and the Taiwan Early-Life Cohort, which enrolled a total of 1526 mother-infant pairs during 2004 and 2005. We collected umbilical cord blood and analyzed perfluorooctanoic acid (PFOA), perfluorooctanyl sulfonate (PFOS), perfluorononanoic acid (PFNA), and perfluoroundecanoic acid (PFUA) levels. When a child was 7 years old, to evaluate ADHD related neurobehavioral symptoms, their parents completed the Swanson, Nolan, and Pelham IV scale (SNAP-IV), the Child Behavior Checklist (CBCL), and the Strengths and Difficulties Questionnaire (SDQ) questionnaires. We used linear regression models with inverse probability weighting to explore the association between prenatal exposure to four PFASs and ADHD rating scores. RESULTS A total of 282 subjects have completed the PFASs analysis and questionnaire survey. After adjusted for potential confounders, we observed that PFNA is inversely associated with inattention and oppositional defiant disorder of SNAP-IV, and hyperactivity/inattention of SDQ. No association between PFOA, PFOS, or PFUA and ADHD symptoms was found. CONCLUSIONS Prenatal exposure to PFNA was found to associate with neurobehavioral symptoms related to ADHD among Asian seven-year-old children. Further studies are needed to elucidate the causal relationship.