Monocarboxy-isononyl Phthalate Research Articles

Urinary concentrations of phthalate metabolites in relation to preeclampsia and other hypertensive disorders of pregnancy in the environmental influences on child health outcomes (ECHO) program

BackgroundPhthalate exposure may contribute to hypertensive disorders of pregnancy (HDP), including preeclampsia/eclampsia (PE/E), but epidemiologic studies are lacking. ObjectivesTo evaluate associations of pregnancy phthalate exposure with development of PE/E and HDP. MethodsUsing data from 3,430 participants in eight Environmental influences on Child Health Outcomes (ECHO) Program cohorts (enrolled from 1999 to 2019), we quantified concentrations of 13 phthalate metabolites (8 measured in all cohorts, 13 in a subset of four cohorts) in urine samples collected at least once during pregnancy. We operationalized outcomes as PE/E and composite HDP (PE/E and/or gestational hypertension). After correcting phthalate metabolite concentrations for urinary dilution, we evaluated covariate-adjusted associations of individual phthalates with odds of PE/E or composite HDP via generalized estimating equations, and the phthalate mixture via quantile-based g-computation. We also explored effect measure modification by fetal sex using stratified models. Effect estimates are reported as odds ratios (OR) with 95% confidence intervals (95% CIs). ResultsIn adjusted analyses, a doubling of mono-benzyl phthalate (MBzP) and of mono (3-carboxypropyl) phthalate (MCPP) concentrations was associated with higher odds of PE/E as well as composite HDP, with somewhat larger associations for PE/E. For example, a doubling of MCPP was associated with 1.12 times the odds of PE/E (95%CI 1.00, 1.24) and 1.02 times the odds of composite HDP (95%CI 1.00, 1.05). A quartile increase in the phthalate mixture was associated with 1.27 times the odds of PE/E (95%CI 0.94, 1.70). A doubling of mono-carboxy isononyl phthalate (MCiNP) and of mono-carboxy isooctyl phthalate (MCiOP) concentrations were associated with 1.08 (95%CI 1.00, 1.17) and 1.11 (95%CI 1.03, 1.19) times the odds of PE/E. Effect estimates for PE/E were generally larger among pregnancies carrying female fetuses. DiscussionIn this study, multiple phthalates were associated with higher odds of PE/E and HDP. Estimates were precise and some were low in magnitude. Interventions to reduce phthalate exposures during pregnancy may help mitigate risk of these conditions.

The association between urinary phthalate metabolites and serum thyroid function in US adolescents

The aim was to investigate the association between mixed exposure to phthalates and serum thyroid function among US adolescents. The study used 2007–2008 survey data from the National Health and Nutrition Examination Survey (NHANES). Data on urinary phthalates metabolites and serum thyroid function indicators were collected. The weighted multivariable linear regression models and Bayesian kernel machine regression (BKMR) analyses were used to analyze the relationship between phthalates metabolites and thyroid function. A total of 356 adolescents aged 12–19 years were included in the analysis. Linear regression models showed that mono-(carboxyisoctyl) phthalate (MCOP) was positively correlated with total triiodothyronine (TT3) (β = 0.045, 95% confidence interval [CI] 0.022, 0.068) and thyroid stimulating hormone (TSH) (β = 0.1461, 95% CI 0.059, 0.232), while mono-(carboxyisononyl) phthalate (MCNP) was negatively correlated with TSH (β = − 0.119, 95% CI − 0.196, − 0.042). BKMR analyses showed phthalate metabolites mixtures have significantly positive overall effect on TT3. Exposure to phthalate mixtures might be positively correlated with increased TT3 serum level in US adolescents. The study provided evidence for the association between mixed phthalates exposure and thyroid health in adolescent population.

Phthalates and Incident Diabetes in Midlife Women: The Study of Women's Health Across the Nation (SWAN).

Phthalates are hypothesized to contribute to diabetes, but longitudinal evidence in humans is limited. We examined whether phthalate exposure was associated with a higher incidence of diabetes in a racially/ethnically diverse cohort of midlife women. In the Study of Women's Health Across the Nation Multipollutant Study, we followed 1308 women without diabetes in 1999-2000 for 6 years. Eleven phthalate metabolites were measured in spot urine samples in 1999-2000 and 2002-2003. Incident diabetes was ascertained between 1999-2000 and 2005-2006. Cox proportional hazards models with time-varying exposure were used to estimate the hazard ratio (HR) of diabetes associated with each phthalate metabolite, adjusting for demographic, lifestyle, and health-related factors. Effect modification by race/ethnicity was examined with interaction terms. Sixty-one women developed diabetes over 6 years (cumulative incidence = 4.7%). Among all women, several high-molecular-weight phthalate metabolites were associated with a higher incidence of diabetes, but none were statistically significant. There was effect modification by race/ethnicity. Among White women, each doubling of the concentrations of mono-isobutyl phthalate (MiBP), monobenzyl phthalate, mono-carboxyoctyl phthalate, mono-carboxyisononyl phthalate (MCNP), and mono(3-carboxypropyl) phthalate was associated with a 30% to 63% higher incidence of diabetes (HR = 1.30, 95% CI, 1.03-1.65 for MCNP; HR = 1.63, 95% CI, 1.18-2.25 for MiBP). In contrast, phthalates were not associated with diabetes incidence in Black or Asian women. Some phthalate metabolites were associated with a higher incidence of diabetes over 6 years, but the associations were inconsistent across racial/ethnic groups. Whether phthalates cause diabetes requires further investigation.

Association of phthalate exposure with low birth weight in couples conceiving naturally or via assisted reproductive technology in a prospective birth cohort

BackgroundFew studies have investigated the adverse effects of preconception phthalate (PAE) exposure on birth weight in couples receiving assisted reproductive technology (ART) compared to naturally conceived newborns. ObjectivesWe examined the association between parental preconception/prenatal urinary phthalate exposure and low birth weight (LBW) risk in couples who conceived using ART or naturally. MethodsFrom the Jiangsu Birth Cohort Study (China), we recruited 544 couples who conceived after infertility treatment and 940 couples who conceived naturally and gave birth to a singleton infant between November 2014 and December 2019. Seventeen metabolites of phthalate and three metabolites of phthalate alternatives were analyzed in parental spot urine samples. Clinical data were collected from medical records. We used generalized linear models, elastic net regression, Bayesian kernel machine regression, and quantile-based g-computation to examine the individual and joint effects of parental phthalate exposure on birth weight and LBW risk ratios (RR). ResultsThe relationship between parental phthalate exposure and birth weight was consistent between ART and natural conception. Maternal exposure to mono-ethyl phthalate and mono-carboxyisooctyl phthalate was associated with an increased risk of LBW in ART-conceived infants (RR = 1.27; 95 % confidence interval (CI): 1.03, 1.56; and RR = 1.31; 95 % CI: 1.03, 1.67, respectively). In contrast, in the spontaneously conceived infants, higher paternal prenatal concentrations of mono-benzyl phthalate and mono-carboxyisononyl phthalate were associated with a 40 % and 53 % increase in LBW risk, respectively. Exposure to PAE mixtures was associated with LBW in ART-conceived infants, with the effects primarily driven by di-ethyl phthalate, benzylbutyl phthalate, and di-isononyl phthalate metabolites. Sex-specific LBW was observed, with females appearing to be more susceptible than males. ConclusionsMaternal preconception and paternal prenatal exposure to phthalates were associated with increased risk of LBW in infants. Compared with natural conception, ART-conceived fetuses were more sensitive to PAE mixtures, which requires further attention.

Associations between repeated measures of urinary phthalate metabolites and biomarkers of oxidative stress in a rural agricultural cohort of children with asthma

Phthalate exposure is widespread, and studies suggest an adverse relationship with asthma morbidity, including some support for oxidative stress as an underlying pathophysiological mechanism. Urinary phthalate metabolites have been associated with biomarkers of oxidative stress, but data are few in children diagnosed with asthma. We used participant data from the Home Air in Agriculture Pediatric Intervention Trial (HAPI) to examine longitudinal relationships between phthalates and oxidative stress in a cohort of Latino children with asthma residing in an agricultural community. We used linear mixed-effects models to estimate associations between 11 urinary phthalate metabolites (and one summed measure of di-2-ethylhexyl phthalate (DEHP) metabolites, ∑DEHP) and two urinary biomarkers of oxidative stress: a biomarker of lipid peroxidation via measure of 8-isoprostane and a biomarker of DNA/RNA oxidative damage via combined measure of 8-hydroxydeoxyguanosine (8-OHdG), 8-hydroxyguanosine (8-OHG), and 8-hydroxyguanine. Seventy-nine participants provided 281 observations. In covariate-adjusted models, we observed significant positive relationships between all phthalate metabolites and 8-isoprostane, effect sizes ranging from a 9.3 % (95 % CI: 4.2 %–14.7 %) increase in 8-isoprostane for each 100 % increase (i.e., doubling) of mono-(carboxy-isooctyl) phthalate (MCIOP), to a 21.0 % (95 % CI: 14.3 %–28.2 %) increase in 8-isoprostane for each doubling of mono-n-butyl phthalate (MNBP). For each doubling of mono-(carboxy-isononyl) phthalate (MCINP) and mono-ethyl phthalate (MEP), the DNA/RNA oxidative damage biomarker increased by 6.0 % (95 % CI: 0.2 %–12.2 %) and 6.5 % (95 % CI: 1.4 %–11.9 %), respectively. In conclusion, we provide unique data suggesting phthalate exposure is positively associated with oxidative stress in children with asthma. Our repeat measures provide novel identification of a consistent effect of phthalates on oxidative stress in children with asthma via lipid peroxidation. Confirmation in future studies of children with asthma is needed to enhance understanding of the role of phthalates in childhood asthma morbidity.

Associations of Phthalate Metabolites and Bisphenol A Levels with Obesity in Children: The Korean National Environmental Health Survey (KoNEHS) 2015 to 2017.

BackgroundPhthalates and bisphenol A (BPA) are synthetic chemicals widely used in daily life. This study investigated urinary phthalate and BPA levels in Korean children and their associations with obesity. MethodsA total of 2,351 children aged 3 to 17 years who participated in the Korean National Environmental Health Survey 2015 to 2017 were included. Urinary dilution was corrected using covariate-adjusted standardization (CAS). We examined the geometric mean (GM) concentrations of urinary phthalate metabolites, including di (2-ethylhexyl) phthalate (DEHP) metabolites (mono [2-ethyl-5-hydroxyhexyl] phthalate, mono [2-ethyl-5-oxohexyl] phthalate, and mono [2-ethyl-5-carboxypentyl] phthalate [MECPP]), mono-benzyl-phthalate (MBzP), mono (carboxyoctyl) phthalate (MCOP), mono (carboxy-isononyl) phthalate (MCNP), mono (3-carboxypropyl) phthalate, and mono-n-butyl-phthalate (MnBP), and BPA. We also analyzed the odds ratio (OR) for obesity according to the quartiles of each analyte. ResultsThe urinary GM levels of DEHP metabolites and MnBP were notably higher among Korean children than among American, Canadian, and German children. The CAS-applied GM concentrations of most analytes, except for MBzP, MCOP, and MCNP, were higher in children aged 3 to 5 years than in those aged 6 to 17 years. The OR for obesity in the highest quartile of MECPP was significantly higher than in the lowest quartile after adjusting for covariates. However, the other phthalate metabolites and BPA were not significantly associated with obesity. ConclusionThe concentrations of urinary DEHP metabolites and MnBP were higher in Korean children than in children in Western countries. Urinary MECPP exposure, but not other phthalates or BPA, showed a positive association with obesity in Korean children. Further studies are required to elucidate the causal relationships.

Prenatal maternal phthalate exposures and trajectories of childhood adiposity from four to twelve years.

Adiposity trajectories reflect dynamic process of growth and may predict later life health better than individual measures. Prenatal phthalate exposures may program later childhood adiposity, but findings from studies examining these associations are conflicting. We investigated associations between phthalate biomarker concentrations during pregnancy with child adiposity trajectories. We followed 514 mother-child pairs from the Mexico City PROGRESS cohort from pregnancy through twelve years. We measured concentrations of nine phthalate biomarkers in 2nd and 3rd trimester maternal urine samples to create a pregnancy average using the geometric mean. We measured child BMI z-score, fat mass index (FMI), and waist-to-height ratio (WHtR) at three study visits between four and 12 years of age. We identified adiposity trajectories using multivariate latent class growth modeling, considering BMI z-score, FMI, and WHtR as joint indicators of latent adiposity. We estimated associations of phthalates biomarkers with class membership using multinomial logistic regression. We used quantile g-computation to estimate the potential effect of the total phthalate mixture and assessed effect modification by sex. We identified three trajectories of child adiposity, a "low-stable", a "low-high", and a "high-high" group. A doubling of the sum of di (2-ethylhexyl) phthalate metabolites (ΣDEHP), was associated with 1.53 (1.08, 2.19) greater odds of being in the "high-high" trajectory in comparison to the "low-stable" group, whereas a doubling in di-isononyl phthalate metabolites (ΣDiNP) was associated with 1.43 (1.02, 2.02) greater odds of being in the "low-high" trajectory and mono (carboxy-isononyl) phthalate (MCNP) was associated with 0.66 (0.45, 97) lower odds of being in the "low-high" trajectory. No sex-specific associations or mixture associations were observed. Prenatal concentrations of urinary DEHP metabolites, DiNP metabolites, and MCNP, a di-isodecyl phthalate metabolite, were associated with trajectories of child adiposity. The total phthalate mixture was not associated with early life child adiposity.

Phthalates mixture on allergies and oxidative stress biomarkers among children: The Hokkaido study

Exposure to individual phthalates and the mediation effect of oxidative stress in association with asthma and allergic symptoms have been studied previously. Little is known about the mixture effect of phthalates on health outcomes. Thus, we investigated the effect of a mixture of ten phthalate metabolites in association with wheeze, rhino-conjunctivitis, and eczema. The mediating effect of three oxidative stress biomarkers was also assessed. Levels of 10 phthalate metabolites and 3 oxidative stress biomarkers were measured in 386 urine samples from 7-year-old children. Parents reported demographic and allergic symptoms using ISAAC questionnaires. Logistic regression for individual metabolites and mixture analysis weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) were fitted to examine the association between phthalate metabolite exposure and health outcomes. Baron and Kenny's regression approach was used for mediation analysis. In logistic regression model showed mono (2-ethyl-5-carboxypentyl) phthalate (MECPP) (OR=1.41, 95% CI 1.02-1.97) and mono carboxy-isononyl phthalate (cx-MINP) (OR=1.40, 95% CI 1.07-1.86) were associated with wheeze. The WQS index had a significant association (OR=1.46, 95% CI 1.09-1.96) with wheeze and (OR=1.40, 95% CI 1.07-1.82) with eczema. Mono-isononyl phthalate (MINP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) were the most highly weighted metabolites. In the BKMR model, diisononyl phthalate (DINP) metabolites showed the highest group posterior inclusion probability (PIP). Among DINP metabolites, MINP in wheeze, cx-MINP in rhino-conjunctivitis and OH-MINP in eczema showed the highest conditional PIPs. The overall metabolites mixture effect was associated with eczema. We did not find any mediation of oxidative stress in the association between phthalates and symptoms. No significant association between phthalate metabolites and oxidative stress was observed in this study. Mixture of phthalate metabolites were associated with wheeze and eczema. The main contributors to the association were DEHP and DINP metabolites. No mediation of oxidative stress was observed.

Toxicokinetics of di-isodecyl phthalate and its major metabolites in rats through the application of a developed and validated UHPLC-ESI-MS/MS method.

Di-isodecyl phthalate (DiDP) is a high-molecular-weight phthalate that is mainly used as a plasticizer for plastics. Therefore, exposure to DiDP in the environment has become common with the increasing use of plastics around the world. Environmental regulations and scientific risk management for DiDP, which can be associated with endocrine disruption and various metabolic diseases, are urgently needed. The purpose of this study was to provide useful reference material for future human DiDP risk assessments by conducting toxicokinetic studies on DiDP. Rats were given 100mg/kg of DiDP orally or intravenously, and plasma, urine, feces, and various tissues were sampled at preset times. DiDP and its major metabolites mono-isodecyl-phthalate (MiDP), mono-hydroxy-isodecyl-phthalate (MHiDP), mono-carboxy-isononyl-phthalate (MCiNP), and mono-oxo-isodecyl-phthalate (MOiDP) were simultaneously quantified from collected biological samples through the application of a newly developed and verified ultrahigh-performance liquid chromatography-electrospray ionization-tandem mass spectrometer (UHPLC-ESI-MS/MS) method. Based on the quantitative results for each analyte, toxicokinetic analyses were performed. DiDP was rapidly and extensively metabolized to MiDP, MHiDP, MCiNP, and MOiDP. The major metabolite excreted in the urine was MCiNP, suggesting that it could be a useful biomarker. The conjugated forms of DiDP and its metabolites have been significantly quantified in the plasma, urine, and feces. DiDP and its major metabolites were also distributed in various tissues in significant quantities. The toxicokinetic properties of DiDP, which have not been clearly reported previously, were identified through this study. This report will serve as a useful reference for future DiDP environmental regulation and scientific human risk assessment studies.

Prenatal Maternal Phthalate Exposures and Trajectories of Childhood Adiposity from Four to Twelve Years

BACKGROUND AND AIM: Trajectories of child adiposity have lifelong consequences for future cardiometabolic risk. Prenatal phthalate exposures may affect processes that pre-program later childhood adiposity, but findings from studies examining these associations are conflicting. We examined associations between individual phthalate exposure biomarkers and total phthalate mixture during pregnancy with child adiposity trajectories. METHODS: Data were from 514 mother-child pairs in the PROGRESS cohort of Mexico City. We quantified 15 phthalate metabolites in 2nd and 3rd trimester maternal urine samples and created an average pregnancy measure using the geometric mean. We evaluated the 15 metabolites as nine biomarkers, including four metabolite molar sums. We measured child BMI z-score, bioimpedance-based fat mass index (FMI), and waist-to-height ratio (WHtR) at three visits between four and twelve years of age. We identified trajectories using multivariate latent class growth modeling, considering BMI z-score, FMI, and WHtR as joint indicators of latent adiposity. We then estimated associations of phthalate biomarkers with class membership using multinomial logistic regression. We used quantile g-computation to estimate the effect of the total phthalates mixture and assessed effect modification by sex. RESULTS:We detected three trajectories of child adiposity, “low-stable” remained stable at low adiposity (n=260), “low-high” started low then increased to high (n=147), and “high-high” started high and remained high (n=107). A doubling of the sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP), was associated with greater odds of being in the “high-high” trajectory (adjusted odds ratio [OR] = 1.53 [1.08, 2.19]; p = 0.02) in comparison to the “low-stable” group, whereas a doubling in mono(carboxy-isononyl) phthalate (MCNP) was associated with lower odds of being in the “low-high” trajectory (adjusted OR = 0.66 [0.45, 97]; p = 0.03). No sex-specific or total mixtures associations were detected. CONCLUSIONS:Pregnancy urinary concentrations of ΣDEHP metabolites and MCNP were associated with trajectories of child adiposity in opposing directions. KEYWORDS: Phthalates, Children's environmental health, Environmental epidemiology, Mixtures analysis

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

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

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.

Associations of gestational phthalate exposure and non-nutritive suck among infants from the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) birth cohort study

BackgroundInfant non-nutritive suck (NNS), or sucking on a pacifier with no nutrients being delivered, has been used as in index of brain function and has been linked to subsequent neurodevelopment. Yet, no data are available connecting NNS to environmental exposures in utero. The goal of this study was to examine the relationship between gestational exposure to phthalates (a group of chemicals found in personal care products, PVC plastics, and other products) and NNS among infants in a birth cohort study in Puerto Rico. MethodsUrinary phthalate metabolite levels were measured in women at up to three time points in pregnancy as a measure of in utero exposure to the child. We calculated the geometric mean of each metabolite for each woman as a measure of exposure across gestation. Infants had their NNS sampled using our custom research pacifier between 4-6 (± 2 weeks) weeks of age, yielding the following NNS dependent measures: cycles/burst, frequency, amplitude, bursts/min, and cycles/min. ResultsTwo hundred and eight mother-infant dyads completed this study We used multiple linear regression to assess associations between individual phthalate metabolites and NNS measurements, adjusting for infant sex, birthweight, and urinary specific gravity. An interquartile range (IQR) increase in mono carboxyisononyl phthalate across pregnancy was associated with 3.5% (95%CI: -6.2, -0.8%) lower NNS frequency and 8.9% (0.6, 17.3%) higher NNS amplitude. Similarly, an IQR increase in mono-2-ethylhexyl phthalate was also associated with 3.4% (-6.5, -0.2%) lower NNS frequency, while an IQR increase in di-2-ethylhexyl terephthalate metabolites was associated with 11.2% (2.9, 19.5%) higher NNS amplitude. Gestational exposure to phthalates may alter NNS amplitude and frequency in full-term infants. These findings indicate that the infants may be increasing their NNS amplitude to compensate for their slower NNS frequency. These preliminary findings could have important clinical implications for earlier detection of exposure-related deficits in neurofunction as well as implications for subsequent neurodevelopment and related interventions.

Urinary levels of phthalate esters and heavy metals in adolescents with thyroid colloid cysts

ABSTRACT We aimed to evaluate 14 urinary phthalate metabolites and 4 toxic metals in adolescents having thyroid colloid cyst (TCC) and compare with age and sex-matched others without TCC. Phthalate metabolites were analysed with UPLC-MS/MS and heavy metals with ICP-MS. TCC ratios in tertile subgroups of pollutants were compared with multiple logistic regression analysis after adjusting for age, sex, z-scores for body mass index and urinary creatinine values. Adolescents having the highest tertile of mono (2-ethylhexyl) phthalic acid and mercury had increased odds and those with the highest tertiles of monocarboxy-isononyl phthalate, mono (3-carboxypropyl) phthalate, monoisobutyl phthalate had lower odds for TCC than counterparts. The odds of TCC were lower for those in the second and the third tertiles. No differences in TCC ratios were detected with other pollutants. Given phthalate esters’ and toxic metals’ specific interactions on TCC, further studies were necessary to assess the influence of chemicals on TCC.

Associations of urinary concentrations of phthalate metabolites, bisphenol A, and parabens with obesity and diabetes mellitus in a Korean adult population: Korean National Environmental Health Survey (KoNEHS) 2015–2017

Phthalates and bisphenol A (BPA) have been suspected as risk factors for obesity and diabetes mellitus (DM) among humans. However, associations between phthalates and environmental phenols are often inconsistent across different populations. In this study, we recruited the adult population (n = 3782) of the Korean National Environmental Health Survey (KoNEHS) 2015–2017 (Cycle 3) and assessed the associations between urinary biomarkers of phthalate, BPA, and paraben exposure with obesity and DM. A potential collider issue with the use of urinary creatinine (Cr) or specific gravity (SG) exists when adjusting urinary dilution; therefore, a covariate-adjusted standardization (CAS) was employed for adjustment, and the results were compared. In the present population, the direction of the association often varied depending on the choices made to adjust urinary dilution. When using CAS, the direction of association resembled those of previously reported experimental observations. With Cr or SG adjustment, ORs for obesity decreased in the highest quartiles of monocarboxyoctyl phthalate (MCOP) [OR (95% CI) = Cr: 0.71 (0.54, 0.93); SG: 0.68 (0.52, 0.90)], monocarboxy-isononyl phthalate (MCNP) [OR (95% CI) = Cr: 0.67 (0.52, 0.87); SG: 0.68 (0.52, 0.89)], and mono(3-carboxylpropyl) phthalate (MCPP) in the urine [OR (95% CI) = Cr: 0.60 (0.47, 0.76); SG: 0.61 (0.48, 0.77)]; however, with CAS, these negative associations disappeared. Instead, mono-benzyl phthalate (MBzP) [OR (95% CI) = 1.31 (1.03, 1.66)], BPA [OR (95% CI) = 1.62 (1.27, 2.06)], or ethyl paraben (EtP) [OR (95% CI) = 1.51 (1.19, 1.91)] concentrations in the highest quartile showed positive associations with a higher risk of obesity. On the other hand, for DM, an overall decrease in ORs was observed for phthalate metabolites and BPA following SG adjustment and disappeared with CAS adjustment. In addition, the highest quartiles of BPA, methyl paraben (MeP), and ethyl paraben (EtP) showed a significantly higher risk of DM than those in the lowest quartiles following CAS [OR (95% CI) = BPA: 1.65 (1.06, 2.59); MeP: 1.68 (1.08, 2.60); and EtP: 2.74 (1.77, 4.24), respectively]. The present observations outline the importance of using an appropriate adjustment method for urinary dilution in association studies on obesity and DM. In addition, several phthalates, BPA, and parabens were identified as potential chemical risk factors for these outcomes. Further studies are warranted in other populations to confirm these observations.

Diet quality during pregnancy predicts maternal concentrations of phthalates and phthalate alternatives

Background/Objectives: Phthalates are endocrine disrupting chemicals that may be particularly disruptive during pregnancy. Pregnancy diet is a vehicle for some phthalate exposures. Therefore, we evaluated whether diet quality predicts urinary phthalate/phthalate alternative biomarkers concentrations in pregnant women.Methods: This study includes 427 pregnant women from Champaign-Urbana, Illinois. Alternative Healthy Eating Index (AHEI) scores were estimated from 3-month food frequency questionnaires administered at 34-37 weeks gestation, with higher AHEI scores representing lower chronic diseases risk. We quantified 19 phthalate/phthalate alternative metabolites in cross-pregnancy pools of five first-morning urines in three approximately equal batches based on year of enrollment (2013-2019). In analyses, we used individual metabolites, molar-sums of metabolites of the same parent phthalates (e.g., di(2-ethylhexyl) phthalate (SumDEHP), dibutyl phthalate (SumDBP), di-isononyl phthalate (SumDiNP)) or phthalate replacements (1,2-cyclohexane,dicarboxylic acid diisononyl ester (SumDiNCH), di(2-ethylhexyl) terephthalate (SumDEHTP)). Linear regression models evaluated associations between AHEI and ln-transformed specific-gravity adjusted biomarker concentrations while controlling for demographic/lifestyle characteristics, and stratified by chemical analysis batch.Results: Median AHEI score in these predominantly White, college-educated women was 55.9 (possible 110, range: 24.9-82.4) and varied little across time. Biomarker concentrations were similar to U.S. women and many varied over time: monobenzyl phthalate (MBzP), mono(carboxyisononyl) phthalate (MCNP), mono(3-carboxypropyl) phthalate (MCPP), SumDEHP, and SumDiNP decreased from 2013 to 2019, whereas SumDiNCH and SumDEHTP increased. Women with higher AHEI scores had lower SumDEHP, SumDEHTP, and SumDiNP regardless of time, and MBzP, MCNP, MCPP, and SumDBP only in the earliest batch. The strongest association was between AHEI and SumDEHTP, which decreased by 2.5% for each unit increase in AHEI (95%CI: -3.8, -1.3). Conclusions: In this cohort, pregnant women with high diet quality were the least exposed to plasticizer phthalates/alternatives. While these patterns should be confirmed in other populations, we also noted that associations between diet quality and some phthalates/phthalate alternatives have changed over time.

Non-home-prepared meal and fast food intake as exposure sources to non-persistent pollutant among the US population, NHANES 2013-2014

Background: Non-persistent pollutants (NPPs) have been widely used in commercial products, and proven to have adverse health impacts. Despite the various exposure pathways, dietary intake has received more attention due to potential contamination from food processing and packaging. Non-home-prepared meals and fast food are likely more processed and packaged, which may be important exposure pathways for some NPPs. Methods: To assess the associations of urinary NPPs with non-home-prepared meals, and with fast food intake, the data from the National Health and Nutrition Examination Survey (NHANES 2013-2014) were used (N=2,666 for organophosphate ester; N=2,777 for the other chemicals). Dietary information was collected through the questionnaire during household interview and 24-hr dietary recall interview; participants at or below the median were assigned to low exposure group, whereas those above were assigned to high exposure group. Multivariate linear regression accounting for the complex sampling design was applied, and all models were adjusted for sex, age, race/ethnicity, BMI, income, and urinary creatinine. Results: Based on the significance of trend, dose-response relationships were found in some phthalates metabolites, but not for bisphenols, parabens or organophosphate esters with non-home-prepared meals, and with fast food intake. The participants with low and high frequency of non-home-prepared meals have 15.3% (CI 3.7-28.1%) and 66.8% (CI 39.9-98.8%) increase in urinary Σdiisononyl phthalate metabolites (ΣDiNPm) levels compared to non-exposed group. Those with low and high fast food intake with in the past 24 hours have 31.1% (CI 9.8-56.4%) and 70.4% (CI 51.2-92.0%) increase in urinary ΣDiNPm levels compared to no intake group. Similar findings were also found for urinary Σdi(2-ethylhexyl)phthalate metabolites (ΣDEHPm), mono(carboxyisononyl) phthalate (MCiNP), and mono-(3-carboxypropyl) phthalate (MCPP). Conclusion: Human phthalate exposure may be attributed to non-home-prepared and fast food consumption, whereas paraben, bisphenol, and organophosphate ester exposures may have different exposure pathways among the US population.

Phthalate exposure in pregnant women with systemic lupus erythematous (SLE)

TPS 632: Health effects of flame retardants and plasticizers, Johan Friso Foyer, Floor 1, August 27, 2019, 3:00 PM - 4:30 PM Background: Environmental chemicals might contribute to the pathogenesis of autoimmune diseases in combination with established genetic factors. Phthalate exposure in pregnant women may influence fetal growth and birth outcomes. Hence, we assessed phthalate exposure in pregnant women with systemic lupus erythematous (SLE) and compared levels with nationally-representative and pregnant populations. Methods: Participants were 50 pregnant women from the New York City (NYC) sample of PROMISSE (2003-2010), a multi-ethnic/racial cohort designed to prospectively assess adverse pregnancy outcomes in SLE women with inactive or mild/moderate disease activity. We measured urinary concentrations of 21 phthalate metabolites during each trimester and compared median concentrations with 1) 15-to-50 year-old women in the National Health and Nutrition Examination Survey (NHANES) 2003-2010; and 2) a contemporary population-based cohort of pregnant women in NYC (n=240). Results: Intraclass correlations for three measurements across pregnancy varied between r=0 [mono-carboxy isooctyl phthalate (mCIOP)] and r=0.57 [mono-n-butyl-phthalate (mBP)]. Mono-(3-carboxypropyl) phthalate (mCPP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), mono-(2-ethyl-5-carboxypentyl) phthalate (mECPP), mono-(2-ethyl-5-oxohexyl) phthalate (mEOHP), mCIOP, and mono-carboxy isononyl phthalate (mCINP) were detected in all pregnant women, comparable to NHANES. Metabolites of di-(2-propylheptyl) phthalate (DPHP) and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) were detected in 4-55% of participant. Compared to NHANES, pregnant women with SLE had higher first trimester concentration of mono-(2-ethylhexyl) phthalate (MEHP) [median=3.9 ng/mL interquartile range (IQR)=6.0 vs 2.5 ng/mL, IQR=5.45], mono-isobutyl phthalate (mIBP) (median=12.8 vs 7.6 ng/mL), mono-isononyl phthalate (mINP) (median=2.7 vs. 0.87 ng/mL), and mCIOP (median=14.9 vs 6.9 ng/mL). Concentrations of other phthalate metabolites were comparable between groups. Pregnant women with SLE had higher phthalate levels than the NYC cohort. Conclusions: Pregnant women with SLE had higher concentrations of certain phthalate metabolites than controls. This cross-sectional analysis cannot rule out that SLE might influence phthalate metabolism. Sociodemographic and lifestyles factors might also explain the results; therefore, further investigation is needed.

Associations of Phthalates and Phthalate Replacements With CRH and Other Hormones Among Pregnant Women in Puerto Rico.

ContextPhthalates are endocrine-disrupting chemicals that may be associated with adverse birth outcomes. Dysregulation of maternal endocrine homeostasis could be a possible biological pathway between phthalates and birth outcomes.ObjectiveExamine associations between 19 maternal urinary phthalate or phthalate replacement metabolites and 9 serum hormones measured over two time points during pregnancy.DesignLongitudinal study conducted in the PROTECT pregnancy cohort.SettingPuerto Rico.PatientsSix hundred seventy-seven women in the first trimester of pregnancy.Main Outcome Measures SerumCRH, estriol, SHBG, progesterone, TSH, total T3, free T4, total T4, and testosterone.ResultsT3 was significantly associated with most metabolites. CRH was inversely associated with mono carboxyisononyl phthalate [MCNP; percent change (%Δ), −4.08; 95% CI, −7.24, −0.804], mono-3-carboxypropyl phthalate (MCPP; %Δ, −5.25; 95% CI, −8.26, −2.14), mono-2-ethyl-5-carboxypentyl phthalate (MECPP; %Δ, −18.4; 95% CI, −30.4, −4.37), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP; %Δ, −13.4; 95% CI, −22.7, −2.92), and mono-2-ethyl-5-oxohexyl phthalate (MEOHP; %Δ, −12.7; 95% CI, −22.2, −2.20). Positive associations were found between numerous phthalate metabolites and free T4, T4, and the T3/T4 ratio. Testosterone was positively associated with mono hydroxybutyl phthalate (MHBP; %Δ, 4.71; 95% CI, 0.27, 9.35) and inversely associated with monoethyl phthalate (MEP; %Δ, −14.5; 95% CI, −24.3, −3.42), and relationships with MCNP and mono carboxyisooctyl phthalate (MCOP) were significantly modified by study visit. Finally, an inverse association was found between mono-2-ethyl-5-hydrohexyl terephthalate (MEHHTP), a terephthalate metabolite, and progesterone at visit 3 only (%Δ, −13.1; 95% CI, −22.3, −2.75).ConclusionsThese results indicate that exposure to phthalates may differentially impact the maternal endocrine system at different points during pregnancy, and that exposures to phthalate replacement chemicals may be particularly important to consider in future human health studies.