Phthalate Metabolites Research Articles

Effects of Di-2-Ethylhexyl Phthalate on Central Nervous System Functions: A Narrative Review.

Phthalates are widely used in the plastics industry. Di-2-Ethylhexyl Phthalate (DEHP) is one of the most important phthalate metabolites that disrupt the function of endocrine glands. Exposure to DEHP causes numerous effects on animals, humans, and the environment. Low doses of DEHP increase neurotoxicity in the nervous system that has arisen deep concerns due to the widespread nature of DEHP exposure and its high absorption during brain development. In this review article, we evaluated the impacts of DEHP exposure from birth to adulthood on neurobehavioral damages. Then, the possible mechanisms of DEHP-induced neurobehavioral impairment were discussed. Peer-reviewed articles were extracted through Embase, PubMed, and Google Scholar till the year 2021. The results showed that exposure to DEHP during pregnancy and infancy leads to memory loss and irreversible nervous system damage. Overall, it seems that increased levels of oxidative stress and inflammatory mediators possess a pivotal role in DEHP-induced neurobehavioral impairment.

Prenatal Exposures to Common Phthalates and Prevalent Phthalate Alternatives and Infant DNA Methylation at Birth.

Phthalates are a diverse group of chemicals used in consumer products. Because they are so widespread, exposure to these compounds is nearly unavoidable. Recently, growing scientific consensus has suggested that phthalates produce health effects in developing infants and children. These effects may be mediated through mechanisms related to the epigenome, the constellation of mitotically heritable chemical marks and small compounds that guide transcription and translation. The present study examined the relationship between prenatal, first-trimester exposure of seven phthalates and epigenetics in two pregnancy cohorts (n = 262) to investigate sex-specific alterations in infant blood DNA methylation at birth (cord blood or neonatal blood spots). Prenatal exposure to several phthalates was suggestive of association with altered DNA methylation at 4 loci in males (all related to ΣDEHP) and 4 loci in females (1 related to ΣDiNP; 2 related to BBzP; and 1 related to MCPP) at a cutoff of q < 0.2. Additionally, a subset of dyads (n = 79) was used to interrogate the relationships between two compounds increasingly used as substitutions for common phthalates (ΣDINCH and ΣDEHTP) and cord blood DNA methylation. ΣDINCH, but not ΣDEHTP, was suggestive of association with DNA methylation (q < 0.2). Together, these results demonstrate that prenatal exposure to both classically used phthalate metabolites and their newer alternatives is associated with sex-specific infant DNA methylation. Research and regulatory actions regarding this chemical class should consider the developmental health effects of these compounds and aim to avoid regrettable substitution scenarios in the present and future.

Determinants of phthalate exposures in pregnant women in New York City

Previous studies have provided data on determinants of phthalates in pregnant women, but results were disparate across regions. We aimed to identify the food groups and demographic factors that predict phthalate exposure in an urban contemporary pregnancy cohort in the US. The study included 450 pregnant women from the New York University Children's Health and Environment Study in New York City. Urinary concentrations of 22 phthalate metabolites, including metabolites of di-2-ethylhexylphthalate (DEHP), were determined at three time points across pregnancy by liquid chromatography coupled with tandem mass spectrometry. The Diet History Questionnaire II was completed by pregnant women at mid-pregnancy to assess dietary information. Linear mixed models were fitted to examine determinants of urinary phthalate metabolite concentrations. Using partial-linear single-index (PLSI) models, we assessed the major contributors, among ten food groups, to phthalate exposure. Metabolites of DEHP and its ortho-phthalate replacement, diisononyl phthalate (DiNP), were found in >90% of the samples. The sum of creatinine-adjusted DiNP metabolite concentrations was higher in older and single women and in samples collected in summer. Hispanic and non-Hispanic Black women had lower urinary concentrations of summed metabolites of di-n-octyl phthalate (DnOP), but higher concentrations of low molecular weight phthalates compared with non-Hispanic White women. Each doubling of grain products consumed was associated with a 20.9% increase in ∑DiNP concentrations (95%CI: 4.5, 39.9). PLSI models revealed that intake of dried beans and peas was the main dietary factor contributing to urinary ∑DEHP, ∑DiNP, and ∑DnOP levels, with contribution proportions of 76.3%, 35.8%, and 27.4%, respectively. Urinary metabolite levels of phthalates in pregnant women in NYC varied by age, marital status, seasonality, race/ethnicity, and diet. These results lend insight into the major determinants of phthalates levels, and may be used to identify exposure sources and guide interventions to reduce exposures in susceptible populations.

Prenatal exposure to phthalates and peripheral blood and buccal epithelial DNA methylation in infants: An epigenome-wide association study

BackgroundPrenatal exposure to phthalates has been associated with adverse health and neurodevelopmental outcomes. DNA methylation (DNAm) alterations may be a mechanism underlying these effects, but prior investigations of prenatal exposure to phthalates and neonatal DNAm profiles are limited to placental tissue and umbilical cord blood. ObjectiveConduct an epigenome-wide association study (EWAS) of the associations between prenatal exposure to phthalates and DNAm in two accessible infant tissues, venous buffy coat blood and buccal epithelial cells (BECs). MethodsParticipants included 152 maternal-infant pairs from the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Maternal second trimester urine samples were analyzed for nine phthalate metabolites. Blood (n = 74) or BECs (n = 78) were collected from 3-month-old infants and profiled for DNAm using the Infinium HumanMethylation450 (450K) BeadChip. Robust linear regressions were used to investigate the associations between high (HMWPs) and low molecular weight phthalates (LMWPs) and change in methylation levels at variable Cytosine-phosphate-Guanine (CpG) sites in infant tissues, as well as the sensitivity of associations to potential confounders. ResultsOne candidate CpG in gene RNF39 reported by a previous study examining prenatal exposure to phthalates and cord blood DNAm was replicated. The EWAS identified 12 high-confidence CpGs in blood and another 12 in BECs associated with HMWPs and/or LMWPs. Prenatal exposure to bisphenol A (BPA) associated with two of the CpGs associated with HMWPs in BECs. DiscussionPrenatal exposure to phthalates was associated with DNAm variation at CpGs annotated to genes associated with endocrine hormone activity (i.e., SLCO4A1, TPO), immune pathways and DNA damage (i.e., RASGEF1B, KAZN, HLA-A, MYO18A, DIP2C, C1or109), and neurodevelopment (i.e., AMPH, NOTCH3, DNAJC5). Future studies that characterize the stability of these associations in larger samples, multiple cohorts, across tissues, and investigate the potential associations between these biomarkers and relevant health and neurodevelopmental outcomes are needed.

Risk of Abdominal Obesity Associated with Phthalate Exposure of Nurses.

Background: Occupational health hazards associated with phthalate exposure among nurses are still not well understood. Methods: We used high-performance liquid chromatography and tandem mass spectrometry to analyze phthalates. Anthropometric measurements and questionnaires were conducted. Results: We observed associations between mono-benzyl phthalate (MBzP) and body mass index (BMI), hip circumference (HC), waist circumference (WC), waist to height ratio (WHtR), and fat mass index (FMI), visceral fat content, BMI risk and hip index risk (HIrisk), adjusted to consumer behavior and consumer practices (r = 0.36–0.61; p ≤ 0.046). In the same model, we detected an association between mono-n-butyl phthalate (MnBP) and waist to hip ratio (WHR; r = 0.36; p = 0.046), mono-carboxy-isononyl phthalate (cx-MiNP) and BMI (r = 0.37; p = 0.043), HC (r = 0.4; p = 0.026) and WHtR (r = 0.38; p = 0.037), between mono-oxo-isononyl phthalate oxo (MiNP) and HC (r = 0.36; p = 0.045), mono-2-ethylhexyl phthalate (MEHP), mono(2-ethyl-5-oxohexyl) phthalate (oxo-MEHP) and HIrisk (r = 0.38–0.41; p ≤ 0.036), between oxo-MEHP and Anthropometric Risk Index (ARI risk; r = 0.4; p = 0.028). We detected a relationship between BMI and MBzP (β = 0.655; p < 0.001) and mono-2-ethylhexyl phthalate (MEHP; β = −0.365; p = 0.003), between hip circumference and MBzP (β = 0.486; p < 0.001), MEHP (β = −0.402; p = 0.001), and sum of secondary metabolites of diisononyl phthalate (∑DiNP; β = 0.307; p = 0.016). We observed a relationship between fat content and MBzP (β = 0.302; p = 0.033), OH-MnBP (β = −0.736; p = 0.006) and MiBP (β = 0.547; p = 0.046), visceral fat content and MBzP (β = 0.307; p = 0.030), HI-risk and MBzP (β = 0.444; p = 0.001), ARI-risk and sum of di-n-butyl phthalate metabolites (∑DnBP; β = 0.337; p = 0.018). We observed an association between the use of protective equipment with cx-MiNP. Conclusions: Occupational exposure to phthalates may induce abdominal obesity and result in obesity-related metabolic disorders.

Lag associations of gestational phthalate exposure with maternal serum vitamin D levels: Repeated measure analysis

Few studies have investigated the relationships between gestational phthalate exposure and maternal circulating vitamin D. In the Ma'anshan birth cohort, 3265 pregnant women were included. Each woman provided up to three urine and serum samples for measurement of phthalates and 25(OH)D and calcium, respectively. Linear mixed models were performed to analyse the association between phthalate metabolites and 25(OH)D and calcium. Stratified analyses of the relationship between phthalates and 25(OH)D by urine collection season were conducted. Finally, the post hoc lag effect of phthalate exposure on 25(OH)D was determined if longitudinal associations were significant. Some phthalate metabolites were associated with increased 25(OH)D but with decreased calcium. Furthermore, the relationship of phthalate exposure with 25(OH)D varied with urine collection season. Phthalate metabolites collected in summer and autumn were associated with an increase in 25(OH)D, while monobenzyl phthalate collected in winter and spring was inversely associated with 25(OH)D. Finally, high-molecular-weight phthalates had lag associations with 25(OH)D with a 1-trimester lag period. Low-molecular-weight phthalates exhibited lag associations with 25(OH)D with a 2-trimester lag period. In conclusion, the positive cross-sectional correlation between phthalate metabolites and 25(OH)D was partly affected by urine collection season. This study suggested that gestational phthalate exposure would have a lag association with maternal 25(OH)D levels.

Urinary Phthalate Biomarkers during Pregnancy, and Maternal Endocrine Parameters in Association with Anthropometric Parameters of Newborns.

Adverse birth outcomes present risk factors resulting in neonatal morbidity and mortality. Sufficient maternal hormonal concentrations are crucial for normal foetal development. Previous studies have shown a relationship between phthalate exposure and maternal hormonal levels during pregnancy. This study aims to investigate if neonatal anthropometric parameters are associated with maternal endocrine parameters during the ≤15th week of gestation and the third trimester of pregnancy concerning phthalate exposure in pregnant women from Nitra, Slovakia. We used high-performance liquid chromatography, tandem mass spectrometry (HPLC-MS/MS), and electro-chemiluminescence immunoassay to quantify urinary concentrations of phthalates and serum concentrations of hormones and sex hormone-binding globulin (SHBG), respectively. We observed a mostly positive correlation between neonatal anthropometric parameters (gestational age, birth length, birth weight, head circumference) and maternal concentration of phthalate metabolites (p ≤ 0.05). The hierarchical multivariate regression results showed a statistically significant association between Apgar score at 5 min after delivery, gestational age, birth weight, head circumference, and maternal endocrine parameters during pregnancy (p ≤ 0.05), adjusted to phthalate metabolites. To the best of our knowledge, our study is the first to indicate that prenatal exposure to phthalates may also affect birth outcomes through interaction with the maternal endocrine system.

Risk of Nonalcoholic Fatty Liver Disease Is Associated with Urinary Phthalate Metabolites Levels in Adults with Subclinical Hypothyroidism: Korean National Environmental Health Survey (KoNEHS) 2012-2014.

Nonalcoholic fatty liver disease (NAFLD) is a condition of excess accumulation of fats in the liver. Thyroid dysfunction is commonly observed in adult populations with NAFLD. In subjects with thyroid dysfunction, phthalates, which are chemical compounds widely used to increase the flexibility of various plastic products, may increase the risk of NAFLD prevalence. Therefore, our study aimed to evaluate the relationship between the levels of urinary phthalate metabolites and the risk of NAFLD stratified by the levels of thyroid-stimulating hormone (TSH). Data (n = 2308) were obtained from the Korean National Environmental Health Survey II (2012–2014). Using the hepatic steatosis index, participants were classified into non-NAFLD (<30) and NAFLD (>36) groups. Participants with euthyroidism were defined as 0.45–4.5 mIU/L for serum TSH and normal thyroxine (T4) levels (n = 2125). Subclinical hypothyroidism (SCH) was defined as a higher TSH level (4.5–10 mIU/L) with normal total T4 levels in the serum (n = 183). A multivariate analysis was performed to assess the association of the urinary phthalate concentration with the risk of NAFLD after stratification based on the thyroid hormone levels. The levels of phthalate metabolites in urine were not significantly associated with NAFLD in adults with euthyroidism. However, a significant increased risk of NAFLD in those with SCH was observed in the fourth quartile of mono (2-ethyl-5-hydroxyhexyl) phthalate (odds ratio (OR) 13.59, 95% confidence interval (CI) 12.13–86.44), mono (2-ethyl-5-oxohexyl) phthalate (OR 8.55, 95% CI 1.20–60.53), mono-(2-ethyl-5-carboxypentyl) phthalate (OR 9.06, 95% CI 1.78–45.96), and mono-benzyl phthalate (OR 6.05, 95% CI 1.62–22.54) compared to those of the lowest quartile after being adjusted with covariates. In conclusion, the levels of phthalate metabolites in urine are positively associated with NAFLD in adults with SCH. More experimental studies are needed to clarify the risk of NAFLD caused by phthalate exposure in cases with poor thyroid function.

Low-level plasticizer exposure and all-cause and cardiovascular disease mortality in the general population

BackgroundPlasticizers, also called phthalates, are a group of chemicals widely used in daily life. A previous report showed no significant association between phthalate metabolite concentrations and mortality. We investigated the association of urinary phthalate levels and individual phthalate metabolite levels with all-cause and cardiovascular disease (CVD) mortality after standardizing the phthalate concentration.MethodsA total of 6,625 participants were recruited from a nationally representative sample of adults aged 40 years or older who were enrolled in the National Health and Nutrition Examination Survey (NHANES) between 2003 and 2014 and were followed up through December 31, 2015. Data were analyzed from January 2021 to June 2021. NHANES-linked updated National Death Index public access files were used to acquire information on mortality status and cause of death. The present study conducted extended follow-up of an earlier analysis. Cox proportional hazard models were performed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) of covariate-adjusted creatinine standardization urinary phthalate concentrations with all-cause and CVD mortality after adjusting for demographics, lifestyle factors and comorbidity variables.ResultsThe mean ± standard deviation age of all participants in the final study was 59.9±12.6 years old, and 49.6% of the participants were male. The median follow-up time was 73 months (range 1-157 months). At the censoring date of December 31, 2015, 3,023 participants were identified as deceased (13.4%). A fully adjusted Cox model showed that a urinary di(2-ethylhexyl) phthalate (DEHP) concentration >= 83.4 ng/mL was associated with a slight increase in all-cause mortality (HR 1.27, 95% CI 1.03, 1.57, P for trend= 0.014) and CVD mortality (HR 2.19, 95% CI 1.35, 3.54, P for trend= 0.002). Similarly, urinary mono-2-ethyl-5-carboxypentyl phthalate (MECPP) levels >= 39.2 ng/mL were associated with increased CVD mortality (HR 2.33, 95% CI 1.45, 3.73, P for trend < 0.001). Restricted cubic spline analyses suggested linear associations of DEHP and MECPP levels with all-cause and CVD mortality.ConclusionIn this large nationally representative sample of American adults, high urinary DEHP and MECPP were significantly associated with all-cause and CVD mortality after adjusting for demographics, lifestyle factors and comorbidity variables.

Urine Phthalate Levels and Liver Function in US Adolescents: Analyses of NHANES 2007-2016.

BackgroundPhthalates are non-persistent chemicals with endocrine-disrupting abilities widely used in a variety of consumer products. Evidence for the effects of phthalate exposure on liver function in adolescents is lacking.MethodsData were analyzed from the combined 2007–2016 National Health and Nutrition Examination Survey (NHANES). Ultimately, a total of 1,650 adolescents aged 12–19 years were selected as the samples. Weighted linear regression was used to investigate the effects of urinary phthalate metabolites on liver function indexes.ResultsWeighted Linear regression models showed that MCOP was negatively associated with TBIL (β = −0.0435, PFDR = 0.007), ΣDEHP (β = −0.0453, PFDR = 0.003) and MCOP (β = −0.0379, PFDR = 0.006) were negatively correlated with ALB, while MCPP was positively correlated with ALB (β = 0.0339, PFDR = 0.024), and MCOP was negatively correlated with TP (β = −0.0551; PFDR = 0.004).ConclusionsPhthalate metabolites were significantly but weakly associated with changes in liver function indicators among US adolescents. Future work should further examine these relationships.

Biomarkers of Exposure to Phthalate Mixtures and Adverse Birth Outcomes in a Puerto Rico Birth Cohort.

Background:Humans are exposed to complex mixtures of phthalate chemicals from a range of consumer products. Previous studies have reported significant associations between individual phthalate metabolites and pregnancy outcomes, but mixtures research is limited.Objectives:We used the Puerto Rico Testsite for Exploring Contamination Threats longitudinal pregnancy cohort to investigate associations between phthalate metabolite mixtures and pregnancy outcomes.Methods:Women ( carrying females, carrying males) provided up to three urine samples throughout gestation (median 18, 22, and 26 wk), which were analyzed for 13 phthalate metabolites. Pregnancy outcomes including preterm birth (PTB), spontaneous PTB, small and large for gestational age (SGA, LGA), birth weight z-score, and gestational age at delivery were abstracted from medical records. Environmental risk scores (ERS) were calculated as a weighted linear combination of the phthalates from ridge regression and adaptive elastic net, which are variable selection methods to handle correlated predictors. Birth outcomes were regressed on continuous ERS. We assessed gestational average and visit-specific ERS and stratified all analyses by fetal sex. Finally, we used Bayesian kernel machine regression (BKMR) to explore nonlinear associations and interactions between metabolites.Results:Differences in metabolite weights from ridge and elastic net were apparent between birth outcomes and between fetal sexes. An interquartile range increase in gestational average phthalate ERS was associated with increased odds of PTB [male ; 95% confidence interval (CI): 1.08, 2.27; female ; 95% CI: 1.23, 2.98], spontaneous PTB (male ; 95% CI: 1.46, 3.68; female ; 95% CI: 1.04, 3.82), and reduced gestational age at birth (male wk, 95% CI: , ; female wk, 95% CI: , ). Analyses by study visit suggested that exposure at wk (range 20–24 wk) was driving those associations. Bivariate plots from BKMR analysis revealed some nonlinear associations and metabolite interactions that were different between fetal sexes.Discussion:These results suggest that exposure to phthalate mixtures was associated with increased risk of early delivery and highlight the need to study mixtures by fetal sex. We also identified various metabolites displaying nonlinear relationships with measures of birth weight. https://doi.org/10.1289/EHP8990

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.

Phthalate exposure and risk of diabetes mellitus: Implications from a systematic review and meta-analysis.

Epidemiologic studies indicated that phthalate exposure might be associated with diabetes mellitus (DM). However, discrepancies existed. The link between phthalate exposure and risk of DM remained unclarified. We conducted a meta-analysis to explore the association between phthalate exposure and risk of DM. Effects of phthalate exposure on insulin resistance were also evaluated by systematic review. Seven studies involving 12,139 participants were included in this meta-analysis. Our results showed that urinary concentrations of phthalates were positively associated with risk of DM. The pooled ORs were 3.11 (95% CI: 1.16-8.37) for monomethyl phthalate (MMP), 1.27 (95% CI: 1.03-1.56) for mono-n-butyl phthalate (MnBP), 2.59 (95% CI: 1.10-6.10) for mono-isobutyl phthalate (MiBP), 1.99 (95% CI: 1.52-2.61) for mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), 1.90 (95% CI: 1.40-2.57) for mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), 1.55 (95% CI: 1.10-2.20) for mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), and 2.39 (95% CI: 1.18-4.85) for mono-(3-carboxypropyl) phthalate (MCPP), respectively. Molar summation of di-2-ethylhexyl phthalate metabolites (∑DEHP) was also found to be correlated with risk of DM (OR 2.15, 95% CI: 1.48-3.13). No significant association with risk of DM was found regarding monoethyl phthalate (MEP), monobenzyl phthalate (MBzP) and mono(2-ethylhexyl) phthalate (MEHP). In literature review, most studies showed positive correlations of phthalates, especially ∑DEHP, with homeostasis model assessment of insulin resistance and fasting glucose. Exposure to phthalates, especially MMP, MnBP, MiBP, MCPP and DEHP metabolites, might be a risk factor of DM. Our results should be interpreted with caution due to heterogeneous design of enrolled studies.

Prenatal exposure to phthalates and phenols and preclinical vascular health during early adolescence.

Exposure to endocrine-disrupting chemicals may increase cardiovascular risk from early life, but studies in children have shown inconsistent results, most focused on analysis of single chemicals, and none included measures of micro-vascularization as early preclinical markers. This study aimed to evaluate the association between prenatal exposure to phthalates and phenols and macro- and microvascular health during early adolescence. Using data from a Spanish birth cohort (n=416), prenatal exposure to eight phthalate metabolites and seven phenols (bisphenol A, four parabens, benzophenone-3, triclosan) were assessed using first and/or third trimester spot-urine concentrations. Macrovascular health (systolic and diastolic blood pressure (SBP and DBP, mmHg), pulse wave velocity (PWV, m/s)) and microvascular health (central retinal artery/vein equivalent (CRAE/CRVE, μm)), were measured at 11 years old. Linear regression models assessed associations for individual chemicals and Bayesian weighted quantile sum regression (BWQS) evaluated the overall association of the phthalate and phenol mixture with cardiovascular health. In single exposure models, bisphenol-A was associated with decreased PWV (β per doubling of exposure=-0.06; 95% CI: -0.10, -0.01). Mono-iso-butyl phthalate was associated with an increase in CRAE (β=1.89; 95% CI: 0.34, 3.44). Methyl- and butyl-parabens were associated with a decrease in CRVE (β=-0.71; 95% CI: -1.41, -0.01) and (β=-0.96; 95% CI: -1.57, -0.35), respectively. No statistically significant associations were observed between any of the exposures and SBP or DBP. BWQS models showed no evidence of associations between the phthalate and phenol mixture and any of the outcomes. Our results provide little evidence to suggest that prenatal exposure to phthalates and phenols is associated with macro- or microvascular health during early adolescence, except a few associations with certain compounds. Errors in exposure measurement and reduced variability in cardiovascular measures at this early age limit our ability to draw strong conclusions.

Dietary correlates of urinary phthalate metabolite concentrations in 6-19 Year old children and adolescents.

Children are vulnerable to adverse health effects associated with phthalates, and food is one source of exposure. A comprehensive analysis investigating urinary phthalate metabolite concentrations in relation to 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 metabolites in children in a large US study. We used data from 2369 participants 6-19 years old from the 2011-2016 National Health and Nutrition Examination Survey who recalled their diet over the 24h prior to urine collection. We used dietary data to estimate intake and source (i.e., prepared at a restaurant vs. purchased from a grocery store) of 136 food groups. We used reduced rank regression to identify dietary patterns explaining variation in overall urinary concentrations of ∑di-2-ethylhexyl phthalate and seven phthalate metabolites. We also examined pairwise associations between food groups and urinary phthalate metabolites. We identified eight dietary patterns that cumulatively explained 12.1% of variation in urinary phthalate metabolites, including a dietary pattern characterized by certain starchy vegetables (e.g., plantains and lima beans), quick breads, and citrus juice prepared at a restaurant. A one SD increase in this food pattern score was associated with a 37.2% higher monocarboxyoctyl phthalate (MCOP) concentration (95% CI: 30.3, 44.4). We also observed weak associations between certain food groups and urinary phthalate metabolites (e.g., a one SD increase in intake of certain starchy vegetables prepared at a restaurant was associated with a 1.8% [95% CI: 0.7, 2.8] higher MCOP). Children whose diets were characterized by higher consumption of certain starchy vegetables, quick breads, and citrus juices prepared at a restaurant had higher urinary phthalate metabolites. More detailed information on the specific methods of food processing and details on packaging materials is needed.

Urinary phthalate and DINCH metabolite concentrations and gradations of maternal glucose intolerance.

Studies suggest a link between pregnancy phthalate exposures and gestational diabetes mellitus (GDM). Few studies have evaluated associations between phthalate biomarkers (individual or mixtures) with gradations of maternal glucose intolerance. In a subset of 606 women participating in LIFECODES pregnancy cohort, a combination of 50-gram 1-h non-fasting glucose load test (GLT) and 100-gram 3-h fasting oral glucose tolerance test was used to determine pregnancy glycemic status (median: 27weeks gestation): normoglycemia (n=136), impaired glucose tolerance (IGT) (n=296), and GDM (n=174). Nineteen metabolites of phthalates and their replacements were measured during each trimester. We used multivariable logistic regression models to evaluate associations between biomarkers (in quartiles) and maternal glycemic status (GDM v. normoglycemia and IGT v. normoglycemia), adjusting for potential confounders. We also used principal component analysis to evaluate associations jointly accounting for metabolites as chemical mixtures. Higher 1st trimester mono-3-carboxypropyl phthalate (MCPP) was associated with decreased odds of GDM (Q4 v. Q1: 0.30; 95% CI: 0.13, 0.67) and IGT (Q4 v. Q1 OR: 0.37; 95% CI: 0.17, 0.79). Higher 2nd trimester mono-isobutyl phthalate (MiBP) was associated with increased IGT (Q4 v. Q1 OR: 2.07; 95% CI: 1.06, 4.07), and 2nd trimester mono-3-hydroxybutyl phthalate (MHBP) was non-monotonically associated with increased GDM (Q2 v. Q1 OR: 3.21; 95% CI: 1.54, 6.87). Mixture analyses showed similar associations (Q4 v. Q1 for 2nd trimester dibutyl phthalates metabotlites mixtures OR: 2.08; 95% CI: 1.04, 4.22). Some phthalate biomarkershad trimester-specific associations with glycemic outcomes, with long and short term health implications.

Midlife Urinary Phthalate Metabolite Concentrations and Prior Uterine Fibroid Diagnosis.

Fibroid etiology is poorly understood but is likely hormonally mediated. Therefore, we evaluated associations between midlife phthalates (hormone-altering chemicals) and prior fibroid diagnosis, and considered differences by weight gain status. Women (ages: 45–54; n = 754) self-reported past fibroid diagnosis. We pooled 1–4 urines collected after fibroid diagnosis over the consecutive weeks to analyze nine phthalate metabolites and calculate relevant molar sums (e.g., di(2-ethylhexyl) phthalate, ΣDEHP; anti-androgenic phthalates, ΣAA; all metabolites, ΣPhthalates). Using Poisson regression, we evaluated associations between phthalate biomarkers and the risk of having fibroid diagnosis. We explored if associations differed by weight gain from age 18 to 45–54 or in women diagnosed with fibroids within 5 years of phthalate assessment. Our major finding was that women had a 13% (RR: 1.13; 95%CI: 1.02, 1.26) and 16% (RR: 1.16; 95% CI: 1.03, 1.31) greater risk of prior fibroid diagnosis for each two-fold increase in ΣDEHP or ΣAA, respectively. These associations were strongest in women who became overweight/obese from age 18 to 45–54 and in those diagnosed <5 years before phthalate assessment. Based on these results, prospective studies should corroborate our findings related to associations between phthalates and fibroids, and may consider evaluating the role that weight gain may play in these associations.

Identification and Quantification of Phthalates in Drinking, River and Lake Water using Solid phase extraction followed by UHPLC-MS

Phthalates are endocrine disruptive compounds that are commonly employed in everyday consumer items. Anti-androgenic action is the possible negative consequences are associated with phthalates and hence there is growing worry regarding human exposure to phthalates. It is critical to have a validated analytical approach that can measure trace quantities of phthalate metabolites in drinking water when investigating environmental exposure to phthalates. In this investigation, we developed and validated an accurate, sensitive and robust LC–MS technique to concurrently detect six phthalates in drinking water samples: dimethyl (DMP), diethyl (DEP), dipentyl (DPrP), diisobutyl (DIBP), dibutyl (DBP) and dioctyl (DOP). These analytes were quantified by using LC– MS system with electrospray ionization. The validated approach has been utilised effectively in measuring phthalate exposure in drinking water samples and water samples collected at various locations. Packaged drinking water samples separated into two groups, room temperature samples (15 days, 30 days, 60 days, 120 days, 150 days and 180 days) and heated samples at 50 oC with similar interval samples.

Monitoring Phthalates in Maternal and Cord Blood: Implications for Prenatal Exposure and Birth Outcomes.

Although many phthalates are endocrine-disrupting chemicals that are associated with adverse birth outcomes, the relationship between maternal phthalate exposure and birth outcomes is not yet conclusive. The objective of the present study was to investigate the association between prenatal exposure to phthalates in human maternal and cord blood and birth outcomes of the infants. Sixty-five mother-infant pairs were recruited in Taipei City and New Taipei City, and birth outcomes of the infants were recorded. Twelve phthalate metabolites were measured in maternal and cord blood samples. The mean of mono-ethyl phthalate, mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), and mono-(2-ethylhexyl) phthalate (MEHP) was relatively higher than that of the other metabolites in both maternal and infant blood. There was a significant difference (p < 0.05) for mono-methyl phthalate (MMP) and MnBP between the maternal blood and cord blood of male infants. Mono-benzyl phthalate (MBzP), MMP, MiBP, and ∑di-2-ethylhexyl phthalate (∑DEHP) in maternal blood were inversely correlated with the anogenital index (AGI) of male infants, with a p value between 0.011 and 0.033. Mono-n-octyl phthalate, MMP, MiBP, MnBP, and MBzP were positively correlated with the AGI of female infants, with a p value between 0.001 and 0.034. Cord blood levels of MnBP, mono-(2-ethyl-5-oxohexyl)-phthalate, MEHP, and ∑DEHP were found to be inversely associated with head circumference in all the infants, adjusted for gestational age. Phthalate monoesters are potentially estrogenic and antiandrogenic chemicals. Longitudinal follow-up of the present study population could help clarify the long-term impact of phthalates on growth and the health effects of background exposure levels. Environ Toxicol Chem 2022;41:715-725. © 2022 SETAC.

Association between recurrent breast cancer and phthalate exposure modified by hormone receptors and body mass index

The association between phthalate exposure and breast cancer remains controversial. We performed a prospective patient cohort design to explore the interaction between creatinine-corrected urinary phthalate metabolites and hormone receptors as well as body mass index (BMI) on recurrent breast cancer. In this follow-up study, 636 female breast cancer patients and 45 new recurrent cases diagnosed for a total of 1576.68 person-years of follow-up were recruited. Mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively associated with breast cancer recurrence, with adjusted hazard ratio (aHR) 3rd vs. 1st quartile of 0.15 (95% CI 0.04–0.51). The MEOHP presented as a non-monotonic dose–response (NMDR) curve, being U-shaped. In the stratification of hormone receptors, MEOHP still exhibited a U-shaped dose–response curve. The third quartile of MEOHP showed significant lowest recurrent risk in the status of ER-positive (aHR 0.18, 95% CI 0.05–0.66), PR-negative (aHR 0.14, 95% CI 0.03–0.63), and HER2-negative (aHR 0.24, 95% CI 0.08–0.76). Whether in BMI < 25 or in BMI ≥ 25, the third quartile of MEOHP was negatively associated with recurrent breast cancer, and there was a negative interaction on an additive scale between MEOHP and BMI (pinteraction = 0.042). The association between MEOHP and recurrent breast cancer was modified by hormone receptors and BMI.