Mono-(2-ethyl-5-hydroxyhexyl) Phthalate Research Articles

Phthalate Metabolites in Urine of Chinese Children and Their Association with Asthma and Allergic Symptoms.

Phthalates are ubiquitous 'modern' chemical compounds with potential negative impacts on children's health. A nested case-control study was designed to investigate associations of phthalate exposure with children's asthma and allergic symptoms. We collected 243 first morning urine samples from 4-8-year-old children in Tianjin, China. Eight metabolites (i.e., mono-ethyl phthalate (MEP), mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono-benzyl phthalate (MBzP) and mono-2-ethylhexyl phthalate (MEHP), mono-(2-ethyl-5-carboxylpentyl) phthalate (MECPP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP)) of five phthalates were analyzed using HPLC-MS. MiBP, MnBP and MECPP were the dominant phthalate metabolites in urine of children in Tianjin with median concentrations of 31.6 μg/L, 26.24 μg/L and 46.12 μg/L, respectively. We found significantly positive associations of diagnosed asthma with MnBP (adjusted odds ratios (AOR): 1.96; 95% confidence intervals (CIs): 1.07-3.61), MEHHP (AOR: 2.00; 95% CI: 1.08-3.71) and MEOHP (AOR: 2.09; 95% CI: 1.06-4.10). Our study indicates that phthalate exposure in childhood, especially to di-n-butyl phthalate (DnBP) and di(2-ethylhexyl) phthalate (DEHP), may be a risk factor for children's asthma.

Association between co-exposure to phenols and phthalates mixture and infertility risk in women

BackgroundExposure to phenols and phthalates has been separately linked to increased risks of infertility in women of reproductive age. However, the combined effect of phenols and phthalates exposure on infertility has not been explored. MethodsData from the National Health and Nutrition Examination Surveys (NHANES) were used. A total of 857 women of reproductive age (18–45 years) with available information on urinary phenol and phthalate metabolites, reproductive questionnaires, and covariates were included in the present study. The definition of infertility was based on self-reports. Multivariable logistic regression, principal component analysis (PCA), and Bayesian kernel machine regression (BKMR) with stratified variable selection were applied to determine what associations were found between combined exposure to these mixtures and risk of infertility among women of reproductive age. ResultsAfter adjusting for potential confounders, bisphenol A (BPA), mono(3-carboxypropyl) phthalate (MCPP) and four di(2-ethylhexyl) phthalate (DEHP) metabolites [mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP)] were positively associated with infertility. PCA revealed that the DEHP-BPA factor's PC score was significantly positively related to the likelihood of infertility [adjusted odds ratio (aOR) = 1.45; 1.08, 1.82]. The DEHP-BPA component consistently had the highest group posterior inclusion probability (PIP) in BKMR models. The BKMR model also found that MEOHP, MEHHP, and BPA were positively associated with infertility risk when the remaining combination concentrations were held at their median values. In addition, we observed that the probability of infertility increased dramatically as the quantiles of total mixture concentration increased. ConclusionOur findings indicate that a combination of phenol and phthalate metabolites is linked to infertility among reproductive-age women. BPA and DEHP, in particular, are significantly related to the risk of infertility.

Exposure to phthalates, phenols, and parabens mixture and alterations in sex steroid hormones among adolescents

Exposure to phthalates (PAEs), phenols, and parabens has been linked with sex hormone imbalance; however, previous studies were predominantly limited to adults and failed to examine the combined effects of these chemicals mixture among adolescents. Thus, we used the data from the National Health and Nutrition Examination Survey (2013-2016) to explore the associations of urinary PAEs, phenols, and parabens biomarkers with sex hormones among participants aged 12-19 years old (n=613). Latent class analysis (LCA) and quantile-based g-computation (QGC) were applied to assess the associations of the latent exposure profiles and chemicals mixture with sex hormone indicators, including steroid hormones and sex hormone binding globulin (SHBG), in adolescents and by sex. Using LCA, four latent classes were identified among all participants. Compared with the class characterized by "Low exposure", the class represented by "High PAEs" [mono (2-ethyl-5-carboxypentyl) phthalate (MECPP), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and monobenzyl phthalate (MBZP)] had lower level of estradiol (E2) [β=-0.249, 95% confidence interval (CI): -0.419, -0.08], free androgen index (FAI) (β=-0.258, 95%CI: -0.512, -0.005) and free testosterone (FT) (β=-0.248, 95%CI: -0.496, -0.001) among male adolescents. These results were echoed by the results in QGC analyses, where PAEs mixture was negatively associated with E2 (β=-0.137, 95% CI: -0.263, -0.011), FAI (β=-0.198, 95%CI: -0.387, -0.008) and FT (β=-0.189, 95%CI: -0.375, -0.002) among male adolescents. By contrast, the associations of the identified latent classes or chemicals mixture with sex hormone indicators were generally nonsignificant among female counterparts, except for a positive association between PAEs mixture and SHBG (β=0.121, 95%CI: 0.012, 0.23). Our study demonstrated that exposure to PAEs, particularly MECPP, MEHHP, and MBZP, would be a threat to the sex hormone homeostasis of male adolescents.

The relationship between exposure to phthalate metabolites and adult-onset hypogonadism.

ObjectiveAdult-onset hypogonadism (AOH) is a common disease for males >40 years old and is closely associated with age-related comorbidities. Phthalates are compounds widely used in a number of products with endocrine-disrupting effects. However, little is known about the association between exposure to phthalates and the risk of AOH. Thus, we conducted this study to explore the potential association using the 2013-2016 National Health and Nutrition Examination Survey (NHANES) data.MethodData on AOH and urinary phthalate metabolites were collected, and univariable and multivariable logistic regression analyses were adapted to evaluate the association. The concentrations of each metabolite were calculated and grouped according to their quartiles for the final analysis.ResultFinally, we found that the odds ratio (OR) increased with increased concentrations of di-(2-ethylhexyl) phthalate (DEHP) metabolites, including mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP). Simultaneously, a significant dose-dependent effect was also observed. The OR for the fourth quartile was highest among all three groups. Specifically, the ORs for the third quartile and fourth quartile were 1.774 and 1.858, respectively, in the MECPP group. For the MEHHP group, the OR increased from 1.580 for the second quartile to 1.814 for the fourth quartile. Similarly, the OR for the higher three quartiles varied from 1.424 to 1.715 in the MEOHP group.ConclusionThis study first revealed that there was a positive association between exposure to DEHP metabolites and the risk of AOH. These findings add limited evidence to study this topic, while further studies are needed to explain the potential molecular mechanisms.

Application of growth modeling to assess the impact of hospital-based phthalate exposure on preterm infant growth parameters during the neonatal intensive care unit hospitalization

In this study, we use advanced growth modeling techniques and the rich biospecimen and data repositories of the NICU Hospital Exposures and Long-Term Health (NICU-HEALTH) study to assess the impact of NICU-based phthalate exposure on extrauterine growth trajectories between birth and NICU discharge. Repeated holdout weighed quantile sum (WQS) regression was used to assess the effect of phthalate mixtures on the latency to first growth spurt and on the rate of first growth spurt. Further, we assessed sex as an effect modifier of the relationship between a phthalate mixture and both outcomes. Nine phthalate metabolites, mono-ethyl phthalate (MEP), mono-benzyl phthalate (MBzP), mono-n-butyl phthalate (MBP), mono-isobutyl phthalate (MiBP), mono-(3-carboxypropyl) phthalate (MCPP), mono-2-ethylhexyl phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) were measured in weekly urine specimens from 101 NICU-HEALTH participants between birth and the first growth spurt. Phthalate levels varied by species but not by infant sex, and decreased over the course of the NICU hospitalization as presented in detail in Stroustrup et al., 2018. There was evidence of nonlinearity when assessing the effect of phthalates on latency to first growth spurt. Above a threshold level, a higher phthalate mixture with dominant contributors MCPP, MBzP, and MEP predicted a shorter latency to the first inflection point, or an earlier growth spurt. A higher phthalate mixture with dominant contributors MECPP, MEHHP, and MEOHP was associated with an increased rate of growth. Results of both models were clearly different for boys and girls, consistent with other studies showing the sexually dimorphic impact of early life phthalate exposure. These results suggest that growth curve modeling facilitates evaluation of discrete periods of rapid growth during the NICU hospitalization and exposure to specific phthalates during the NICU hospitalization may both alter the timing of the first growth spurt and result in more rapid growth in a sexually dimorphic manner.

High exposure to phthalates is associated with HbA1c worsening in type 2 diabetes subjects with and without edentulism: a prospective pilot study

BackgroundPhthalates exposure and complete edentulism are related to both low socioeconomic status. No study by far has verified if and to what extent these two conditions are related. We aimed to explore their potential association and interplay in the metabolic control and cardiovascular risk profile.MethodsIn our small (n = 48) prospective pilot study twenty-four patients with type 2 diabetes (DnE) and twenty-four patients with type 2 diabetes and edentulism (DE) followed for 19 ± 2 months were treated according to best clinical standards. Phthalates’ exposure was evaluated by urinary concentration of di-2-ethylhexylphthalate (DEHP), metabolites, i.e. mono 2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) and mono 2-ethyl-5-hydroxyhexyl phthalate (MEHHP).ResultsNo association between phthalates and edentulism was found, nor did edentulism affect glucose control. Higher phthalates exposure was associated with a glycated haemoglobin worsening. This association was found for all the measured phthalates metabolites, both as a whole (DEHP; r = 0.33, p = 0.0209) and individually: MEHP (r = 0.41, p = 0.0033), MEHHP (r = 0.32, p = 0.028), MEOHP (r = 0.28, p = 0.0386).ConclusionsPhthalates are not associated with edentulism but predict the worsening of glucose control in subjects with type 2 diabetes. These findings might prove relevant in identifying novel biomarkers of cardiometabolic risk. Further studies are needed to validate our results and estimate the true potential of phthalates in terms of risk assessment.

Associations between phthalate exposure and thyroid function in pregnant women during the first trimester

Phthalates are a class of environmental endocrine disruptors. Previous studies have demonstrated that phthalate exposure can affect thyroid function; however, limited studies have assessed the associations between phthalate exposure and thyroid function, especially thyroid autoimmunity in pregnant women during the first trimester. We recruited participants from a cohort of pregnant women in Beijing, China, and collected urine samples to measure ten phthalate metabolites, serum samples to measure free thyroxine (FT4), thyroid-stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb) during the first trimester. We included 325 pregnant women without thyroid diseases or dysfunction in this study. Associations between phthalate metabolites and thyroid function parameters were assessed with the Bayesian kernel machine regression (BKMR) model, multiple linear regression model, and restricted cubic spline. In the BKMR model analysis, compared to the 50th percentile, total urinary phthalate metabolites levels were negatively associated with serum TPOAb levels when phthalate metabolites were at or below the 40th percentile. Stratifying by body mass index, total urinary phthalate metabolites levels were negatively associated with serum TPOAb levels in normal weight women when phthalate metabolites were at or below the 45th percentile. However, total urinary phthalate metabolites levels were positively associated with serum TPOAb levels in underweight women when phthalate metabolites were at or below the 30th percentile. In restricted cubic spline analysis, L-shaped nonlinear associations of mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), di-(2-ethylhexyl) phthalate (ΣDEHP), and inverted S-shaped nonlinear association of mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) with TPOAb were observed. In conclusion, our findings suggest that phthalate exposure may affect thyroid autoimmunity in underweight pregnant women during early pregnancy, and the potential effects of phthalate exposure on thyroid autoimmunity may be nonlinear.

Gender-specific effects of prenatal mixed exposure to serum phthalates on neurodevelopment of children aged 2-3 years:the Guangxi Birth Cohort Study.

Phthalates have been shown to have adverse effects on neurodevelopment, which may be gender-specific. However, the association between prenatal mixed exposure to phthalates and children's neurodevelopment remains inconsistent. We measured 15 prenatal serum phthalate levels and evaluated children's neurodevelopmental indicators using Gesell Developmental Schedule (GDS) (n = 750). Generalized linear regression was fitted to examine the association. Among boys, mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP) had adverse effects on gross motor [odds ratio (OR): 7.38, 95% confidence interval (CI):1.42, 38.46]. For gross motor in boys, joint effect was discovered between mono-2-ethylhexyl phthalate (MEHP) and MEHHP. Moreover, synergistic effects were found for MEHP with vanadium and cadmium, and antagonistic effects for MEHP with magnesium, calcium, titanium, iron, copper, selenium, rubidium, and strontium. We did not find statistically significant relationships in girls. In the 1st trimester, adverse effects were identified between mono-2-ethyl-5-oxoyhexyl phthalate (MEOHP) and adaptation (P = 0.024), and monomethyl phthalate (MMP) with social area (P = 0.017). In the 2nd trimester, MEHHP had adverse effects on social area (P = 0.035). In summary, we found boys may be more vulnerable to the neurotoxicity than girls in gross motor, and we also discovered the detrimental effects of phthalates on children's neurodevelopment in the 1st and 2nd trimesters. Therefore, the supplementation of appropriate elements in the 1st and 2nd trimesters may help reduce the adverse effects of phthalates on children's neurodevelopment, especially among boys.

Reproducibility of the Blood and Urine Exposome: A Systematic Literature Review and Meta-Analysis.

Endogenous and exogenous metabolite concentrations may be susceptible to variation over time. This variability can lead to misclassification of exposure levels and in turn to biased results. To assess the reproducibility of metabolites, the intraclass correlation coefficient (ICC) is computed. A literature search in three databases from 2000 to May 2021 was conducted to identify studies reporting ICCs for blood and urine metabolites. This review includes 192 studies, of which 31 studies are included in the meta-analyses. The ICCs of 359 single metabolites are reported, and the ICCs of 10 metabolites were meta-analyzed. The reproducibility of the single metabolites ranges from poor to excellent and is highly compound-dependent. The reproducibility of bisphenol A (BPA), mono-ethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), mono-2-ethylhexyl phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-benzyl phthalate (MBzP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), methylparaben, and propylparaben is poor to moderate (ICC median: 0.32; range: 0.15-0.49), and for 25-hydroxyvitamin D [25(OH)D], it is excellent (ICC: 0.95; 95% CI, 0.90-0.99). Pharmacokinetics, mainly the half-life of elimination and exposure patterns, can explain reproducibility. This review describes the reproducibility of the blood and urine exposome, provides a vast dataset of ICC estimates, and hence constitutes a valuable resource for future reproducibility and clinical epidemiologic studies.

Associations of environmental phthalate exposure with male steroid hormone synthesis and metabolism: An integrated epidemiology and toxicology study

Humans are simultaneously and constantly exposed to various lipophilic chain phthalate acid esters. The association of urinary phthalate metabolites with altered male steroid hormone synthesis and metabolism was examined using epidemiology and toxicology studies. We measured 8 phthalate metabolites [monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), mono-benzyl phthalate (MBzP), mono-n-octylphthalate (MOP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono (2-ethyl-5-oxohexyl) phthalate (MEOHP)] and two sex hormones [testosterone (T) and estradiol (E2)] in single serum and repeated spot urine samples among 451 reproductive-age males. Moreover, in vitro experiments with Leydig cell MLTC-1 steroidogenesis and liver cell HepG2 efflux in response to mixed and individual phthalates were designed to simulate real-world scenarios of human exposure. As a joint mixture, the phthalate metabolite was inversely associated with serum T and E2 concentrations but positively associated with urinary T and E2 concentrations. Combined with in vitro experiments, DEHP metabolites were identified as the predominant contributor to the decline in hormone synthesis, and ATP-binding cassette (ABC) gene activation might be involved in hormone excretion. Exposure to environmentally relevant phthalates was associated with both altered steroid synthesis and excretion, which provides additional insights into the endocrine-disrupting potential of phthalates.

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.

Comparison of the exposure assessment of di(2-ethylhexyl) phthalate between the PBPK model-based reverse dosimetry and scenario-based analysis: A Korean general population study

Di (2-ethylhexyl) phthalate (DEHP), classified as a reproductive toxicant, is a ubiquitous pollutant in foodstuffs, dust, and commercial products. In this study, to provide a useful cross-check on the accuracy of the exposure assessment, the estimated daily intake of DEHP was compared using reverse dosimetry with a physiologically-based pharmacokinetic (PBPK) model and a scenario-based probabilistic estimation model for six subpopulations in Korea. For reverse dosimetry analysis, the concentrations of urinary DEHP metabolites, namely mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono (2-ethyl-5-oxohexyl)phthalate (MEOHP), from three human biomonitoring program datasets were used. For the scenario-based model, we evaluated the various exposure sources of DEHP, including diet, air, indoor dust, soil, and personal care products (PCPs), and also determined its levels based on the literature review and measurements of indoor dust. The DEHP exposure doses using both exposure assessment approaches were similar in all cases, except for the 95th percentile exposure doses in toddlers (1–2 years) and young children (3–6 years). The PBPK-reverse dosimetry estimated daily intakes at the 95th percentile ranged between 22.53 and 29.90 μg/kg/day for toddlers and young children. These exceeded the reference dose (RfD) of 20 μg/kg bw/day of the US Environmental Protection Agency (EPA) based on the increased relative liver weight. Although, food was considered the primary source of DEHP, contributing to a total exposure of 50.8–75.1%, the effect of exposure to indoor dust should not be overlooked. The occurrence of high levels of DEHP in indoor dust collected from Korean homes suggests the use of a wide variety of consumer products containing DEHP. Furthermore, more attention should be paid to the high exposure levels of DEHP, especially in young children. Therefore, it is necessary to perform continuous monitoring of the indoor dust, consumer products, and the body burden of children.

The Role of Di(2-Ethylhexyl) Phthalate as an Exacerbating Factor in Chronic Spontaneous Urticaria.

Phthalates are one of the most commonly used endocrine disruptors and have been considered a risk factor for respiratory disease including asthma. However, it is not yet known how they are related to urticaria. We investigated the association between phthalate exposure and urticaria in 10 healthy controls and 20 adult patients with active urticaria. The urinary levels of mono-n-butyl phthalate (MnBP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP), mono-(2-ethyl-5-oxohexyl) phthalate, and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) were measured by using high performance liquid chromatography tandem mass spectrometry, and mast cell releasability was determined after phthalate treatment. The levels of phthalate metabolites, especially di-ethylhexyl phthalate (DEHP), are significantly increased in the urine of patients with urticaria compared to the healthy controls. The release of β-hexosaminidase in human mast cells is more significantly increased by MnBP, mono-benzyl phthalate, MEHHP, and MECPP compared to the negative controls; interestingly, the highest secretion of β-hexosaminidase is observed after the lowest stimulation of MECPP. Phthalates, including DEHP, may act as aggravating factors for chronic spontaneous urticaria and can be used as potential therapeutic targets in future studies.

Association between urinary phthalate metabolites and dyslipidemia in children: Results from a Chinese cohort study

Rising evidence of both experimental and epidemiological studies suggests that phthalate exposure may contribute to increased risks of metabolic disorders. But there is limited research on the childhood dyslipidemia. Our cohort study was conducted in Xiamen city, Fujian Province, China. A total of 829 children (mean age 8.5 years) were included with collection of urine, blood samples and demographic data in May 2018 and followed up once a year from 2018 to 2020. We performed adjusted log-binomial regressions to examine associations between sex-specific tertiles of seven phthalate metabolites and dyslipidemia in visit 1, as well as persistent dyslipidemia and occasional dyslipidemia. We also used generalized estimating equation models (GEE) to explore the relationships between log-transformed phthalate metabolites and lipid profiles. In adjusted models, the prevalence and RRs of dyslipidemia increased with tertile group of mono-n-butyl phthalate (MnBP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), and summed di-(2-ethylhexyl) phthalate (∑DEHP) metabolites with a dose-response relationship in visit 1, as well as persistent dyslipidemia. Higher MnBP, ∑LMWP, MEHHP, MEOHP, and ∑DEHP concentrations were also associated with higher levels of log-transformed triglycerides (TG). Boys were more vulnerable to phthalates exposure than girls. In conclusion, children in China were widely exposed to phthalates, and phthalates exposure during childhood might significantly increase the risk of dyslipidemia and a higher level of lipid profiles, particularly in boys.

Association of phthalate exposure with autistic traits in children.

Phthalates are synthetic chemicals with endocrine-disrupting properties. They are reportedly associated with various neurotoxic outcomes. Studies on exposure to phthalates and children's autistic traits have shown inconsistent results with respect to sex and susceptible time periods. We investigated the association of phthalate exposure during the prenatal period and childhood with autistic traits over time using a birth cohort in South Korea. Five phthalate metabolites were measured during mid-term pregnancy and children's follow-up at ages of 4, 6, and 8years among a total of 547 mother-child pairs. The social communication questionnaire (SCQ) was used to assess autistic traits of children at each time point. The relationship between phthalate metabolites and SCQ scores were analyzed by exposure windows and sex. A 2.7 fold increase in di-(2-ethylhexyl) phthalate metabolite levels, mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) during pregnancy was associated with increased SCQ scores at 4years by 8.5% (95% confidence intervals [CI]: 1.9%, 15.5%) and 7.4% (95% CI: 0.3%, 15.0%), respectively, but not at the age of 6 or 8years. Moreover, MEHHP levels at ages of 4 and 8years were associated with increased SCQ scores at 8years by 9.9% (95% CI: 1.8%, 18.6%) and 9.6% (95% CI: 1.3%, 18.6%), respectively. Boys showed stronger associations between phthalate exposure and SCQ scores than girls. The study suggested different susceptible time windows of phthalate exposure: exposure during pregnancy is associated with autistic traits in young children, whereas exposure during early childhood years leads to autistic traits in school-aged children, particularly boys.

Urinary levels of Phthalate metabolite mixtures and pulmonary function in adolescents

Although an association between urinary phthalate (PAE) metabolites and respiratory symptoms and diseases has been reported, knowledge regarding its effect on pulmonary function is limited, especially in adolescents. Using cross-sectional data from 1389 adolescents (aged 10–19 years) in the 2007–2012 National Health and Nutrition Examination Survey, the association of mixed urinary PAE metabolites with pulmonary function was evaluated using the weighted quantile sum. Moreover, multivariate linear regression was performed to investigate associations between each urinary PAE metabolite and pulmonary function indicators and to estimate the interaction effects between urinary PAE metabolites and demographic characteristics. We found that mixed urinary PAE metabolites were negatively associated with forced expiratory volume at the 1 s (FEV1, p < 0.001) and forced vital capacity (FVC, p = 0.008) levels. In individual PAE metabolite analyses, mono (carboxynonyl) pthalate (MCNP), mono-n-butyl pthalate (MnBP), mono-isobutyl pthalate (MiBP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono-benzyl phthalate (MBzP) correlated negatively with both FVC and FEV1 values (Holm-Bonferroni corrected p < 0.05). Mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) was negatively associated with the FVC value. Significant interactions between sex and urinary MnBP or MBzP levels for the risk of FEV1 decrease in girls were found (p = 0.005), as was a significant interaction between sex and urinary MBzP level for the risk of FVC decline. Our findings suggest that higher PAE exposure is associated with respiratory dysfunction; the association is more pronounced among girls.

Assessment of metabolic perturbations associated with exposure to phthalates among pregnant African American women

BackgroundPhthalates have been linked with numerous harmful health effects. Limited data are available on the molecular mechanism underlying phthalate toxicity on human health. In this study, we measured urinary phthalate metabolites and used high-resolution metabolomics (HRM) to identify biological perturbations associated with phthalate exposures among pregnant African American (AA) women, who are disproportionately exposed to high phthalates levels. MethodsWe used untargeted HRM profiling to characterize serum samples collected during early (8–14 weeks gestation) and late (24–30 weeks gestation) pregnancy from 73 participants from the Atlanta AA Maternal-Child cohort. We measured eight urinary phthalate metabolites in early and late pregnancy, including Monoethyl phthalate (MEP), Mono(2-ethlyhexyl) phthalate (MEHP), and Mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), to assess maternal exposures to phthalates. Metabolite and metabolic pathway perturbation were evaluated using an untargeted HRM workflow. ResultsGeometric mean creatinine-adjusted levels of urinary MEP, MEHP, and MEHHP were 67.3, 1.4, and 4.1 μg/g creatinine, respectively, with MEP and MEHP higher than the mean levels of non-Hispanic blacks in the general US population (2015–2016). There were 73 and 1435 metabolic features significantly associated with at least one phthalate metabolite during early and late pregnancy (p < 0.005), respectively. Pathway enrichment analysis revealed perturbations in four inflammation- and oxidative-stress-related pathways associated with phthalate metabolite levels during both early and late pregnancy, including glycerophospholipid, urea cycle, arginine, and tyrosine metabolism. We confirmed 10 metabolites with level-1 evidence, which are associated with urinary phthalates, including thyroxine and thiamine, which were negatively associated with MEP, as well as tyramine and phenethylamine, which were positively associated with MEHP and MEHHP. ConclusionOur results demonstrated that urinary phthalate levels were associated with perturbations in biological pathways connected with inflammation, oxidative stress, and endocrine disruption. The findings support future targeted investigations on molecular mechanisms underlying the impact of maternal phthalates exposure on adverse health outcomes.

The exposure levels of phthalates in pregnant women and impact factors of fetal malformation.

Urine samples were collected from 157 women with fetal malformations (case group) and 147 women with normal fetuses (control group). High-performance liquid chromatography-mass spectrometry (HPLC-MS) was used to detect the content of eight metabolites of phthalate compounds in urine, including monoethyl phthalate (MEP), mononbutyl phthalate (MBP), monoisobutyl phthalate (MiBP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-benzyl phthalate (MBzP). Demographic data were collected from questionnaires administered in specimen collection. The exposure level of MEOHP and MEHP in the case group was higher than the others. And there were significant differences between structural malformations and chromosomal malformations in the levels of MEHHP and MEOHP. Pregnant women with low income, high body mass index (BMI), frequent plastic contact, and low nutrients intake were at risk of suffering from fetal malformation. This study provides evidence for the correlation between the concentration of phthalates and fetal malformation. In addition, decreasing plastic exposure and supplementing nutrients may reduce the incidence of fetal malformations.

The associations of urinary DEHP metabolite levels, serum thyroid hormones, and thyroid-related genes among the adolescent students from China: a cross-sectional study.

Our study aimed to investigate the associations between DEHP exposure and serum thyroid hormone levels in 347 adolescents and young adults. We measured DEHP metabolites including mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), and mono(2-carboxymethyl)hexyl phthalate (MCMHP) in their urine. Total thyroxine (TT4), total triiodothyronine, free triiodothyronine, free thyroxine (FT4), thyroid-stimulating hormone and the mRNA levels of thyroid peroxidase (TPO), thyroglobulin (TG), sodium iodide symporter (NIS), thyroid transcription factor 1 (TTF-1), and paired box gene 8 (PAX-8) in serum were measured. The results of statistical analysis showed that urinary DEHP metabolites were generally negatively associated with TT4 levels in serum. In the males, the FT4 levels showed positive associations with urinary MEHP, MECPP, MCMHP, and ∑DEHP. The mRNA level of TG was significantly positively correlated with the levels of MECPP, MCMHP, and ∑DEHP, while the levels of TTF-1 and PAX-8 mRNA were significantly positively correlated with the levels of DEHP metabolites. Taken together, DEHP may affect the synthesis of TG by altering the normal transcription of TTF-1 and PAX-8, leading to decreased TT4 levels in Chinese adolescents.

Effect of childhood phthalates exposure on the risk of overweight and obesity: A nested case-control study in China

BackgroundThere was growing interest in endocrine disrupting chemicals that might have effect on the obesity epidemic, but few studies on the association of phthalates (PAEs) with childhood overweight and obesity in China based on longitudinal cohort study were available, which was the purpose of the present study. MethodsA nested case-control study was conducted in a prospective cohort of 2298 children aged 7–13 years from October 2017 to October 2020 with five waves visits in Xiamen city, China. A total of 829 children remained in the first wave of follow up with collection of urine for measuring seven PAEs metabolites, including mono-methyl phthalate (MMP), mono-ethyl phthalate (MEP), mono-n-butyl phthalate (MBP), mono-iso-butyl phthalate (MiBP), mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) and mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), utilizing ultra high performance liquid chromatography-triple quadrupole mass spectrometry. Overweight and obesity, defined by WHO classifications, were allocated to the cases group, and those of all normal weight and matched cases with normal weight in each wave of follow-up as two control groups. Logistic regression models after adjusting for confounders were utilized to analyze the effect of PAEs on overweight and obesity in children with divided four groups based on the quartile distribution of each and total PAEs concentration. ResultsThe detection rates of children for each PAEs metabolite were 99.4% for MMP, 99.4% for MEP, 99.8% for MBP, 54.5% for MEHP, 84.4% for MEOHP, 99.9% for MEHHP, and 97.2% for MiBP. The geometric mean of concentrations of PAEs, MMP, MEP, MBP, MEHP, MEHHP, and MiBP were 310.085, 34.658, 9.127, 166.347, 7.043, 3.400, 18.571, and 24.093 (ng/ml), respectively. The total PAEs and seven metabolites concentrations were positively associated with childhood BMI Z-Scores with statistically significant slope rates and correlation coefficients, and were higher in the cases group than those in two controls groups in each wave of follow-up. The PAEs concentrations in the cases group was 5.90 (95 %CI: 5.79, 6.01) ng/ml in the first wave of survey, which was higher than those normal controls group (5.68 (95 %CI: 5.61, 5.75) ng/ml, P < 0.001) and matched controls group (5.72 (95 %CI: 5.61, 5.84) ng/ml, P = 0.018). The prevalence and ORs of overweight and obesity increased with quartile group of each and total PAEs concentrations accompanying a dose-response relationship. Compared with the quartile1 reference group with lowest total PAEs concentrations, the ORs of overweight and obesity in quartile2, quartile3 and quartile4 group increased gradually and reached at 1.20 (0.74–1.95), 1.49 (0.93–2.38) and 2.22 (1.41–3.48), respectively (Ptrend < 0.001). The strength of the associations between PAEs and overweight and obesity was sex-specific in children. DiscussionChildren in China were extensively exposed to PAEs, and the exposure to PAEs during childhood could significantly increase the risk of overweight and obesity with a dose-response relationship, particularly in girls. While limiting the exposure of PAEs products, the determination of exposure limit of plasticizer should be further strengthened.