High Molecular Weight Phthalates Research Articles

Phthalate and phthalate replacement concentrations in relationship to adiposity in a multi-racial cohort of children.

Phthalates and phthalate replacements are used in multiple everyday products, making many of them bioavailable to children. Experimental studies suggest that phthalates and their replacements may be obesogenic, however, epidemiologic studies remain inconsistent. Therefore, our objective was to examine the association between phthalates, phthalate replacements and childhood adiposity/obesity markers in children. A cross-sectional study was conducted in 630 racial/ethnically diverse children ages 4-8 years. Urinary oxidative metabolites of DINCH and DEHTP, three low molecular weight (LMW) phthalates, and eleven high molecular weight (HMW) phthalates were measured. Weight, height, waist circumference and % body fat were measured. Composite molar sum groups (nmol/ml) were natural log-transformed. Linear regression models adjusted for urine specific gravity, sex, age, race-ethnicity, birthweight, breastfeeding, reported activity level, mother's education and pre-pregnancy BMI. All children had LMW and HMW phthalate metabolites and 88% had DINCH levels above the limit of detection. One unit higher in the log of DINCH was associated with 0.106 units lower BMI z-score [β = -0.106 (95% CI: -0.181, -0.031)], 0.119 units lower waist circumference z-score [β = -0.119 (95% CI: -0.189, -0.050)], and 0.012 units lower percent body fat [β = -0.012 (95% CI: -0.019, -0.005)]. LMW and HMW group values were not associated with adiposity/obesity. We report an inverse association between child urinary DINCH levels, a non-phthalate plasticizer that has replaced DEHP in several applications, and BMI z-score, waist circumference z-score and % body fat in children. Few prior studies of phthalates and their replacements in children have been conducted in diverse populations. Moreover, DINCH has not received a great deal of attention or regulation, but it is a common exposure. In summary, understanding the ubiquitous nature of these chemical exposures and ultimately their sources will contribute to our understanding of their relationship with obesity.

Serum Phthalate Concentrations and Biomarkers of Oxidative Stress in Adipose Tissue in a Spanish Adult Cohort.

The relationship between phthalates, a group of chemical pollutants classified as endocrine disruptors, and oxidative stress is not fully understood. The aim of the present hospital-based study was to explore the associations between circulating levels of 10 phthalate metabolites and 8 biomarkers of oxidative stress in adipose tissue. The study population (n = 143) was recruited in two hospitals in the province of Granada (Spain). Phthalate metabolite concentrations were analyzed by isotope diluted online-TurboFlow-LC-MS/MS in serum samples, while oxidative stress markers were measured by commercially available kits in adipose tissue collected during routine surgery. Statistical analyses were performed by MM estimators' robust linear regression and weighted quantile sum regression. Mainly, positive associations were observed of monomethyl phthalate (MMP), monoiso-butyl phthalate (MiBP), and mono-n-butyl phthalate (MnBP) (all low molecular weight phthalates) with glutathione peroxidase (GPx) and thiobarbituric acid reactive substances (TBARS), while an inverse association was found between monoiso-nonyl phthalate (MiNP) (high molecular weight phthalate) and the same biomarkers. WQS analyses showed significant effects of the phthalate mixture on GSH (β = -30.089; p-value = 0.025) and GSSG levels (β = -19.591; p-value = 0.030). Despite the limitations inherent to the cross-sectional design, our novel study underlines the potential influence of phthalate exposure on redox homeostasis, which warrants confirmation in further research.

Assessment of phthalic acid esters plasticizers in sediments of coastal Alabama, USA: Occurrence, source, and ecological risk

Considering the ubiquitous occurrences and ecotoxicity of phthalates (PAEs), it is essential to understand their sources, distribution, and associated ecological risks of PAEs in sediments to assess the environmental health of estuaries and support effective management practices. This study provides the first comprehensive dataset on the occurrence, spatial variation, inventory, and potential ecological risk assessment of PAEs in surface sediments of commercially and ecologically significant estuaries in the southeastern United States, Mobile Bay and adjoining eastern Mississippi Sound. Fifteen PAEs were widely detected in the sediments of the study region, with total concentrations varying between 0.02 and 3.37 μg/g. The dominance of low-molecular-weight (LMW) PAEs (DEP, DBP and DiBP) relative to high-molecular-weight (HMW) PAEs (DEHP, DOP, DNP) indicates that residential activities have stronger impacts than industrial activities on PAE distributions. The total PAE concentrations displayed an overall decreasing trend with increasing bottom water salinity, with the maximum concentrations occurring near river mouths. These observations suggest that river inputs were an important pathway by which PAEs were transported to the estuary. Linear regression models identified sediment adsorption (measured by total organic carbon and median grain size) and riverine inputs (measured by bottom water salinity) as significant predictors for the concentrations of LMW and HMW PAEs. Estimated 5-year total inventories of sedimentary PAEs in Mobile Bay and the eastern Mississippi Sound were 13.82 tons and 1.16 tons, respectively. Risk assessment calculations suggest that LMW PAEs posed a medium-to-high risk to sensitive aquatic organisms, and DEHP posed a low or negligible risk to the aquatic organisms. The results of this study provide important information needed for establishing and implementing effective practices for monitoring and regulating plasticizer pollutants in estuaries.

Biodegradation of low, medium and high molecular weight phthalate by Gordonia sp. in a batch system: Kinetics and phytotoxicity analyses

ABSTRACTPhthalic acid esters (PAEs) are highly toxic compounds and can disrupt the hormonal balance of human, animal, and aquatic organisms. Due to the hazardous nature of such compounds, their removal from constituent wastewater before discharging into the environment is mandatory. This study focused on the biodegradation of dimethyl phthalates (DMP), di-n-butyl phthalates (DBP), and di-n-octyl phthalates (DnOP) by Gordonia sp. in a batch system. Initially, five different concentrations of DBP, DMP, and DnOP (200–1000 mg/L) were chosen individually as the sole carbon source to examine their effect on the biodegradation and biomass growth of Gordonia sp. Complete degradation of DBP and DMP was achieved up to 1000 mg/L initial concentration within 96 h, whereas in case of DnOP, the degradation value was only 83.5% at 120 h for the same initial concentration. The experimental data were fitted into various substrate inhibition kinetic models, and accurate predicted values of degradation of all the three PAEs were obtained using the Tiesser model in comparison with other models, which yielded the highest and lowest R2 and SSE values of 0.99 and 0.02 × 10−4, respectively. In addition, the phytotoxicity of PAEs degraded samples was assessed and more than 50% germination index value was observed for DMP and DBP degraded sample which established the treatment efficiency of Gordonia sp. in degrading DMP and DBP. Hence, high DMP and DEP degradation and phytotoxicity removal efficiency of Gordonia sp. demonstrate its potential for the treatment of PAEs contaminated wastewater.

Urine phthalate levels were associated with skin barrier dysfunction and atopic sensitization in children.

Phthalates can cause immunological disorders and aggravate allergic diseases. Thus, we investigated the relationship between urinary phthalate, skin barrier function, and atopic sensitization in children. In total, 448 school children [334 with severe allergic disease; and 123 with severe atopic dermatitis (AD)] aged 10-12 years were enrolled in this study between June and July 2017. Four high-molecular-weight phthalates (HMWP) [Σ4HMWP] and three low-molecular-weight phthalates (LMWP) [Σ3LMWP] metabolites in urine samples, specific immunoglobulin E (IgE), and total eosinophil count were measured. Four-part trans epidermal water loss (TEWL) (cheek, leg, and upper/lower arm; Σ4TEWL) was measured to evaluate the skin barrier function. After adjusting for confounding variables, Σ4TEWL was significantly associated with the quartiles of urinary Σ4HMWP [adjusted β=7.897, 95% confidence interval (CI): 0.636-15.158, p=0.033] and Σ3LMWP (adjusted β=9.670, 95% CI: 2.422-16.919, p=0.009). The adjusted analyses revealed that the quartiles of urinary Σ4HMWP and Σ3LMWP were not significantly associated with total eosinophil count, atopic sensitization, and severe AD (p>0.05). According to the quartiles of urinary Σ4HMWP and Σ3LMWP, there were significant differences in the TEWL of the lower arm and leg (p<0.05) but not in cheek and upper arm. Exposure to HMWPs and LMWPs was significantly associated with skin barrier dysfunction but not with atopic sensitization. These results suggest that children exposed to phthalates may be more susceptible to fragile skin barrier function.

Refinement and calibration of a human PBPK model for the plasticiser, Di-(2-propylheptyl) phthalate (DPHP) using in silico, in vitro and human biomonitoring data.

An existing physiologically based pharmacokinetic model for Di-(2-propylheptyl) phthalate (DPHP) was refined to improve the simulations of the venous blood concentrations of the primary monoester metabolite, mono-(2-propylheptyl) phthalate (MPHP). This was considered a significant deficiency that should be addressed because the primary metabolite of other high molecular weight phthalates has been associated with toxicity. The various processes that influence the concentration of DPHP and MPHP in blood were re-evaluated and modified. A few simplifications of the existing model were made, including the removal of enterohepatic recirculation (EHR) of MPHP. However, the primary development was describing the partial binding of MPHP to plasma proteins following uptake of DPHP and metabolism in the gut affording better simulation of the trends observed in the biological monitoring data. Secondly, the relationship between blood concentrations and the urinary excretion of secondary metabolites was explored further because the availability of two data streams provides a better understanding of the kinetics than reliance on just one. Most human studies are conducted with few volunteers and generally with the absence of blood metabolite measurements which would likely imply an incomplete understanding of the kinetics. This has important implications for the "read across" approach proposed as part of the development of New Approach Methods for the replacement of animals in chemical safety assessments. This is where the endpoint of a target chemical is predicted by using data for the same endpoint from another more "data rich" source chemical. Validation of a model parameterized entirely with in vitro and in silico derived parameters and calibrated against several data streams would constitute a data rich source chemical and afford more confidence for future evaluations of other similar chemicals using the read-across approach.

Associations of phthalates with prostate cancer among the US population

Human exposure to harmful phthalates has raised global health concerns. According to cellular and molecular investigations, phthalates and their metabolites can promote prostate cancer (PCa). Despite being a prevalent cancer afflicting the global male population, the epidemiological association between phthalates and prostate cancer remains understudied. This work aims to investigate whether phthalate metabolites are related to prostate cancer. Moreover, we sought to understand whether their elevated concentrations are associated with increased serum concentrations of prostate-specific antigen (PSA), among non-prostate cancer interviewees. According to National Health and Nutrition Examination Survey (NHANES) data from 2003 to 2010, we screened eligible men aged 20 years or older. Then, crude and multivariate regression models were constructed to assess the relationship. The phthalates significantly related to PCa were analyzed based on variables associated with PCa status and PSA. The molar sum ∑di-2-ethylhexyl phthalate (∑DEHP) was simultaneously associated with increased risk of PCa and increasing PSA concentrations. Among PCa-related phthalates, high molecular weight phthalate metabolites included mono-benzyl phthalate (MBzP) and three metabolites of DEHP. In summary, phthalates are potentially associated with prostate tumorigenesis in the US population. However, additional in-depth prospective studies in different ethnic groups are required to validate the causality between both.

Association between urinary phthalate metabolites and hyperuricemia in US adults.

Phthalate metabolites have been detected from urine in most of the US population and have become a public health problem. However, the association between phthalate metabolites and hyperuricemia has been scarcely studied so far. We aimed to evaluate if phthalate metabolites were associated with hyperuricemia in US adults. A total of 8816 participants of the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018 were included in our study. We used multivariable logistic regression models and restricted cubic spline (RCS) models to explore the association between urinary phthalate metabolites and hyperuricemia. Then, stratified analyses were conducted by sex and age. The prevalence of hyperuricemia in the study sample was 20.35%. Compared to the lowest quantile, the odds ratios (ORs) and 95% confidence intervals (CIs) for hyperuricemia were all statistically significant in following phthalate metabolites: 1.34 (1.13-1.58) for the second quartile in Mono-isobutyl phthalate (MiBP), 1.21 (1.01-1.46) for the highest quartile in Mono-(carboxyoctyl) phthalate (MCOP), 0.66 (0.56-0.76) for the second quartile in Mono-(2-ethyl)-hexyl phthalate (MEHP), 1.22 (1.05-1.43) for quartile 2 in Benzyl butyl phthalate (ΣBBP), and 1.43 (1.22-1.66) for the third quartile in high molecular-weight phthalate (ΣHigh MWP), respectively. Our results indicate that several urinary phthalate metabolites are positively associated with the odds of hyperuricemia.

Consequences of in vitro benzyl butyl phthalate exposure for blubber gene expression and insulin-induced Akt activation in juvenile grey seals

Plastic and plasticiser pollution of marine environments is a growing concern. Although phthalates, one group of plasticisers, are rapidly metabolised by mammals, they are found ubiquitously in humans and have been linked with metabolic disorders and altered adipose function. Phthalates may also present a threat to marine mammals, which need to rapidly accumulate and mobilise their large fat depots. High molecular weight (HMW) phthalates may be most problematic because they can accumulate in adipose. We used blubber explants from juvenile grey seals to examine the effects of overnight exposure to the HMW, adipogenic phthalate, benzyl butyl phthalate (BBzP) on expression of key adipose-specific genes and on phosphorylation of Akt in response to insulin. We found substantial differences in transcript abundance of Pparγ, Insig2, Fasn, Scd, Adipoq and Lep between moult stages, when animals were also experiencing differing mass changes, and between tissue depths, which likely reflect differences in blubber function. Akt abundance was higher in inner compared to outer blubber, consistent with greater metabolic activity in adipose closer to muscle than skin, and its phosphorylation was stimulated by insulin. Transcript abundance of Pparγ and Fasn (and Adipoq in some animals) were increased by short term (30 min) insulin exposure. In addition, overnight in vitro BBzP exposure altered insulin-induced changes in Pparγ (and Adipoq in some animals) transcript abundance, in a tissue depth and moult stage-specific manner. Basal or insulin-induced Akt phosphorylation was not changed. BBzP thus acted rapidly on the transcript abundance of key adipose genes in an Akt-independent manner. Our data suggest phthalate exposure could alter seal blubber development or function, although the whole animal consequences of these changes are not yet understood. Knowledge of typical phthalate exposures and toxicokinetics would help to contextualise these findings in terms of phthalate-induced metabolic disruption risk and consequences for marine mammal health.

Effects of Prenatal Phthalate Exposure on Early Childhood Expressive Language Development Trajectories

BACKGROUND AND AIM: Phthalates are common endocrine disruptors that can impair neurodevelopment. We investigated potential links between prenatal exposure to phthalates and child language development trajectories given prior inconsistent evidence across individual phthalates. METHODS: We investigated fourteen urinary phthalate metabolites, measured in maternal urine during pregnancy, and child expressive language scores from the Mullen Scales of Early Learning (MSEL) at 6, 12, 24, and 36 months in 231 children from an enhanced autism-risk cohort (19% with autism): Early Autism Risk Longitudinal Investigation (EARLI), born 2009 - 2013 from California, Maryland, and Pennsylvania. We used multiple imputation to handle missingness in MSEL (~37%) and phthalates (~9%), and assigned children to six distinct expressive language trajectories after selecting the latent class growth analysis model with best goodness-of-fit measures. We estimated relative risk ratios (RRR) of being in different language trajectories (&amp;#x22;high growth” as reference) associated with two-fold change in creatinine adjusted phthalates using multinomial logistic regression with Firth correction, adjusting for child sex, birth season, income, and maternal age, race, and education. RESULTS: Some low molecular weight phthalates were associated with sub-optimal language trajectories, e.g. RRRs of 1.33 or higher for mono-2-hydroxy-iso-butyl phthalate, peaking at 1.51 (1.02, 2.24) for the delayed growth low trajectory. In contrast, some high molecular weight phthalates exhibited protective effects for delayed growth trajectories but adverse effects for plateau and tracking trajectories: e.g. mono-isononyl phthalate with RRR 0.72 (0.59, 0.89) with delayed growth low but 1.29 (1.08, 1.53) with the tracking low trajectory. Some phthalates exhibited null patterns. CONCLUSIONS: Prenatal phthalate exposure may impact the trajectory of expressive language development in early childhood, with differences by individual phthalates, perhaps by molecular weight group. We observed adverse and protective influences of phthalates that may be influenced by small numbers in each trajectory class. KEYWORDS: phthalates, language development, trajectory analysis

Diisononyl phthalate inhibits cardiac glycolysis and oxidative phosphorylation by down-regulating cytosolic and mitochondrial energy metabolizing enzymes in murine model

The recent increase of diisononyl phthalate (DiNP) applications in a wide range of plastic consumer products, as well as its relative environmental exposure and interactions, has compelled an investigation of its toxicity. Phthalate exposure has been associated with heart dysfunction in animals in a few studies, the bulk of which are linked to the high molecular weight phthalates. The effect of DiNP on cardiac energy transduction was assessed utilizing cellular respiration enzymes as indices. Eighteen wistar rats were divided into 3 groups of six rats each: Group A received Tween-80 (control), DiNP (20 mg/kg/BW) was given to Group B, and 200mg/kg DiNP was given to Group C orally (gavage) for 14 days. The activity of cardiac glycolytic, oxidative phosphorylation enzymes and histopathological changes were assessed. The glycolytic and tricarboxylic acid cycle enzymes studied were predominantly down-regulated in a dose-dependent manner, with the exception of cardiac citrate synthase, which showed no significant variation in activity when compared to the control. Furthermore, all respiratory chain complexes (Complex I-IV) decreased significantly relative to control, with the exception of complex IV activity at 20mg/kg/BW which showed no significant difference (P<0.05). Cardiac histopathological alterations confirmed the aforementioned metabolic disturbances. Finally, DiNP exposure impairs cardiac energy transduction enzymes, implying cardiac cells produced insufficient energy (ATP) to carry out its morphological and physiological functions efficiently as the heart requires a constant supply of energy in the form of ATP to support contraction, relaxation, and prevent cardiomyopathies.

Prenatal single and combined exposure to phthalates associated with girls’ BMI trajectory in the first six years

Evidence of the influence of prenatal phthalate exposure on childhood longitudinal obesity markers is limited. Nested on the Ma’anshan birth cohort study, 990 mother-daughter pairs were included. Seven phthalate metabolites were determined in urine collected in each trimester. Each child underwent a physical examination from birth to 6 years of age twelve times. Latent class growth models were used to identify three trajectories of girls’ body mass index (BMI). Logistic regression, quantile g-computation and Bayesian kernel machine regression models analyzed the relationships of prenatal exposure to individual and mixed phthalates with girls’ body mass index (BMI) trajectory. Compared to the “lowest trajectory” class, prenatal average concentrations of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP, ORcrude = 2.095, 95 % CI = 1.014–4.328) and di(2-ethylhexyl) phthalate (DEHP, ORcrude = 2.336, 95 % CI = 1.022–5.338) during pregnancy were associated with an increased probability of being in the “highest trajectory” class. The average concentration of DEHP (ORcrude = 1.879, 95 % CI = 1.002–3.522) was associated with an increased probability of being in the “moderate trajectory” class. Stratified analyses by trimester of pregnancy mainly showed that third-trimester exposure to monoethyl phthalate (MEP, ORadjusted = 1.584, 95 % CI = 1.094–2.292), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP, ORadjusted = 2.885, 95 % CI = 1.367–6.088), MEHHP (ORadjusted = 2.425, 95 % CI = 1.335–4.407), DEHP (ORadjusted = 2.632, 95 % CI = 1.334–5.193) and high molecular weight phthalate (ORadjusted = 2.437, 95 % CI = 1.239–4.792) was associated with an increased probability of being in the “highest trajectory” class. However, the mixture of phthalates was not significantly related to the girl’s BMI trajectory. In conclusion, in utero exposure to phthalates, including MEP and DEHP metabolites (MEHHP and MEOHP), was significantly associated with early childhood high BMI trajectories in girls. The third trimester of pregnancy seemed to be the window of vulnerability to phthalate exposure for girls’ high BMI trajectory at periods of prenatal development. No evidence supported a significant relationship between combined exposure to phthalate metabolites and girls’ high BMI trajectory.

Personal care product use and lifestyle affect phthalate and DINCH metabolite levels in teenagers and young adults

Humans are widely exposed to phthalates and their novel substitutes, and considering the negative health effects associated with some phthalates, it is crucial to understand population levels and exposure determinants. This study is focused on 300 urine samples from teenagers (aged 12–17) and 300 from young adults (aged 18–37) living in Czechia collected in 2019 and 2020 to assess 17 plasticizer metabolites as biomarkers of exposure. We identified widespread phthalate exposure in the study population. The diethyl phthalate metabolite monoethyl phthalate (MEP) and three di (2-ethylhexyl) phthalate metabolites were detected in the urine of >99% of study participants. The highest median concentrations were found for metabolites of low-molecular-weight (LMW) phthalates: mono-n-butyl phthalate (MnBP), monoisobutyl phthalate (MiBP) and MEP (60.7; 52.6 and 17.6 μg/L in young adults). 1,2-cyclohexanedicarboxylic acid diisononyl ester (DINCH) metabolites were present in 68.2% of the samples with a median of 1.24 μg/L for both cohorts. Concentrations of MnBP and MiBP were similar to other European populations, but 5–6 times higher than in populations in North America. We also observed large variability in phthalate exposures within the study population, with 2–3 orders of magnitude differences in urinary metabolites between high and low exposed individuals. The concentrations varied with season, gender, age, and lifestyle factors. A relationship was found between high levels of MEP and high overall use of personal care products (PCPs). Cluster analysis suggested that phthalate exposures depend on season and multiple lifestyle factors, like time spent indoors and use of PCPs, which combine to lead to the observed widespread presence of phthalate metabolites in both study populations. Participants who spent more time indoors, particularly noticeably during colder months, had higher levels of high-molecular weight phthalate metabolites, whereas participants with higher PCP use, particularly women, tended to have higher concentration of LMW phthalate metabolites.

Phthalate exposure and DNA oxidative damage in young people of takeaway food lovers.

Numerous studies have demonstrated the ubiquitous of phthalates in materials of food and food packaging, and the effects of regular eating takeaway food for a long time on human health and phthalate exposure levels were not fully investigated. A total of 288 college students who love eating takeaway food were recruited to explore phthalate exposure and oxidative stress, by measuring metabolites of traditional or alternative phthalates and 8-hydroxydeoxyguanosine (8-OHdG, a biomarker of DNA oxidative damage) in their urine samples. Both traditional and alternative phthalates were highly detected. Based on weekly frequency of takeaway eating collecting from questionnaire, the students were divided into four groups including level 1 (L1, < 3 times), level 2 (L2, 3-7 times), level 3 (L3, 8-12 times) and level 4 (L4, > 12 times). The total concentrations of all phthalate metabolites were 42.5-893ng/mL in all students, which were significantly different among four groups, with the lowest level in L1 (p < 0.05). Checking with the generalized linear model (L1 as the reference), the concentrations of most phthalate metabolites increased 12.0-144% in L2 and L3 compared with those in L1. For each group increase, the concentrations of total metabolites, and metabolites of high and low molecular weight phthalates will increase by 0.156%, 0.128%, and 0.142%, respectively. Besides, levels of 8-OHdG (0.639-33.7ng/mL) were positively correlated with phthalate daily exposure doses. The each increase of a percentage unit of daily exposure of phthalates, the concentrations of 8-OHdG will increase by 0.258-0.405%. However, levels of 8-OHdG were not significantly different among the four groups. The alternative phthalates have already entered the body of Chinese young people. Our results indicated the regular consumption of takeaway food (e.g., more than three times per week) may increase the chance of exposure to certain phthalates, and may not significantly increase the levels of DNA oxidative damage, unless exposed to other pollutants such as phthalates.

Diverging trends of plasticizers (phthalates and non-phthalates) in indoor and freshwater environments—why?

BackgroundEuropean chemicals management aims to protect human health and the environment from legacy and emerging contaminants. The plasticizer market changed in response to the restriction of low molecular weight (LMW) phthalate plasticizers such as Di (2-ethylhexyl) phthalate (DEHP) due to their hazardous properties. We investigated patterns and trends of 19 regulated and emerging plasticizers in house dust from German homes and in suspended particulate matter (SPM) from major German rivers. The samples were used from the mid-2000s and late 2010s from two governmental long-term monitoring programs in Germany.ResultsWhile the sum of the respective plasticizer levels hardly changed over the study period, we observed a significant decrease of LMW phthalates in both house dust (2003/06, 80% of the ∑plasticizer concentration; 2014/17, 31%) and SPM (2005, 48%; 2017, 28%). This was accompanied by their substitution with high molecular weight (HMW) phthalates and non-phthalates. HMW phthalates increased from 19% of the ∑plasticizer concentration to 46% between the mid-2000s and the late 2010s in house dust, and from 50% to 63% in SPM samples. Diisononyl phthalate (DINP) replaced DEHP as the dominant plasticizer in both compartments. A significant tenfold increase (p < 0.05) was observed in SPM samples for Di (2-propylheptyl) phthalate (DPHP) (1–13%), compared to low levels in house dust (2014/17, 1%). Non-phthalates increased to 23% of the ∑plasticizer concentration in house dust but only to 9% in SPM (mid-2000s: house dust, < 1%; SPM, 1.5%). In recent house dust samples, Di (2-ethylhexyl) terephthalate (DEHT) had the third highest concentration of all plasticizers and contributed 18% to the total load, whereas Tris (2-ethylhexyl) trimellitate (TOTM) was one of the major non-phthalates in SPM samples.ConclusionsUnlike in the indoor environment, the substitution of LMW phthalates in the aquatic environment was characterized by a significant shift towards plasticizers with potentially hazardous properties. DPHP and TOTM were identified by European chemical regulation as potentially endocrine disrupting compounds and persistent, bioaccumulative and toxic compounds. Our data document the need for integrated chemicals management to safeguard the transition to a non-toxic environment.

Correlates of non-persistent endocrine disrupting chemical mixtures among reproductive-aged Black women in Detroit, Michigan

Some studies indicate that Black women have higher exposure to multiple non-persistent endocrine disrupting chemicals (EDCs) than white women, but little is known about correlates of exposure to EDC mixtures. Using baseline data from a prospective cohort study of reproductive-aged Black women (N = 751), we characterized profiles of EDC mixtures and identified correlates of exposure. At baseline, we quantified biomarkers of 16 phthalates, 7 phenols, 4 parabens, and triclocarban in urine and collected covariate data through self-administered questionnaires and interviews. We used principal component (PC) analysis and k-means clustering to describe EDC mixture profiles. Associations between correlates and PCs were estimated as the mean difference (β) in PC scores, while associations between correlates and cluster membership were estimated as the odds ratio (OR) of cluster membership. Personal care product use was consistently associated with profiles of higher biomarker concentrations of non-persistent EDCs. Use of nail polish, menstrual and vaginal products (e.g., vaginal powder, vaginal deodorant), and sunscreen was associated with a mixture of phthalate and some phenol biomarkers using both methods. Current vaginal ring use, a form of hormonal contraception placed inside the vagina, was strongly associated with higher concentrations of high molecular weight phthalate biomarkers (k-means clustering: OR = 2.42, 95% CI = 1.28, 4.59; PCA: β = −0.32, 95% CI = −0.71, 0.07). Several dietary, reproductive, and demographic correlates were also associated with mixtures of EDC biomarkers. These findings suggest that personal care product use, diet, and contraceptive use may be sources of exposure to multiple non-persistent EDCs among reproductive-aged Black women. Targeted interventions to reduce exposure to multiple EDCs among Black women are warranted.

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.

Health effects associated with phthalate activity on nuclear receptors.

Phthalates are endocrine disruptors, widely used as plasticizers to impart flexibility in plastics, and as solvents in personal care products. Due to their nearly ubiquitous use in consumer products, most humans are exposed to phthalates daily. There has been extensive research on the reproductive health effects associated with phthalate exposure, but less attention has been paid to other actions. This review aims to summarize the known action of phthalates on different nuclear receptors. Some phthalates bind to and activate the estrogen receptor, making them weakly estrogenic. However, other phthalates antagonize androgen receptors. Some high molecular weight phthalates antagonize thyroid receptors, affecting metabolism. Several phthalates activate and interfere with the normal function of different peroxisome proliferator-activated receptors (PPARs), receptors that have critical roles in lipid metabolism and energy homeostasis. Some phthalates activate the aryl hydrocarbon receptor, which is critical for xenobiotic metabolism. Although phthalates have a short half-life in vivo, because people are continuously exposed, studies should examine the health effects of phthalates associated with long-term exposure. There is limited research on the effects of phthalates on health outcomes aside from reproductive function, particularly concerning are childhood adiposity, behavior, and learning. There is also limited information on actions of phthalates not mediated via nuclear receptors. Humans are exposed to multiple chemicals simultaneously, and how chemical mixtures act on nuclear receptor activity needs study. Although we know a great deal about phthalates, there is still much that remains uncertain. Future studies need to further examine their other potential health effects.

Association between phthalate exposure and insulin resistance: a systematic review and meta-analysis update.

An update on systematic review and meta-analysis was performed to explore effects of phthalate exposure on insulin resistance. A systematic literature search was performed in MEDLINE, Web of Science, and CNKI until March 2021. A conceptual framework was constructed to guide the organization and presentation of results. Besides, beta coefficients with corresponding confidence intervals were extracted from the most adjusted models. Extracted beta coefficients were transformed into correlation, and z Fisher transformation of correlation with the corresponding standard error was included in meta-analysis. Subgroup analyses were performed by age (adult vs. adolescent) and sex (female vs. male) of participants and site of study (America and Europe vs. Asia) to explore potential sources of heterogeneity. Nineteen literatures with 12,533 participants reporting on the association of exposure to specific phthalates and insulin resistance were selected. The majority of included studies revealed positive relationships of insulin resistance with different phthalate metabolites exposure. Meta-analyses were performed on 16 studies. Exposure to MnBP, MBzP, MCPP, MEHP, MEOHP, MEHHP, ∑DEHP, and high-molecular weight phthalate (∑HMWP) was associated with the increase of the homeostasis model assessment of insulin resistance (HOMA-IR) index. The results of sensitivity analyses stratified by age, sex, and site of study remained stable, suggesting the robustness of these meta-analyses. Most of heterogeneity in sensitivity analyses decreased to moderate or low degree. Exposure to MnBP, MBzP, MCPP, MEHP, MEOHP, MEHHP, ∑DEHP, and ∑HMWP was associated with the increased risk of HOMA-IR. Age, sex, and site of study might provide limited source of heterogeneity.

Low and high molecular weight metabolite concentrations in relationship to adiposity in a multi-site, multi-racial cohort of children

BACKGROUND AND AIM: Low molecular weight (LMW) and high molecular weight (HMW) phthalates are used in multiple everyday products, many of which are bioavailable to children. Evidence concerning the effects of these phthalates on child adiposity remain inconsistent. METHODS: Analyses included 540 racial/ethnically diverse children ages 4-8 in the Environmental Influences on Child Health Outcomes (ECHO) study, a follow-up of the NICHD Fetal Growth Studies. Urinary oxidative metabolites of three LMW and eleven HMW phthalates were determined using liquid chromatography tandem-mass spectrometry. Values were divided by molecular weight and summed to obtain composite LMW and HMW group values (nmol/ml) and natural log transformed. Outcomes were child’s body mass index (BMI) z-score, waist circumference z-score, and percent body fat. Linear regression models were adjusted for urine specific gravity, gender, age, race/ethnicity, birth weight, prolonged exclusive breastfeeding, physical activity, fast-food consumption, smoke exposure, neighborhood traffic, mother’s education and pre-pregnancy BMI. RESULTS:All children had LMW and HMW phthalate group levels at or above the limit of detection. LMW levels were not associated with BMI z-score (β [95% CI]: 0.010 [-0.037. 0.057]), waist circumference z-score (β [95% CI]: -0.002 [-0.046, 0.042]) or percent body fat (β [95% CI]: -0.009 [-0.025, -0.007]). There was evidence of a possible interaction with race (p=0.09), with increased LMW levels in Black children being positively associated with percent body fat (β [95% CI]: 0.005 [0.001, 0.010]). HMW levels were not associated with BMI z-score (β [95% CI]: -0.003 [-0.084, 0.078]), waist circumference z-score (β [95% CI]: 0.021 [-0.055, 0.097]) or percent body fat (β [95% CI]: 0.0003 [-0.008, 0.008]). CONCLUSIONS:In this largely null cross-sectional analysis only LMW phthalates in Black children were associated with percent body fat. Additional research is needed to identify possible interactions between LMW phthalates, HMW phthalates and joint exposure to related chemicals. KEYWORDS: Phthalates, Obesity and metabolic disorders, Children's environmental health