Prenatal phthalate exposure and sex steroid hormones in newborns: Taiwan Maternal and Infant Cohort Study.

BACKGROUND: Newborn anogenital distance (AGD) has been associated with prenatal exposure of phthalates. The association between prenatal phthalate exposure and sex steroid hormones in newborns is unclear. OBJECT: This study aimed to examine whether cord-blood sex hormone levels were associated with prenatal phthalate exposure and newborn anogenital distance (AGD). METHODS: In the Taiwan Maternal and Infant Cohort Study, we recruited 1,676 pregnant women in their third trimester in 2012-2015 in Taiwan. We determined 11 urinary phthalate metabolites in pregnant women, three maternal and five cord-blood steroid sex-hormone concentrations. Five hundred and sixty-five mother-infant pairs with sufficient data were included. Trained neonatologists measured 263 newborns' AGD. We examined the associations of prenatal phthalate metabolite levels with AGD and hormones using linear regression models and evaluated correlations between maternal and cord-blood sex hormone levels and AGD. RESULTS: Compared with the male newborns exposed to maternal phthalate metabolites at the first tertile, AGD was -3.75, -3.43, and -3.53 mm shorter among those exposed at the median tertile of di-2-ethylhexyl phthalate (DEHP) metabolites, monobenzyl phthalate (MBzP), and monomethyl phthalate (MMP), respectively. Compared with those who had exposed at the first tertile, cord-blood follicle-stimulating hormone (FSH) decreased among male newborns exposed at higher levels of MMP, mono-n-butyl phthalate (MnBP), MBzP and DEHP, and among female newborns exposed at higher levels of MMP, MBzP and mono(2-ethyl-5-hydroxyhexyl) phthalate. However, we did not observe significant correlations of maternal or cord-blood sex steroid hormones with newborns' AGDs. CONCLUSIONS: Alterations in cord-blood sex steroid hormone levels were associated with prenatal phthalate exposures, particularly in male newborns. Women aspiring to be pregnant should be alerted of the need of reducing phthalate exposure.

Associations of urinary phthalate metabolites with household environments among mothers and their preschool-age children.

Phthalates have become a matter of public health concern due to their extensive use worldwide and negative health effects. The evaluation of potential sources of phthalate exposure is crucial to design prevention strategies, especially for vulnerable populations. This study included 528 mother-child pairs in the Taiwan Mother Infant Cohort Study who were followed up at ages 3-6 years between 2016 and 2020. Each mother was interviewed by using a structured questionnaire containing questions on demographic characteristics and household environment factors, such as the use of plastic food packaging, residential visible mold, insecticide sprays, and electric mosquito repellents. Eleven phthalate metabolites were analyzed in urine samples simultaneously collected from the mother-child pairs. The phthalate metabolite urinary concentrations were higher among the children than among their mothers, except those of mono-ethyl phthalate (MEP) and mono-2-ethylhexyl phthalate (MEHP). Multiple linear regression analyses showed that urine samples collected during the summer showed higher concentrations of phthalate metabolites than those collected during the winter. Family income levels had negative associations with the concentrations of MnBP and metabolites of di-2-ethylhexyl phthalate (DEHP) in children. The use of plastic food packaging was positively associated with mono-n-butyl phthalate (MnBP) and metabolites of DEHP in mothers. Residential visible mold or mold stains were significantly associated with higher MnBP and DEHP metabolite concentrations in children. The use of insecticide sprays was positively associated with MnBP concentrations in children. Significant associations between household environmental factors and phthalate exposure were mostly found in children, potentially indicating different exposure pathways between mothers and their children. Findings from this study provide additional information for the design of prevention strategies to protect the health of children and women.

Reference intervals for thyroid hormone, sex hormone, and clinical biochemical tests in cord blood from Taiwanese newborn - TMICS cohort.

BACKGROUND/PURPOSE: This study aims to establish reference intervals for important biochemical parameters in cord blood of newborn male and female infants in Taiwan and to investigate their sex difference. We also examined the correlation of the same markers between maternal blood levels and neonatal cord blood levels. METHODS: 2,136 pregnant women receiving regular routine prenatal health assessments in their third trimester (weeks 29-40) were recruited from nine hospitals in Taiwan between 2012 and 2015. After exclusion, we were left with 580 cord blood samples to include in this study. RESULTS: Cord blood thyroid-stimulating hormone was higher in males than females (p < 0.05). Males also had significantly higher sex hormone levels (estradiol, follicle-stimulating hormone, and sex hormone-binding globulin), while females had higher levels of luteinizing hormone. Male newborns had higher cord blood immunoglobulin E (IgE), while females had higher insulin-like growth factor-1 (IGF-1) levels. We found a slight positive link between maternal blood and cord blood in thyroid hormones and sex hormones. CONCLUSION: This study found sex differences in cord blood thyroid hormone, sex hormone, IGF-1, and IgE levels and a link between maternal blood levels of thyroid and sex hormones and those in the cord blood of their infants.

Associations between maternal phthalate exposure and neonatal neurobehaviors: The Taiwan maternal and infant cohort study (TMICS).

Previous studies have shown associations between prenatal phthalate exposure and neurobehavioral changes in children. However, few studies have focused on neonatal neurobehavioral development. This study aimed to examine the associations between prenatal phthalate exposure and neonatal neurobehavioral development in the early days of life after birth. This cohort study included 283 mother-infant pairs who participated in the Taiwan Mother Infant Cohort Study during 2012-2015. Each mother was interviewed, and urine samples were collected during the third trimester of pregnancy (weeks 29-40). Eleven common phthalate metabolites in maternal urine were analyzed. The Chinese version of the Neonatal Neurobehavioral Examination was used to evaluate early infant neurobehavioral development within five days of birth. We performed multiple linear regressions to explore the associations between phthalate exposure and neonatal neurobehavioral development. Sex differences in the association between phthalate metabolites and neonatal neurobehaviors were noted. Among girls, tertiles of phthalate metabolite concentrations were associated with worse behavioral responses and tone and motor patterns in the high-molecular-weight phthalate (HMW) and low-molecular-weight phthalate (LMW) groups. Girls in the highest tertile of di-2-ethylhexyl phthalate (DEHP) and mono-isobutyl phthalate (MiBP) had a negative association with tone and motor patterns. Girls in the highest tertile of mono-n-butyl phthalate (MnBP) and MiBP showed a negative association with behavioral responses. In contrast, tertiles of phthalate metabolite exposure were associated with improved neurobehaviors in mono-methyl phthalate (MMP) among boys. The highest tertile of MMP was positively associated with behavioral responses, primitive reflexes, and tone and motor patterns. Our findings suggest that maternal phthalate exposure affects neonatal neurobehavioral development in a sex-specific manner. Despite the relatively small sample size, our findings add to the existing research linking maternal phthalate exposure to neonatal neurobehavioral development. Additional research is needed to determine the potential long-term effects of prenatal phthalate exposure on children.

Relationship of maternal body weight and gestational diabetes mellitus with large-for-gestational-age babies at birth in Taiwan: The TMICS cohort.

OBJECTIVE: To determine if both gestational diabetes mellitus (GDM) and maternal overweight/obesity are independently associated with delivery of large-for-gestational-age (LGA) babies in Taiwan. MATERIALS AND METHODS: Anthropometric parameters were measured and 75-g oral glucose-tolerance tests were administered to a cohort of 1428 pregnant women at 24-28 weeks gestation at nine hospitals in Taiwan. GDM was diagnosed based on the International Association of Diabetes and Pregnancy Study Groups criteria. Reported pre-pregnancy BMI and measured BMI during pregnancy were recorded at the late stage of the second trimester and the third trimester. Neonatal anthropometrics were measured at delivery. Primary outcome was LGA, defined in this study as having a birth weight ≥90th percentile for gestational age defined by WHO or a Chinese growth reference, taking into consideration the racial/ethnic and environmental differences in growth around the world. Multiple logistic regression was used to examine associations of GDM and maternal overweight/obesity with outcomes. RESULTS: Based on WHO growth reference definition of LGA, subjects with pre-pregnancy BMI ≥24 and pregnancy BMI >28.4 were found to be 2.46 times (0.76-7.97) and 3.28 times (1.01-10.60), respectively, more likely to deliver LGA babies than subjects with normal pre-pregnancy and pregnancy BMIs. Compared to those without GDM, subjects with GDM were 7.55 (1.62-35.25) times more likely to deliver LGA babies. The odds ratios for delivering a baby with a birth weight ≥90th percentile were 11.40 (1.65-78.75) for those with GDM alone, 4.10 (1.07-15.65) for those with overweight/obesity alone and 15.75 (1.30-190.40) for those with both GDM and overweight/obesity, compared to those with no GDM and no overweightness. Women with both pre-pregnancy and pregnancy overweightness/obesity were 3.64 (1.07-12.34) times more likely to deliver LGA. The above results remained similar when analyzing data based on Chinese growth reference definition of LGA. CONCLUSION: Maternal overweightness/obesity and GDM are independently associated with LGA. Their combination had a greater impact than either one alone.

Food Processing and Phthalate Exposure: The Nutrition and Health Survey in Taiwan (1993-1996 and 2005-2008).

Background: Phthalates esters are widely used commercially and can leach from a food container or food packaging. Few studies have been conducted in Asia regarding food processed to varying levels and human phthalate exposure. This study aimed to evaluate the association between unprocessed and ultra-processed food intake and urinary phthalate metabolite levels in the Taiwanese adult population. Methods: A total of 516 participant data were extracted from the cross-sectional 1993-1996 and 2005-2008 Nutrition and Health Survey in Taiwan of those aged over 18 years, where urinary measures and one 24-h dietary recall were collected. Urinary concentrations of dimethyl phthalate, diethyl phthalate, dibutyl phthalate, butyl benzyl phthalate, and di-(2-ethylhexyl) phthalate metabolites including monomethyl phthalate, monoethyl phthalate (MEP), monobutyl phthalate (MBP), monobenzyl phthalate, mono-(2-ethylhexyl) phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, and mono-(2-ethyl-5-oxohexyl) phthalate were measured in spot urine samples. The NOVA food processing classification system was applied to divide all consumed foods into four mutually exclusive groups including unprocessed or minimally processed, processed culinary ingredients, processed and ultra-processed food. Generalized linear models were employed to examine the associations between the percentage quartiles (Qs) of unprocessed and ultra-processed foods in the total weight of food and the urinary phthalate metabolites. Results: Compared with participants in the lowest quartiles (Q1) of ultra-processed food intake, highest ultra-processed food intake (Q4) had 65.7% (95% confidence interval [CI]: 4.83, 162) higher urinary concentrations of MEP after adjusted for covariates. In contrast, the higher unprocessed food consumption was inversely associated with urinary concentrations of MEP and MBP (P for trend = 0.03). When compared to the lowest unprocessed food consumers (Q1), higher consumers (Q4) presented 38.6% (95% CI: -61.3, -2.59) lower MEP concentrations and 23.1% (95% CI: -38.5, -3.71) lower MBP concentrations. Conclusion: Ultra-processed food consumption was associated with increased concentrations of urinary MEP. Conversely, consuming unprocessed food was associated with lower concentrations of MEP and MBP in the Asian Taiwanese adult population.

Association Between Prenatal Exposure to Metals and Atopic Dermatitis Among Children Aged 4 Years in Taiwan.

Importance: The prevalence of atopic dermatitis has substantially increased in recent decades, and atopic dermatitis could lead to allergic airway inflammation later in life. A previous study found that inorganic arsenic exposure was associated with allergic airway inflammation in children aged 8 to 14 years. However, the association between prenatal exposure to arsenic and other metals and the risk of atopic dermatitis among young children remains unknown. Objective: To assess the association between prenatal exposure to arsenic and other metals and the occurrence of atopic dermatitis in children at age 4 years. Design, Setting, and Participants: In total, 1152 pregnant women were enrolled in the original Taiwan Maternal and Infant Cohort Study (TMICS), a multicenter birth cohort study conducted at 9 hospitals in northern, central, southern, and eastern Taiwan from October 2012 to May 2015. Of those, 586 mothers and children aged 4 years participated in follow-up questionnaire interviews from August 2016 to January 2019. After excluding 216 participants with missing data, the final statistical analysis of follow-up data included 370 mother and child pairs from the central and eastern regions of Taiwan. Data were analyzed from February 2 to August 12, 2021. Exposures: Arsenic, cadmium, lead, cobalt, copper, nickel, thallium, and zinc during pregnancy. Main Outcomes and Measures: The outcome was parent-reported atopic dermatitis history among children aged 4 years. The presence of atopic dermatitis was defined as a positive response to the question, "Has your child ever had atopic dermatitis diagnosed by a physician?" During the initial TMICS study period, concentrations of arsenic, cadmium, lead, cobalt, copper, nickel, thallium, and zinc were measured in maternal urine during the third trimester of pregnancy using an inductively coupled plasma mass spectrometer. Estimated total inorganic arsenic exposure was calculated using a model that included data on both total arsenic and arsenic species (arsenite, arsenate, monomethylarsonate, and dimethylarsenate) obtained from a previous TMICS cohort. Results: Among 370 children included in the analysis, the mean (SD) age was 3.94 (0.59) years; 208 children (56.2%) were male, and 267 children (72.2%) were from the central region of Taiwan. A total of 110 children (29.7%) had atopic dermatitis at age 4 years. Maternal estimated total inorganic arsenic exposure during pregnancy was associated with increased odds of atopic dermatitis among children at age 4 years (odds ratio [OR], 2.42 [95% CI, 1.33-4.39] for every doubled increase of total inorganic arsenic) after adjusting for parental allergies, child's sex, geographic area, maternal educational level, and exposure to tobacco smoke. Every increased unit in the weighted quantile sum index of maternal metal exposure was significantly associated with atopic dermatitis (OR, 1.63; 95% CI, 1.28-2.07). Arsenic (40.1%) and cadmium (20.5%) accounted for most of the metal mixture index. Conclusions and Relevance: This cohort study found that prenatal exposure to inorganic arsenic and coexposure to inorganic arsenic and cadmium were associated with a higher risk of atopic dermatitis in young children. These findings suggest that prevention of exposure to inorganic arsenic and cadmium during pregnancy may be helpful for the control of atopic dermatitis and other potential allergies in children.

Association between two common environmental toxicants (phthalates and melamine) and urinary markers of renal injury in the third trimester of pregnant women: The Taiwan Maternal and Infant Cohort Study (TMICS).

BACKGROUND: Exposure to either melamine or phthalate, two common toxicants, during pregnancy may cause adverse health effects, including kidney damage. OBJECTIVES: We investigated the independent and interactive effect of exposure to melamine and phthalates, particularly di-(2-ethylhexyl) phthalate (DEHP), on markers of early renal injury in women their third trimester of pregnancy in one nationwide birth cohort, the Taiwan Maternal and Infant Cohort Study (TMICS). METHODS: Between October, 2012 and May, 2015, participants were administered questionnaires, physical examinations, and blood and urine tests during their third trimester. One-spot overnight urine specimens were used to simultaneously measure melamine, 11 phthalate metabolites, and two markers of renal injury, microalbumin and N-acetyl-beta-D-glucosaminidas (NAG). Estimated daily DEHP intake was calculated based on measurement of three urinary DEHP metabolites. Microalbuminuria was defined as having a urinary albumin/creatinine ratio (ACR) higher than 3.5 mg/mmol. RESULTS: Total 1433 pregnant women were analyzed. The median value for urinary melamine was 0.63 µg/mmol Cr and estimated DEHP intake was 1.84 µg/kg/day. We found subjects in the highest quartile of estimated DEHP intake to have significantly higher urinary ACR (ß = 0.095, p = 0.043) and the prevalence of microalbuminuria (adjusted OR = 1.752, 95% confidence interval = 1.118-2.746), compared to those in the lowest quartile. In addition, there was a significant interactive effect between urinary melamine and estimated DEHP intake on urinary ACR and NAG. CONCLUSION: Our results suggest these two ubiquitous chemicals together may be associated with markers of early kidney injury in pregnant women.

New trimester-specific reference intervals for clinical biochemical tests in Taiwanese pregnant women-cohort of TMICS.

BACKGROUND: Because there are no published biochemical reference intervals (RI) for pregnant Taiwanese women, we used an established islandwide birth cohort, the Taiwan Maternal and Infant Cohort Study, to establish RIs for important biochemical parameters in women during their 3rd trimester in Taiwan. Additionally, we compared the differences in these biochemical parameters between early third trimester (weeks 28 to 31) and late third trimester (weeks 37 to 40) of pregnant women as well as the differences in them between the third trimester and after delivery. METHODS: Between 2012 and 2015, we recruited a total of 2,136 pregnant women from nine hospitals located in northern (n = 3), central (n = 3), southern (n = 2), and eastern Taiwan (n = 1) to receive regular prenatal health examinations during their third trimester (weeks 28 to 40). After exclusion, samples obtained from 993 eligible pregnant women were analyzed. RESULTS: There were increases in both lower and upper normal limits for blood neutrophil, thyroid profile (triiodothyronine (T3) and thyroxine (T4)), testosterone, estradiol, and progesterone and decreases for RBC, hemoglobin (Hb), alanine aminotransferase (ALT) and creatinine (Cr) during their third trimesters. Women in their late third trimester (n = 378) had higher median RBC, Hb, aspartate aminotransferase (AST), Cr, thyroid-stimulating hormone (TSH), testosterone, estradiol, and progesterone and lower median platelet and insulin, compared with those in their early third trimester (n = 490). Twenty-three of the women had both third trimester and post-pregnancy data. After delivery, the women had lower median AST, ALT, insulin, T3, T4, testosterone, estradiol, and progesterone and higher median Cr, free T4, FSH, and luteinizing hormone (LH), compared to their third trimesters. CONCLUSIONS: Gestation-related changes in important biochemical parameters should be considered when evaluating clinical laboratory values in pregnant women.

Prenatal and childhood exposure to phthalic acid esters and vaccination antibodies in children: A 15-year follow-up birth cohort study.

Phthalic acid esters (PAE) are widely used during chemical synthesis and do not form covalent linkages with products. It has been reported that exposure to PAE affects the immune response. However, their effect on antibody concentrations in children is still under investigation. We aimed to examine the association between early-life phthalate exposure and antibody concentrations in children in a longitudinal birth cohort established in 2000-2001. We recruited 398 neonates in central Taiwan and followed them up every 2-3 years, with various antibody-related studies at 11- and 14-year follow-ups. Seven urinary phthalate metabolites were quantified in mothers during pregnancy and children aged 11 years. Four antibody concentrations were analyzed in children aged 11 and 14 years. The percent change in antibody concentrations from ages 11 to 14 years was calculated and its association with phthalate exposure was evaluated via multivariate regression analysis. Eighty-one followed-up children were with sufficient data. After adjusting for prenatal exposure and other confounders, double concentrations of the urinary sum of di-2-ethylhexyl phthalate (ΣDEHPm) and mono-n-butyl phthalate (MnBP) were associated with a 18.06% (95% CI = 3.34%, 32.78%) and 22.53% decrease (95% CI = 3.39%, 41.66%) in antibody concentration against hepatitis B, respectively. Phthalate exposure was found to be related to decreased antibody concentrations against hepatitis B (DEHP, DBnP) in the early teens. This exposure is suggested to be considered for clinical re-booster vaccines among junior high school students. Further verification with additional cohorts and studies on the underlying mechanisms of phthalate exposure are warranted.

Prenatal and childhood phthalate exposure and attention deficit hyperactivity disorder traits in child temperament: A 12-year follow-up birth cohort study.

Temperamental tendencies may form the basis of personality development, and specific personality constellations are associated with increased incidences of behavioural problems. Phthalic acid ester (PAE) has been associated with symptoms of attention deficit hyperactivity disorder (ADHD) in cross-sectional studies. We hypothesised that early-life exposure to PAE affects the temperaments of children, particularly ADHD traits. In this study, we analysed the temperament evaluations completed at least once by maternal-infant pairs (n = 208) when the child was aged 2, 5, and/or 11 years between 2000 and 2012. We measured seven PAE metabolites in the urine of the mothers during pregnancy and their children using liquid chromatography-electrospray ionisation-tandem mass spectrometry. These metabolites included mono-methyl phthalate, mono-ethyl phthalate, mono-butyl phthalate (MBP), mono-benzyl phthalate (MBzP), and three metabolites of di (2-ethylhexyl) phthalate. The phthalate metabolite levels in pregnant women were significantly associated with a decreased threshold of responsiveness (coefficients from -0.21 to -0.46) and increased distractibility (coefficients from 0.23 to 0.46) in pre-school children. After adjustment for maternal exposure, the phthalate metabolite concentrations of the children exhibited significantly increased odds ratios (ORs) with respect to the ADHD symptom traits. Specifically, mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), the sum of the DEHP metabolites, and MBzP yielded ORs and 95% confidence intervals of 2.98 (1.05-8.48), 3.28 (1.15-9.35), and 9.12 (1.07-78.06), respectively, for every log10 creatinine unit (g/g creatinine) increase. Thus, early-life phthalate exposure was found to be associated with the behavioural characteristics of children, particularly temperamental traits associated with ADHD.

Phthalate exposure and prostate cancer in a population-based nested case-control study.

BACKGROUND: Phthalic acid esters are established as endocrine disruptors. The study aimed to evaluate the association between urinary phthalate metabolites and prostate cancer occurrence. METHODS: The study was based on the Taiwan Community-Based Cancer Screening Program, which was set up in 1991-1992 and followed periodically. By 2010, 80 incident prostate cancer cases were identified in the 12,020 men. For each case, 2 controls were randomly selected, matched by age (±3 years), urine collection date (±3 months), and residential township. Frequently used phthalate metabolites from the urine samples were quantified by liquid chromatography/electrospray ionization tandem mass spectrometry. Logistic regression was conducted to assess the association between the exposure levels and prostate cancer occurrence. RESULTS: Exposure to di (2-ethylhexyl), butyl-benzyl and di-isobutyl phthalates (DEHP, BBzP, DiBP) was positively associated with prostate cancer in men with waist circumference (WC) ≥90 cm but not in the leans. Odds ratio for the DEHP metabolite summary score (upper tertile compared to the rest) and prostate cancer were 7.76 (95% CI = 1.95-30.9) for WC ≥ 90 cm. CONCLUSIONS: DEHP, BBzP, and DiBP exposure were associated with prostate cancer occurrence in abdominally obese men. The main limitation remains the lack of mechanistic experiments and comparable toxicological data.

Prenatal and childhood exposure to phthalate diesters and neurobehavioral development in a 15-year follow-up birth cohort study.

OBJECTIVE: Longitudinal studies on neurobehavioral development in relation to prenatal and postnatal exposure to phthalates in school-age children and adolescents are limited. We investigated the association of prenatal and childhood phthalate exposure with the development of behavioral syndromes in 8-14-year-old children. METHOD: We recruited 430 pregnant women from 2000 to 2001 and followed their children at the ages of 2, 5, 8, 11, and 14 years, yielding 153 mother-child pairs in total. Urine samples from pregnant women in the third trimester and from children at 2-8 years of age were analyzed for the concentrations of seven urinary phthalate metabolites: monomethyl phthalate, monoethyl phthalate, monobutyl phthalate, monobenzyl phthalate (MBzP), and three di(2-ethylhexyl) phthalate (DEHP) metabolites, namely mono-2-ethylhexyl phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate, and mono(2-ethyl-5-oxohexyl) phthalate. Behavioral syndromes in children aged 8-14 years were assessed using the Child Behavior Checklist. We constructed mixed models to examine these associations after adjustments for potential covariates. RESULTS: Maternal urinary MEHP levels were associated with higher scores for internalizing problems (ß = 0.028, 95% confidence interval [CI]: 0.0004, 0.055) and externalizing problems (ß = 0.040, 95% CI: 0.013, 0.066). Associations of the maternal urinary sum of DEHP metabolite levels with delinquent behavior scores and externalizing problems scores were positive (ß = 0.035, 95% CI: 0.013, 0.057 for delinquent behavior; ß = 0.026, 95% CI: 0.001, 0.050 for externalizing problems). Furthermore, children's urinary MBzP levels were associated with higher scores for social problems (ß = 0.018, 95% CI: 0.001, 0.035). Similar patterns were observed for borderline and clinical ranges. CONCLUSION: Early-life exposure to phthalates may influence behavioral syndrome development in children. Future studies are needed to replicate these findings, and efforts to reduce exposures to phthalates during critical early life stages may be warranted.

Urinary phthalate metabolites, coronary heart disease, and atherothrombotic markers.

Cross-sectional studies have described an association between exposure to phthalate esters and cardiovascular risk factors. However, the association with coronary heart disease (CHD) is still unclear. A total of 180 subjects randomly selected from 336 CHD patients, and 360 age- and sex-matched non-CHD controls were included from 2008 to 2011. Urinary metabolites of phthalate esters were measured by liquid chromatography-tandem mass spectrometry. The geometric means of urinary phthalates metabolites were significantly higher for the three Di-(2-ethylhexyl)-phthalate (DEHP) metabolites, mono-2-ethylhexyl phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate, and mono-(2-ethyl-5-oxohexyl) phthalate among CHD patients in-hospital than those of being discharged. Excluding 89 CHD patients of in-hospital and hospital discharge within 2 days, we found the urinary concentrations of MEHP, mono-n-butyl phthalate (MnBP), and mono-isobutyl phthalate (MiBP) of 91 CHD patients discharged ≥ 3 days were higher than those of controls. Among 451 participants, those with higher tertile levels of urinary MEHP, MnBP, and MiBP showed an increased risk for CHD compared to those with lowest tertile levels; the corresponding odds ratios (95% CI) were 2.77 (1.22-6.28), 2.90 (1.32-6.4), and 3.19 (1.41-7.21), respectively, after adjustment for confounders. Higher levels of hs-CRP, fibrinogen, and D-dimer were linked with increased levels of all DEHP metabolites in CHD patients. In conclusion, exposure to DEHP and dibutyl phthalates was positively associated with CHD and this relationship may be probably mediated via atherothrombosis.

Levels and temporal variations of urinary lead, cadmium, cobalt, and copper exposure in the general population of Taiwan.

Toxic metal contamination in food products and the environment is a public health concern. Therefore, understanding human exposure to cadmium (Cd), lead (Pb), cobalt (Co), and copper (Cu) levels in the general population of Taiwan is necessary and urgent. We aimed to establish the human biomonitoring data of urine toxic metals, exposure profile changes, and factors associated with metal levels in the general population of Taiwan. We randomly selected 1601 participants older than 7 years of age (36.9 ± 18.7 years (7-84 years)) from the Nutrition and Health Survey in Taiwan (NAHSIT) conducted during 1993-1996 (93-96) and 2005-2008 (05-08) periods and measured the levels of four metals in the participants' urine samples using inductively coupled plasma-mass spectrometry. The median (range) levels of urinary Cd, Pb, Co, and Cu in participants from the NAHSIT 93-96 (N = 821)/05-08 (N = 780) were 0.60 (ND-13.90)/0.72 (ND-7.44), 2.28 (ND-63.60)/1.09 (0.04-48.88), 0.91 (0.08-17.30)/1.05 (0.05-22.43), and 16.87 (2.62-158.28)/13.66 (1.67-189.70) µg/L, respectively. We found that the urinary median levels of Pb and Cu in our participants were significantly lower in the NAHSIT 05-08 (Pb 1.09 µg/L, Cu 13.66 µg/L) than in the NAHSIT 93-96 (Pb 2.28 µg/L, Cu 16.87 µg/L; P < 0.01), whereas those of Cd and Co were significantly higher in the NAHSIT 05-08 (Cd 0.72 µg/L, Co 1.05 µg/L; P < 0.01). Youths had higher exposure levels of Pb, Co, and Cu than adults. Participants with alcohol consumption, betel quid chewing, or cigarette smoking had significantly higher median levels of urinary Pb or Cu (P < 0.01) than those without. Principal components and cluster analysis revealed that sex had different exposure profiles of metals. We concluded that levels of urinary Cd, Pb, Co, and Cu exposure in the general Taiwanese varied by age, sex, and lifestyles.

Personal care products use and phthalate exposure levels among pregnant women.

BACKGROUND: Fetuses are susceptible to phthalates, known endocrine disrupting chemicals, within sensitive windows of development. It is crucial to determine the major sources of phthalates to reduce exposure. This study aims to examine the associations between usage patterns of personal care products (PCPs) and urinary levels of phthalate metabolites across pregnancy in a multi-hospital based birth cohort. METHODS: During 2012-2015, we conducted a birth cohort study named the Taiwan Mother Infant Cohort Study (TMICS). Usage patterns of PCPs were obtained using structured questionnaires during the third trimester of pregnancy. Spot urine samples were collected at each trimester, and levels of eleven phthalate metabolites were measured by liquid chromatography tandem mass spectrometry. The association of PCPs use with urinary phthalate metabolite concentrations was assessed using GEE models. RESULTS: Among the 1676 pregnant women participated in TMICS, 281 who provided two or three urine samples across pregnancy were included. The levels of several phthalate metabolites were significantly associated with the use of PCPs, particularly leave-on PCPs. With the increasing use of skin toners (11.7%; 95% CI: 1.5%, 22.9%), lipsticks (13.2%; 95% CI: 4.6%, 22.5%), and essential oils (21.8%; 95% CI: 9.1%, 36.0%), individuals are exposed to higher concentrations of mono-ethyl phthalate (MEP). Additionally, a positive trend was found regarding the number of leave-on PCPs used and the measured change in MEP concentrations (P for trend = 0.01). Other positive associations included MBzP and body lotions (7.9%; 95% CI: 0.1%, 16.2%). With regard to rinse-off PCPs, we found a positive association between urinary MBzP and shampoo use, and a negative association between urinary MMP and face wash. CONCLUSION: Leave-on PCPs were found to be a more probable source of phthalate exposure than the use of rinse-off PCPs. We suggest pregnant women reduce the frequency of leave-on PCPs use during pregnancy to avoid such phthalate exposure.

Early-life arsenic exposure promotes atherogenic lipid metabolism in adolescence: A 15-year birth cohort follow-up study in central Taiwan.

BACKGROUND: Inorganic arsenic (iAs) exposure potentially causes diabetes and cardiovascular diseases in adults. However, its effect on glucose and lipid metabolism in early life remains unknown. OBJECTIVE: We evaluated the associations between early-life arsenic exposure and profiles of glucose and lipids in a 15-year birth cohort in central Taiwan. METHODS: We studied 237 adolescents through 5 waves of follow-up interviews and examinations at ages of approximately 2, 5, 8, 11, and 14 y. We obtained at least one follow-up urine measurement for arsenic species and blood sample collection up to 14 y of age and identified group-based trajectories of serial iAs by semiparametric mixture modeling. Multiple linear and logistic regressions were performed to assess the effect of the arsenic exposure trajectory on serum fasting glucose, total cholesterol (TCHO), triglycerides (TGs), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL). RESULTS: Three trajectories of postnatal arsenic exposure were identified, namely stable-low (31.4%), stable-high (48.2%), and rising-high (20.4%) groups. Compared with the stable-low trajectory group, the percent changes in TCHO and LDL was 14% (95% confidence interval 4-24%) and 23% (9-38%) for the group with "rising-high" trajectory and was 8% (-1-16%) and 16% (4-29%) for the group with "stable-high" trajectory. The rising-high group was also associated with an increase in the TCHO/HDL ratio by 14% (95% CI 3%-25%). The adjusted odds ratios of high developmental trajectories of TCHO, TG, LDL, and non-HDL levels were 4.0 (95% CI 1.2-13.7), 12.2 (2.2-67), 7.3 (1.8-30), and 3.6 (0.9-14.6), respectively, in the rising-high group (reference: stable-low group). CONCLUSION: Our findings suggest that conversion to an atherogenic lipid profile in adolescents may be associated with early-life exposure to environmental arsenic, particularly during the pre-adolescent period. An environmental modification approach for preventing As-related cardiovascular disease is recommended to begin early in life.

Association between fetal exposure to phthalate endocrine disruptor and genome-wide DNA methylation at birth.

BACKGROUND: Phthalic acid esters are ubiquitous and antiandrogenic, and may cause systemic effects in humans, particularly with in utero exposure. Epigenetic modification, such as DNA methylation, has been hypothesized to be an important mechanism that mediates certain biological processes and pathogenic effects of in utero phthalate exposure. OBJECTIVE: The aim of this study was to examine the association between genome-wide DNA methylation at birth and prenatal exposure to phthalate. METHODS: We studied 64 infant-mother pairs included in TMICS (Taiwan Maternal and Infant Cohort Study), a long-term follow-up birth cohort from the general population. DNA methylation levels at more than 450,000 CpG sites were measured in cord blood samples using Illumina Infinium HumanMethylation450 BeadChips. The concentrations of three metabolites of di-(2-ethylhexyl) phthalate (DEHP) were measured using liquid chromatography tandem-mass spectrometry (LC-MS/MS) in urine samples collected from the pregnant women during 28-36 weeks gestation. RESULTS: We identified 25 CpG sites whose methylation levels in cord blood were significantly correlated with prenatal DEHP exposure using a false discovery rate (FDR) of 5% (q-value < 0.05). Via gene-set enrichment analysis (GSEA), we also found that there was significant enrichment of genes involved in the androgen response, estrogen response, and spermatogenesis within those genes showing DNA methylation changes in response to exposure. Specifically, PA2G4, HMGCR, and XRCC6 genes were involved in genes in response to androgen. CONCLUSIONS: Phthalate exposure in utero may cause significant alterations in the DNA methylation in cord blood. These changes in DNA methylation might serve as biomarkers of maternal exposure to phthalate in infancy and potential candidates for studying mechanisms via which phthalate may impact on health in later life. Future investigations are warranted.

Prenatal and Childhood Exposure to Phthalate Diesters and Thyroid Function in a 9-Year Follow-up Birth Cohort Study: Taiwan Maternal and Infant Cohort Study.

BACKGROUND: Phthalates are widely used in industry, personal care products, and medications. Recent studies have suggested that phthalate exposure alters thyroid hormones. However, longitudinal studies concerning the association between phthalate exposure and thyroid function in children are scant. Therefore, we examined the association between pre- and postnatal phthalate exposure and thyroid function in children born in 2000-2001. METHODS: We studied 181 mother-child pairs in central Taiwan and followed-up the children from 2000 to 2009 at 2, 5, and 8 years old. We measured serum levels of thyroxine (T4), free T4, triiodothyronine (T3), and thyroid-stimulating hormone in children by using radioimmunoassay. We quantified seven phthalate metabolites, representing the five most commonly used phthalates, in maternal and child urine samples by using liquid chromatography-tandem mass spectrometry. The metabolites were monoethylhexyl phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) derived from di(2-ethylhexyl) phthalate (DEHP), monomethyl phthalate (MMP), monoethyl phthalate (MEP), monobutyl phthalate (MBP), and monobenzyl phthalate (MBzP). We constructed a linear mixed model to examine these associations after adjustments for covariates. RESULTS: The T4 levels were inversely associated with maternal urinary MEHHP (ß = -0.028 [95% confidence interval (CI) = -0.051, -0.006]) and MEOHP (ß = -0.027 [-0.050, -0.003]), with similar T3 levels being observed in boys, even when the children exposure levels were considered spontaneously. In the girls, the free T4 levels were inversely associated with levels of maternal urinary MEP (ß = -0.042), maternal urinary MBzP (ß = -0.050), and children's urinary MEHP (ß = -0.027). CONCLUSIONS: Early life phthalate exposure was associated with decreased thyroid hormone levels in young children.