Urinary Phthalate Metabolite Concentrations Research Articles

Association of urinary phthalate metabolites with sarcopenia in US adults: NHANES 1999-2006.

Phthalates have been extensively detected in environmental and biological matrices. Exposure to phthalates is implicated in various human diseases. In this study, we conducted a cross-sectional study to determine whether urinary phthalate metabolite concentrations were correlated with prevalence of sarcopenia in US adult population. We included 3562 participants with detailed information on skeletal muscle mass and urinary phthalate metabolites based on National Health and Nutrition Examination Survey (NHANES) 1999-2006 data. A total of 7 main phthalate metabolites were analyzed in the urine sample of each participant. Appendicular skeletal muscle mass (ASM) was measured using dual-energy X-ray absorptiometry. Multivariable linear regression models were conducted following adjustment for multiple covariates. ASM adjusted by body mass index (ASM/BMI) was calculated, and sarcopenia was defined as the lowest quintile for ASM/BMI value. Compared with participants in quartile 1, those in quartile 2 of urinary mono-n-butyl phthalate (MnBP) and quartile 4 of urinary monobenzyl phthalate (MBzP) had decreased ASM/BMI. Urinary MnBP in quartile 4, as well as urinary MBzP in quartile 2, was shown to be significantly correlated with higher sarcopenia prevalence. In subgroup analysis, negative association of MBzP with ASM/BMI was observed in both males and females, while this negative association was only observed in males for MnBP. Females with higher urinary monoethyl phthalate (MEP) concentrations had higher sarcopenia risk. Taken together, the present study found several urinary phthalate metabolites were positively associated with sarcopenia prevalence in US adult population. These findings indicated phthalate exposure might be an important environmental risk factor contributing to sarcopenia development.

The association between maternal urinary phthalate metabolites concentrations and pregnancy induced hypertension: Results from the EDEN Mother-Child Cohort

BackgroundStudies have suggested that exposure to endocrine disruptors such as phthalates that are widely used in our daily life (food wrapping, cosmetics, toys, medical devices, polyvinyl chloride flooring, and building materials) might be related to raised blood pressure and increased risk of cardiovascular diseases. Phthalates might induce a pro-inflammatory response and increased oxidative stress and may be a cause of pregnancy induced hypertension. MethodsWe evaluated the association between maternal exposure to phthalates during pregnancy and pregnancy induced hypertension. 604 pregnant women were included and eleven phthalate metabolites were quantified in spot maternal urine samples collected between the 23rd and 28th week of gestation in a French EDEN mother-child cohort. The associations were assessed by applying multiple logistic regression analysis. ResultsTwenty nine (4,8%) mothers developed pregnancy induced hypertension. Two low molecular weight phthalate metabolites: Monoethyl phthalate (MEP) and Mono-n‑butyl phthalate (MBP) were positively associated with pregnancy induced hypertension in crude (Odds Ratio: 1.43, 95% Confidence Interval: 1.04–1.96, p-value = 0.02 and 1.48, 1.10–2.01, p-value =0.01) and in adjusted (1.47, 1.01–2.14, p-value = 0.04 and 1.66, 1.11–2.47, p-value = 0.01) models respectively. ConclusionOur data suggest that prenatal exposure to some phthalates, including MEP and MBP, might play a role in pregnancy induced hypertension.

Pregnancy exposure to phthalates and placental DNA methylation in the French EDEN cohort

BACKGROUND AND AIM: Foetal growth and development strongly depend upon the health of the placenta. Prenatal exposure to phthalates has been hypothesized to be associated with differential DNA methylation, however epigenome-wide studies on placental tissue are lacking. The aim of this study was to characterize associations between pregnancy urinary concentrations of phthalate metabolites and placental DNA methylation. METHODS: We measured concentrations of 11 phthalate metabolites in maternal spot urine samples collected between 22-29 gestational weeks in 202 mother-son pairs. We analysed DNA methylation levels in term placental tissue using IlluminaHM450 BeadChips. We performed an adjusted epigenome-wide association study (EWAS) and identified differentially methylated regions (DMRs, ≥ 5 CpGs). We also evaluated DNA methylation of repetitive elements Alu and LINE-1. RESULTS:We identified 6 DMRs associated with urinary concentrations of phthalate metabolites. Monoethyl phthalate (MEP) was positively associated with 2 DMRs encompassing imprinted genes (SGCE/PEG10) and a gene involved in the immunological response (GCA). Other positive associations were detected for: monocarboxy-iso-nonyl-phthalate (MCNP) and HSPA1A/HSPA1L genes encoding heat shock proteins; mono(3-carboxypropyl)-phthalate (MCPP) and ART5 encoding protein responsible for protein function regulation; mono-iso-buthyl-phthalate (MiBP) and transcription factor coding REPIN1 gene. The only negative association was identified between mono(2-ethylhexyl)-phthalate (MEHP) exposure and DMR encompassing transcription factor coding ZSCAN16 gene. Finally, we found that pregnancy monobenzyl phthalate concentrations were negatively associated with placental methylation of Alu repeats. CONCLUSIONS:Our study is the first one to describe the genome-wide epigenetic modifications of placental DNA in association with pregnancy exposure to phthalates. Some phthalates may be associated with differential methylation of placental DNA, including changes in repetitive element methylation. Interestingly, 1 of the 5 highlighted phthalate metabolites has been associated with the placental-to-foetal weight ratio in a previous study relying on EDEN cohort. KEYWORDS: Phthalates, Endocrine disrupting chemicals, Chemical exposures, Birth outcomes, Epigenomics

Association between urinary concentration of phthalate metabolites and allergic disorders in Korean children: Korean National Environmental Health Survey (KoNEHS) 2015-2017

BACKGROUND AND AIM: Phthalates are common industrial chemicals used primarily as plasticizers that make plastic flexible. Children are more prone to these chemicals through various routes of exposure including dermal absorption, inhalation, and ingestion (such as food, water, and dust) than adults and several studies have reported that phthalate exposure may increase the risk of allergic diseases. Therefore, we aimed to examine the association between urinary concentration of phthalate metabolites and allergic disorders in a nationally representative sample of Korean children. METHODS: In this study, we used data on urinary phthalate metabolites, allergic symptoms such as atopic dermatitis (AD), asthma, and allergic rhinitis (AR), and serum total immunoglobin E (IgE) levels from participants aged 3–17 in the Korean National Environmental Health Survey 2015–2017. After adjusted for all covariates, Odds ratio (OR) and their 95% confidence intervals (95% CI) per one ln–unit increase change in the concentration of phthalate metabolites were estimated using logistic regression. RESULTS:Urinary high–molecular–weight phthalate metabolites (HMW) were positively associated with current AD and AR. A significant increase of the OR for high group of IgE levels with increase of urinary mono-(carboxynonyl) phthalate (MCNP) concentrations was found [OR=1.43 (1.06, 1.91)]. Mono–benzyl phthalate, mono–(carboxyoctyl) phthalate, and mono–(2–ethyl–5–oxohexyl) phthalate were positively associated with allergic multimorbidity which means co–occurrence of at least two allergic diseases in one individual. Children with high IgE were more likely to have an AR associated MCNP than those with low IgE or high IgE only (p = 0.007). Specifically, we estimated that 14.7% of total effect of MCNP on AR was mediated by IgE. However, no phthalate metabolites were significantly associated with current asthma. CONCLUSIONS:Our observations revealed that some HMW phthalate metabolites were positively associated with current allergic symptoms and high total IgE levels in children. These results suggested that environmental exposure to phthalates could enhance allergic response in children. KEYWORDS: Atopic dermatitis, Asthma, Allergic rhinitis, Allergic multimorbidity, Total immunogliblin E, Phthalate metabolites

Gestational and early childhood phthalate exposures and adolescent body composition: The HOME Study

BACKGROUND AND AIM: Early life phthalate exposures may cause metabolic disruption. However, results from human studies are inconsistent and few have examined body composition during adolescence. We investigated associations of urinary phthalate metabolite concentrations during gestation and childhood with body composition at age 12 years to identify periods of heightened susceptibility. METHODS: We used data from 206 mother-child pairs in a prospective pregnancy and birth cohort enrolled in Cincinnati, OH from 2003-2006. We measured nine phthalate metabolites in spot urine samples collected twice from mothers during pregnancy and up to six times from children at 1, 2, 3, 4, 5 and 8 years. At age 12 years, we assessed whole body fat and lean mass, android, gynoid, and visceral fat mass with dual x-ray absorptiometry, and calculated android to gynoid %fat ratio and age- and sex-standardized fat and lean mass index Z-scores. Using a multiple informant model, we estimated the covariate-adjusted associations between urinary phthalate metabolite concentrations at each time period and adiposity Z-scores at age 12 years. We assessed effect measure modification by child sex using stratified models. RESULTS:Associations of urinary mono-n-butyl, mono-isobutyl, and mono-benzyl phthalate concentrations with 12-year body composition outcomes differed by time period, with stronger associations for exposures during gestation and later childhood. For example, each 10-fold increase in urinary mono-benzyl phthalate concentrations during gestation at ages 5 and 8 years was associated with a -0.34 (95%CI: -0.72,0.05), -0.44 (95%CI: -0.83,-0.05), and -0.35 (95%CI:-0.71,0.00) Z-score difference in whole body lean mass at age 12 years, respectively, but not for exposure in in early childhood. Slightly weaker but similar patterns of association were found with other body composition measures; associations did not differ by child sex. CONCLUSIONS:Exposure to certain phthalates during gestation and late childhood may be associated with adolescent body composition, particularly lean mass. KEYWORDS: Children’s environmental health, Endocrine disrupting chemicals, Obesity and metabolic disorders, Phthalates

Dietary Correlates of Urinary Phthalate Metabolite Concentrations in 6-19 Year Old Children and Adolescents from NHANES

BACKGROUND AND AIM: Children are particularly vulnerable to phthalates, and food is one source of exposure. However, a comprehensive analysis that investigates exposure from food type and source has yet to be undertaken. We use reduced rank regression, a dimension reduction method, to identify dietary patterns associated with urinary phthalate metabolite concentrations in children in a large, US study with detailed data on dietary intake. METHODS: We used data from 2,402 participants 6-19 years old from the 2005-2010 National Health and Nutrition Examination Survey who had urinary phthalate metabolites measured by mass spectrometry. Participants recalled their diet during the 24 hours before urine collection. We quantified dietary intake and source (i.e., home-prepared vs. prepared away from the home) of 135 food groups. We used reduced rank regression to identify dietary patterns explaining variation in overall urinary concentrations of ∑di-2-ethylhexyl phthalate (DEHP) and seven phthalate metabolites, adjusting for urinary creatinine and sociodemographics. We also examined pairwise associations between food groups and phthalate concentrations. RESULTS:We identified eight dietary patterns that cumulatively explained 11.2% of variation in phthalates. The most variation was explained by a diet high in breakfast foods prepared away from home (e.g., bacon, low-sugar cereal, and reduced-fat milk). A one SD increment in adherence to the breakfast food dietary pattern was associated with an 11.3% higher monocarboxy-isononyl phthalate concentration (95% CI: 6.5, 15.9) and a 7.4% higher monobutyl phthalate concentration (95% CI: 3.0, 12.1). We observed some weak pairwise associations between food group intake and urinary phthalates (e.g., 0.1% [95% CI: 0.0, 0.2] higher DEHP per SD increment in milk intake). CONCLUSIONS:We identified dietary factors that may be sources of phthalate exposure or reflect lifestyle correlates. Diet and preparation location explained a small percent variation in phthalate concentrations, suggesting the need for more detailed information on food processing and packaging. KEYWORDS: food/nutrition, phthalates, children's environmental health, biomarkers of exposure

The association of gestational and childhood phthalate exposure with adolescent hair cortisol: The HOME Study

BACKGROUND AND AIM: Phthalate exposure during gestation and childhood may disrupt the hypothalamic-pituitary-adrenocortical (HPA) axis to adversely impact children’s neurodevelopment and cardiometabolic health. We evaluated associations of serial urinary phthalate metabolite concentrations with hair cortisol, a measure of HPA-axis homeostasis, to identify periods of heightened susceptibility during gestation, infancy, and childhood. METHODS: We recruited pregnant women from Cincinnati, Ohio (2003-2006) and followed their children until age 12 years. We quantified urinary phthalate metabolites twice during gestation and up to six-times during childhood (1, 2, 3, 4, 5, 8 years). At age 12 years, we quantified children’s hair cortisol concentrations (pg/mg hair). We estimated covariate-adjusted associations of log10-transformed average gestational or average childhood (1-8 years) phthalate metabolites with log10-transformed hair cortisol using linear regression. We used multiple informant models to estimate associations of serial phthalate measures with hair cortisol and assess the heterogeneity of this association across ages (n=207). RESULTS:The median hair cortisol concentration was 2.2 pg/mg (25th,75th percentile= 1.3, 5.2). We did not find evidence of an association between gestational phthalate metabolites and hair cortisol. However, each interquartile range (IQR) increase in average childhood ∑DEHP, MCPP, and MEP was associated with 289% (95%CI: 38, 996%), 78% (95%CI: -9, 255%), and 78% (95%CI: 15, 175%) higher hair cortisol concentrations, respectively; these associations did not vary by exposure period (heterogeneity p-values=0.53, 0.41, and 0.35, respectively). Positive associations of MBzP and MCOP with hair cortisol were stronger for exposure at infancy than in later childhood (heterogeneity p-values=0.06 and 0.16, respectively). An IQR increase in MBzP at age one year and MCOP at age two years was associated with 164% (95%CI: 56, 349%) and 77% (95%CI: 22, 155%) higher hair cortisol concentrations, respectively. CONCLUSIONS:Higher urinary concentrations of several phthalate metabolites during childhood, but not gestation, were associated with elevated hair cortisol concentrations in adolescence. KEYWORDS: phthalates, cortisol, development, susceptibility

Cumulative phthalate exposure and risk of hot flashes within the Midlife Women’s Health Study

BACKGROUND AND AIM: Hot flashes are intermittent and disruptive sensations of heat in the upper body and can have a significant impact on quality of life in perimenopausal women. Low estrogen levels are associated with an increased risk of hot flashes. Phthalates are endocrine disrupting chemicals of widespread exposure, with some metabolites having estrogenic properties; however, few studies have evaluated the association between phthalate concentrations and hot flash occurrence, especially across multiple years in perimenopausal women. METHODS: The Baltimore Midlife Women’s Health Study recruited women aged 45 and 54 years (2007 – 2015), collecting data on self-report of hot flash outcomes and biospecimens for laboratory analyses, including urinary phthalate metabolite concentrations. We employed generalized linear mixed models (GLMMs), with phthalate measures operationalized as cumulatively averaged geometric means updated for each year, to conduct mixed effects logistic regression and calculate odds ratios (ORs) for risk of ever-experiencing hot flashes and hot flash severity (dichotomized as none or mild vs moderate or severe), adjusting for participant characteristics as potential confounders. RESULTS:A total of 758 participants provided up to 4 years of follow-up data. At baseline, 343 (45.8%) women reported ever experiencing a hot flash and 225 (30.1%) reported experiencing moderate or severe hot flashes. In adjusted models, only the sum of personal care product phthalate metabolites (∑PCP, the sum of monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), and mono-isobutyl phthalate (MiBP)) updated over the 4-year study period was associated with moderate and severe hot flashes (OR: 1.18; 95%CI: 1.01 – 1.38). No other individual phthalate metabolite or summary measure was associated with ever experiencing hot flashes or hot flash severity. CONCLUSIONS:Higher concentrations of phthalates from PCPs were associated with experiencing moderate or severe hot flashes across the perimenopausal period. Reducing exposure to phthalates from PCPs may help to reduce risk of moderate/severe hot flashes in middle-aged women. KEYWORDS: phthalates, endocrine disrupting chemicals, reproductive outcomes

Prenatal Exposure to Di-Ethyl Phthalate (DEP) Is Related to Increasing Neonatal IgE Levels and the Altering of the Immune Polarization of Helper-T Cells.

Introduction: Phthalates are substances that are added to plastic products to increase their plasticity. These substances are released easily into the environment and can act as endocrine disruptors. Epidemiological studies in children have showed inconsistent findings regarding the relationship between prenatal or postnatal exposure to phthalates and the risk of allergic disease. Our hypothesis is that prenatal exposure to phthalates may contribute to the development of allergies in children. Material and methods: The objective of this study was to determine the associations between urinary phthalate metabolite concentrations in pregnant women, maternal atopic diathesis, maternal lifestyle, and cord blood IgE. Pregnant mothers and paired newborns (n = 101) were enrolled from an antenatal clinic. The epidemiologic data and the clinical information were collected using standard questionnaires and medical records. The maternal blood and urine samples were collected at 24–28 weeks gestation, and cord blood IgE, IL-12p70, IL-4, and IL-10 levels were determined from the newborns at birth. The link between phthalates and maternal IgE was also assessed. To investigate the effects of phthalates on neonatal immunity, cord blood mononuclear cells (MNCs) were used for cytokine induction in another in vitro experiment. Results: We found that maternal urine monoethyl phthalate (MEP) (a metabolite of di-ethyl phthalate (DEP)) concentrations are positively correlated with the cord blood IgE of the corresponding newborns. The cord blood IL-12p70 levels of mothers with higher maternal urine MEP groups (high DEP exposure) were lower than mothers with low DEP exposure. In vitro experiments demonstrated that DEP could enhance IL-4 production of cord blood MNCs rather than adult MNCs. Conclusion: Prenatal DEP exposure is related to neonatal IgE level and alternation of cytokines relevant to Th1/Th2 polarization. This suggests the existence of a link between prenatal exposure to specific plasticizers and the future development of allergies.

Prenatal urinary concentrations of phthalate metabolites and behavioral problems in Mexican children: The Programming Research in Obesity, Growth Environment and Social Stress (PROGRESS) study

BackgroundPhthalate exposure has been associated with increased childhood behavioral problems. Existing studies failed to include phthalate replacements and did not account for high correlations among phthalates. Phthalates’ exposure is higher in Mexico than in U.S. locations, making it an ideal target population for this study. AimTo examine associations between 15 maternal prenatal phthalate metabolite concentrations and children's behavioral problems. MethodsWe quantified phthalate metabolites in maternal urine samples from maternal-child dyads (n = 514) enrolled in the Programming Research in Obesity, Growth Environment and Social Stress (PROGRESS) birth cohort in Mexico City. We performed least absolute shrinkage and selection operator (LASSO) regressions to identify associations between specific-gravity adjusted log2-transformed phthalate metabolites and parent-reported 4–6 year old behavior on the Behavior Assessment System for Children (BASC-2), accounting for metabolite correlations. We adjusted for socio-demographic and birth-related factors, and examined associations stratified by sex. ResultsHigher prenatal mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) urinary concentrations were associated with increased hyperactivity scores in the overall sample (β = 0.57, 95% CI = 0.17, 1.13) and in girls (β = 0.54, 95% CI = 0.16, 1.08), overall behavioral problems in boys (β = 0.58, 95% CI = 0.20, 1.15), and depression scores in boys (β = 0.44, 95% CI = 0.06, 0.88). Higher prenatal monobenzyl phthalate (MBzP) concentrations were associated with reduced hyperactivity scores in girls (ß = −0.54, 95% CI = −1.08, −0.21). DiscussionOur findings suggested that prenatal concentrations of phthalates and their replacements altered child neurodevelopment and those associations may be influenced sex.

Urinary phthalate metabolite concentrations and serum hormone levels in pre- and perimenopausal women from the Midlife Women's Health Study.

Phthalate exposure is associated with altered reproductive function, but little is known about associations between phthalate and hormone levels in midlife women. This cross-sectional analysis includes 45-54-year-old pre- and perimenopausal women from Baltimore, MD and its surrounding counties enrolled in the Midlife Women's Health Study (n=718). Serum and urine samples were collected from participants once a week for four consecutive weeks to span the menstrual cycle. Serum samples were assayed for estradiol, testosterone, progesterone, sex hormone binding globulin (SHBG), follicle-stimulating hormone (FSH), and anti-Müllerian hormone (AMH), and geometric means were calculated for each hormone across all four weeks. Urine samples were analyzed for nine phthalate metabolites from pools of one-to-four urine samples. Phthalate metabolite concentrations were specific gravity-adjusted and assessed as individual metabolites or as molar sums of metabolites from common parents (di(2-ethylhexyl) phthalate metabolites, ∑DEHP), exposure sources (plastic, ∑Plastics; personal care products, ∑PCP), biological activity (anti-androgenic, ∑AA), and sum of all metabolites (∑Phthalates). We used linear regression models to assess overall associations of phthalate metabolites with hormones, controlling for important demographic, lifestyle, and health factors. We also explored whether associations differed by menopause status, body mass index (BMI), and race/ethnicity. Most participants were non-Hispanic white (67%) or black (29%), college-educated (65%), employed (80%), and had somewhat higher mean urinary phthalate metabolite concentrations than other U.S. women. Overall, the following positive associations were observed between phthalate metabolites and hormones: ∑DEHP (%Δ: 4.9; 95%CI: 0.5, 9.6), ∑Plastics (%Δ: 5.1; 95%CI: 0.3, 10.0), and ∑AA (%Δ: 7.8; 95%CI: 2.3, 13.6) with estradiol; MiBP (%Δ: 6.6; 95%CI: 1.5, 12.1) with testosterone; ∑DEHP (%Δ: 8.3; 95%CI: 1.5, 15.6), ∑Plastics (%Δ: 9.8; 95%CI: 2.4, 17.7), MEP (%Δ: 4.6; 95%CI: 0.1, 9.2), ∑PCP (%Δ: 6.0; 95%CI: 0.2, 12.2), ∑Phthalates (%Δ: 9.0; 95%CI: 2.1, 16.5), and ∑AA (%Δ: 12.9; 95%CI: 4.4, 22.1) with progesterone; and MBP (%Δ: 8.5; 95%CI: 1.2, 16.3) and ∑AA (%Δ: 9.0; 95%CI: 1.3, 17.4) with AMH. Associations of phthalate metabolites with hormones differed by menopause status (strongest in premenopausal women for estradiol, progesterone, and FSH), BMI (strongest in obese women for progesterone), and race/ethnicity (strongest in non-Hispanic white women for estradiol and AMH). We found that phthalate metabolites were positively associated with several hormones in midlife women, and that some demographic and lifestyle characteristics modified these associations. Future longitudinal studies are needed to corroborate these findings in more diverse midlife populations.

Pubertal urinary phthalate metabolite concentrations and semen quality among young Russian men: exploring potential windows of susceptibility

Pubertal urinary phthalate metabolite concentrations and semen quality among young Russian men: exploring potential windows of susceptibility

Association between prenatal phthalate exposure and anthropometric measures of newborns in a sample of Iranian population.

Phthalates or phthalic acid esters (PAEs) are a group of compounds which they can be entered into the human body through the various pathways. The aim of this study was to examine associations between prenatal phthalates exposure with anthropometric measures of neonates. Urine samples were obtained from 121 Iranian pregnant women at their first trimester of pregnancy, and the levels of monobutyl phthalate (MBP), mono-benzyl phthalate (MBzP), mono-2-ethylhexyl phthalate (MEHP), and mono (2-ethyl-5hydroxyhexyl) phthalate (MEHHP) metabolites were determined by gas chromatography mass spectrometry (GC/MS). The correlations between the maternal urinary concentrations of phthalate metabolites with anthropometric measures of neonates as well as with the socio-demographic factors of participants (maternal education, age, family income, pre-pregnancy body mass index), their lifestyle variables (smoking habit, food pattern, and physical activity), and use of cleaning products (cosmetic and household cleaning products) were investigated. MBzP, MBP, MEHP, and MEHHP were detected in 100% of the participants with the concentration ranged 120 to 860 μg/g creatinine. Significant correlations were observed between the urinary levels of maternal MBzP (adjusted β = 0.3 (0.001), p = 0.03) and MEHHP (adjusted β = 0.3 (0.001), p = 0.04) with the birth weight of female neonates. MBP (adjusted β = -0.3 (0.02), p = 0.04) and MBzP (adjusted β = -0.3 (0.001), p = 0.02) had negative associations with the head circumference in male and female newborns, respectively. Furthermore, plastic packaging for pickle and passive smoking during pregnancy were identified to be significantly associated with low birth weight (p value < 0.05). Iranian pregnant women had higher concentrations of urinary phthalates compared to the other countries. Based on the findings, the higher prenatal exposure to phthalates could adversely impact the health status of newborns.

Associations between urinary phthalate metabolite concentrations and markers of liver injury in the US adult population

BackgroundPhthalates have been largely used for years in varieties of products worldwide. However, research on the joint toxic effect of various phthalates exposure on the liver is lacking. ObjectivesWe aimed to assess exposure to phthalates on liver function tests (LFTs). MethodsThis analysis included data on 6046 adults (≥20 years old) who participated in a National Health and Nutrition Examination Survey (NHANES) in 2007–2016. We employed linear regression and Bayesian kernel machine regression (BKMR), to explore the associations of urinary phthalate metabolites with 8 indicators of LFTs. ResultsDi(2-ethylhexyl) phthalate (ΣDEHP) was found to be positively associated with serum alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) (all P FDR < 0.05). We found significant positive associations of ∑DEHP, mono-ethyl phthalate (MEP) and mono-(carboxyisononyl) phthalate (MCNP) with total bilirubin (TBIL) (all P FDR < 0.05). ΣDEHP, mono-n-butyl phthalate (MBP), mono-(3-carboxypropyl) phthalate (MCPP) and mono-benzyl phthalate (MBzP) were negatively associated with serum ALB (all P FDR < 0.05). The BKMR analyses showed a significantly positive overall effect on ALT, AST, ALP and TBIL levels with high concentrations of phthalate metabolites and a significantly negative overall effect on ALB and TP, when all the chemicals at low concentrations. ConclusionsOur results add novel evidence that exposures to phthalates might be adversely associated with the indicators of LTFs, indicating the potential toxic effect of phthalate exposures on the human liver.

Association between follicular fluid phthalate concentrations and extracellular vesicle microRNAs expression.

Are phthalate metabolite concentrations in follicular fluid (FF) associated with the expression of extracellular vesicle microRNAs (EV-miRNAs)? Phthalate metabolite concentrations are associated with the expression of EV-miRNA and their associated pathways in FFs. Phthalate metabolites were recently detected in FF. Urinary phthalate metabolite concentrations alter the expression of EV-miRNAs in FF. Prospective study including 105 women recruited between January 2014 and August 2016 in a tertiary university-affiliated hospital. We assessed FF concentrations of 12 phthalate metabolites. EV-miRNAs were isolated from aliquots of the same FF, and their expression profiles were measured using a human miRNA panel. Associations between EV-miRNAs that were present in >50% of the samples and phthalate metabolites that were measured in >74% of the FF samples were tested. Genes regulated by EV-miRNAs that were found to be significantly (false discovery rate q-value < 0.1) correlated with FF-phthalates were analyzed for pathways linked with female fertility using miRWalk2.0 Targetscan database, DAVID Bioinformatics Resources and Kyoto Encyclopedia of Genes and Genomes (KEGG). Of 12 phthalate metabolites, 11 were measured in at least one FF sample. Mono (6-COOH-2-methylheptyl) phthalate (MCOMHP), mono-2-ethyl-5-carboxypentyl phthalate (mECPP), mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), mono-isobutyl phthalate (MiBP), monoethyl phthalate (MEP) and mono (7-COOH-2-methyloctyl) phthalate (MCOMOP) were detected in more than 74% of the samples. Of 754 EV-miRNAs tested, 39 were significantly associated either with MEP, MBzP, MCOMOP, MCOMHP and/or with mECPP, after adjusting for multiple testing (P < 0.05). KEGG-based pathway enrichment analysis of the genes regulated by these miRNAs showed that these EV-miRNAs may be involved in pathways related to ovary or oocyte development, maturation and fertilization. The use of miRNA panel array limits the number of potential relevant miRNAs. Moreover, several of the phthalate metabolites examined may be biased due to internal (enzymatic activity) or external (contamination in medical interventions) causes. Phthalate metabolites may alter follicular EV-miRNAs profile and thus impair pathways that are involved with oocyte development, maturation and fertilization. Our results contribute to understanding of possible mechanism(s) in which endocrine disruptor chemicals interfere with female fertility. This work was supported by the National Institutes of Environmental Health Sciences [Grant R21-ES024236]; and Environmental Health Fund, Israel [Grant 1301], no competing interests. N/A.

Urinary phthalate metabolite concentrations and adolescent sleep duration.

Background:Some environmental chemicals, such as phthalates, are capable of disrupting endocrine function related to the development and regulation of sleep patterns. However, the contribution of phthalate exposure to inadequate sleep during adolescence is unknown. We aim to evaluate the association between phthalate exposure and short sleep duration during adolescence.Methods:We used data from participants 16–17 years of age in the 2005–2010 cycles of the National Health and Nutrition Examination Survey. Participants reported typical sleep duration during weekdays, which we categorized into short sleep duration (less than 8 hours per night) and adequate sleep duration (8 or more hours) based on consensus guidelines. We used weighted logistic regression to evaluate the association between log10-transformed urinary phthalate metabolite concentrations and odds of short sleep duration.Results:An interquartile range increase in di(2-ethylhexyl) phthalate metabolites, monocarboxynonyl phthalate, monocarboxyoctyl phthalate, and mono-isobutyl phthalate was associated with 1.48 (95% confidence interval [95% CI] = 1.02, 2.16), 1.64 (95% CI = 1.17, 2.32), 1.46 (95% CI = 0.99, 2.16), and 1.92 (95% CI = 1.08, 3.43) times the odds of short sleep duration, respectively. Furthermore, we observed monotonic dose-response relations between some phthalate metabolites and odds of short sleep duration.Conclusions:Our results suggest that higher urinary concentrations of several phthalate metabolites are associated with short sleep duration during adolescence. Understanding the contribution of modifiable environmental factors to inadequate sleep duration is of great public health importance because inadequate sleep can have substantial health implications.

Urinary phthalate metabolite concentrations and hot flashes in women from an urban convenience sample of midlife women

ContextPhthalate exposure is associated with altered reproductive function, but little is known about associations of phthalate exposure with risk of hot flashes. ObjectiveTo investigate associations of urinary phthalate metabolite levels with four hot flash outcomes in midlife women. DesignA cross-sectional study of the first year of a prospective cohort of midlife women, the Midlife Women's Health Study (2006–2015), a convenience sample from an urban setting. Participants728 multi-racial/ethnic pre- and perimenopausal women aged 45–54 years. Outcome measuresWomen completed questionnaires about hot flash experience and provided 1–4 urine samples over four consecutive weeks that were pooled for analysis. Phthalate metabolites were assessed individually and as molar sums representative of common compounds (all phthalates: ƩPhthalates; DEHP: ƩDEHP), exposure sources (plastics: ƩPlastic; personal care products: ƩPCP), and modes of action (anti-androgenic: ƩAA). Covariate-adjusted logistic regression models were used to assess associations of continuous natural log-transformed phthalate metabolite concentrations with hot flash outcomes. Analyses were conducted to explore whether associations differed by menopause status, body mass index (BMI), race/ethnicity, and depressive symptoms. ResultsOverall, 45% of women reported a history of hot flashes. Compared to women who never experienced hot flashes, every two-fold increase in ƩPlastic was associated with 18% (OR: 1.18; 95%CI: 0.98, 1.43) and 38% (OR: 1.38; 95%CI: 1.11, 1.70) higher odds of experiencing hot flashes in the past 30 days and experiencing daily/weekly hot flashes, respectively. Some associations of phthalates with certain hot flash outcomes differed by menopause status, BMI, race/ethnicity, and depressive symptoms. ConclusionsThis study suggests that phthalates are associated with hot flash experience and may impact hot flash risk in women who are susceptible to experiencing hot flashes.

Association between Urinary Phthalate Metabolite Concentration and Atopic Dermatitis in Korean Adolescents Participating in the Third Korean National Environmental Health Survey, 2015-2017.

Previous studies have highlighted the potential health effects of phthalate exposure, such as atopic dermatitis and asthma. However, evidence supporting the association between phthalate exposure and atopic dermatitis is limited and based on data collected from Western populations. This study aimed to analyze the association between phthalate exposure and atopic dermatitis in Korean adolescents aged 12–17 years using a nationally representative dataset. We conducted a cross-sectional study using a publicly available dataset from the third Korean National Environmental Health Survey (n = 797). We divided the study participants into four quartiles according to urinary phthalate metabolite concentrations. The odds ratio of having atopic dermatitis was calculated using the first quartile as the reference group in binary logistic regression. We found that in the logistic regression model, both the urinary Mono-(2-ethyl-5-carboxypentyl) phthalate (MECCP; OR: 1.81; CI: 1.01–3.25) and Mono-benzyl phthalate (MBzP; OR: 1.81; CI: 1.01–3.25) concentrations in the highest quartile were positively associated with atopic dermatitis. The atopic dermatitis group had a significantly higher mean urinary MECCP and MBzP concentration. In the future, longitudinal studies involving repeated measurements are warranted to analyze the long-term effects of phthalate.

Urinary phthalates and body mass index in preschool children: The MIREC Child Development Plus study.

Childhood exposure to phthalates, a class of chemicals with known reproductive and developmental effects, has been hypothesized to increase the risk of obesity, but this association is not well understood in preschool children. We examined the association between urinary concentrations of phthalate metabolites and concurrently measured body mass index (BMI) and skinfolds among children between the ages of two and five years. We collected anthropometric measures and biomonitoring data on approximately 200 children enrolled in the Maternal-Infant Research on Environmental Chemicals Child Development Plus study. We measured 22 phthalate metabolites in children's urine and used the 19 metabolites detected in at least 40% of samples. Our primary outcome was BMI z-scores calculated using the World Health Organization growth standards. Skinfold z-scores were secondary outcomes. We used multivariable linear regression to evaluate the association between tertiles of phthalate concentrations and each anthropometric measure. We also used weighted quantile sum regression to identify priority exposures of concern. Our analytic sample included 189 singleton-born children with complete anthropometric data. Children with concentrations of the parent compound di-n-butyl phthalate (∑DnBP) in the third tertile had 0.475 (95% CI: 0.068, 0.883) higher BMI z-scores than those in the lower tertile. ∑DnBP was identified as a priority exposure in the weighted quantile sum regression BMI model. In this population of Canadian preschool aged children, we identified DnBP as a potential chemical of concern in regard to childhood obesity. Future research with serial phthalate measurements and anthropometric measurements in young children will help confirm these findings.

Urinary phthalate metabolite concentrations, oxidative stress and thyroid function biomarkers among patients with thyroid nodules.

Prior human studies have explored effects of phthalate exposures on thyroid function, but the underlying biological mechanisms remain poorly unclear. We aimed to explore the associations between phthalate exposures and thyroid function among a potentially susceptible population such as patients with thyroid nodules, and further to assess the mediating role of oxidative stress. We measured eight phthalate metabolites, three oxidative stress biomarkers [8-hydroxy-2-deoxyguanosine (8-OHdG), 8-iso-prostaglandin F2α (8-isoPGF2α) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)] in urine and three thyroid function biomarkers [thyroid-stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4)] in serum among 214 patients with thyroid nodules. Multivariate regression models were applied to assess the associations among urinary phthalate metabolites, oxidative stress and thyroid function biomarkers. The potential mediating role of oxidative stress was explored by mediation analysis. We observed that multiple urinary phthalate metabolites were associated with altered FT4 and increased oxidative stress biomarkers (all FDR-adjusted P≤0.05). Meanwhile, we found that 8-isoPGF2α was negatively associated with FT3/FT4 among patients with benign thyroid nodules (FDR-adjusted P=0.08). The mediation analysis indicated that 8-isoPGF2α mediated the associations of urinary MEHHP and %MEHP with FT3/FT4, with 55.6% and 32.6% proportion of the mediating effects, respectively. Our data suggest that lipid peroxidation may be an intermediate mechanism involved in the effects of certain phthalate exposures on altered thyroid function among patients with benign thyroid nodules.