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Li-Mei You,* De-Chang Zhang,* Chang-Shui Lin, Qiong Lan Department of Otolaryngology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian, 364000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiong Lan, Department of Otolaryngology, Longyan First Affiliated Hospital of Fujian Medical University, No. 105, Jiuyi Northern Street, Xinluo District, Longyan, Fujian, 364000, People’s Republic of China, Email 13860239930@163.comBackground: Phthalate metabolites are pervasive in the environment and linked to various health issues. This study aimed to investigate the relationship between phthalate metabolites and hearing loss.Methods: We conducted a cross-sectional study with 1713 participants based on the National Health and Nutrition Examination Survey 2015– 2018. Participants were defined as speech-frequency hearing loss (SFHL) or high-frequency hearing loss (HFHL). We analyzed the baseline characteristics of participants and assessed the detection rates of phthalate metabolites in samples. Phthalate metabolites with detection rates of > 85% were enrolled. Then, restricted cubic spline and multivariable logistic regression analyses were conducted to explore the association of phthalate metabolites with hearing loss. Multi-model analysis was employed to select an optimal predictive model for HFHL based on phthalate metabolites and clinical factors.Results: Among participants, 24.518% had SFHL and 41.998% had HFHL, associated with older age, higher BMI, male, non-Hispanic white, lower physical activity levels, higher exposure to work noise, hypertension, and diabetes. Monobenzyl phthalate (MBZP) showed a positive linear association with both SFHL and HFHL. Multivariable logistic regression revealed MBZP as a significant risk factor for HFHL (odds ratio=1.339, 95% confidence interval, 1.053– 1.707). According to the area under curve (AUC) values, the logistic regression model had the best diagnostic performance of HFHL, with the highest AUC values of 0.865 in the test set. In the model, gender, diabetes, and MBZP were the top predictors of HFHL.Conclusion: The study identified a significant association between MBZP exposure and HFHL, highlighting the need to reduce phthalate exposure.Keywords: hearing loss, phthalate metabolites, monobenzyl phthalate, machine learning models, cross-sectional

Abstract Background Current evidence from epidemiologic studies suggested that phthalate metabolites might be associated with blood pressure (BP) changes. However, the special relationship between phthalate metabolites and BP changes in children has not been clearly elucidated in existing researches. Objectives We investigated the links between phthalate metabolites and various BP parameters, including systolic/diastolic BP, mean arterial pressure (MAP), and the presence of hypertension. Methods The population sample consisted of 1036 children aged 8 to 17 years from the 2013–2018 NHANES in the United States. High performance liquid chromatography-electrospray ionization-tandem mass spectrometry was used to measure urinary concentrations of 19 phthalate metabolites. Systolic/diastolic BP were derived from the average of three valid measurements, and MAP was calculated as (systolic BP + 2 × diastolic BP)/3. Hypertension was defined as mean systolic BP and/or diastolic BP that was ≥ 95th percentile for gender, age, and height reference. Linear regression, logistic regression, and weighted quantile sum (WQS) regression models were employed to assess the associations between phthalate exposure and systolic/diastolic BP, MAP, and hypertension. Results Ten of 19 phthalate metabolites including MCNP, MCOP, MECPP, MBP, MCPP, MEP, MEHHP, MiBP, MEOHP, and MBzP had detection frequencies > 85% with samples more than 1000. MCNP, MCOP, MECPP, MBP, MCPP, MEHHP, MiBP, MEOHP, and MBzP were generally negatively associated with systolic/diastolic BP and MAP, but not protective factors for hypertension. These associations were not modified by age (8–12 and 13–17 years) or sex (boys and girls). The above-mentioned associations were further confirmed by the application of the WQS analysis, and MCOP was identified as the chemical with the highest weight. Conclusion Phthalate metabolites were associated with modest reductions in systolic/diastolic BP, and MAP in children, while appeared not protective factors for hypertension. Given the inconsistent results among existing studies, our findings should be confirmed by other cohort studies.

Background: Current evidence from epidemiologic studies suggested that phthalate metabolites might be associated with blood pressure (BP) changes. However, the special relationship between phthalate metabolites and BP changes in children has not been clearly elucidated in existing researches. Objectives: We investigated the links between phthalate metabolites and various BP parameters, including systolic/diastolic BP, mean arterial pressure (MAP), and the presence of hypertension. Methods: The population sample consisted of 1036 children aged 8 to 17 years from the 2013–2018 NHANES in the United States. High performance liquid chromatography-electrospray ionization-tandem mass spectrometry was used to measure urinary concentrations of 19 phthalate metabolites. Systolic/diastolic BP were derived from the average of three valid measurements, and MAP was calculated as (systolic BP + 2 × diastolic BP)/3. Hypertension was defined as mean systolic BP and/or diastolic BP that was ≥ 95th percentile for gender, age, and height reference. Linear regression, logistic regression, and weighted quantile sum (WQS) regression models were employed to assess the associations between phthalate exposure and systolic/diastolic BP, MAP, and hypertension. Results: Ten of 19 phthalate metabolites including MCNP, MCOP, MECPP, MBP, MCPP, MEP, MEHHP, MiBP, MEOHP, and MBzP had detection frequencies > 85% with samples more than 1000. MCNP, MCOP, MECPP, MBP, MCPP, MEHHP, MiBP, MEOHP, and MBzP were generally negatively associated with systolic/diastolic BP and MAP, but not protective factors for hypertension. These associations were not modified by age (8–12 and 13–17 years) or sex (boys and girls). The above-mentioned associations were further confirmed by the application of the WQS analysis, and MCOP was identified as the chemical with the highest weight. Conclusion: Phthalate metabolites were associated with modest reductions in systolic/diastolic BP, and MAP in children, while appeared not protective factors for hypertension. Given the inconsistent results among existing studies, our findings should be confirmed by other cohort studies. [ABSTRACT FROM AUTHOR]

Results of toxicological studies indicate that phthalates and per-/polyfluoroalkyl substances (PFAS), 2 classes of endocrine-disrupting chemicals, may alter the functioning of the hypothalamic-pituitary-adrenocortical (HPA) axis. We evaluated the associations of urinary phthalate metabolites and serum PFAS during gestation and childhood with adolescent hair cortisol concentrations (pg/mg hair) at age 12 years, an integrative marker of HPA axis activity (n  = 205 mother-child pairs; Cincinnati, Ohio; enrolled 2003–2006). We used quantile-based g-computation to estimate associations between mixtures of urinary phthalate metabolites or serum PFAS and hair cortisol. We also examined whether associations of individual phthalate metabolites or PFAS with cortisol varied by the timing of exposure. We found that a 1-quartile increase in all childhood phthalate metabolites was associated with 35% higher adolescent hair cortisol (phthalate mixture ψ = 0.13; 95% confidence interval: 0.03, 0.22); these associations were driven by monoethyl phthalate, monoisobutyl phthalate, and monobenzyl phthalate. We did not find evidence that phthalate metabolites during gestation or serum PFAS mixtures were related to adolescent hair cortisol concentrations. We found suggestive evidence that higher childhood concentrations of individual PFAS were related to higher and lower adolescent hair cortisol concentrations. Our results suggest that phthalate exposure during childhood may contribute to higher levels of chronic HPA axis activity. [ABSTRACT FROM AUTHOR]

To determine phthalate exposure in 32 firefighters, the concentrations of urinary phthalate metabolites, immediately (exposure day) and three weeks (control day) after fire suppression, were compared. Mono-(2-ethyl-5-carboxypentyl) phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, mono-n-butyl phthalate (MBP), mono-n-benzyl phthalate (MBzP), and total phthalates (∑phthalates) levels, and creatinine-adjusted levels of MBP, MBzP, and ∑phthalates were significantly higher on exposure day than on control day. Phthalate concentration was significantly higher in firefighters who performed the fire extinguishing tasks (geometric mean [GM], 149.9 μg/L) than in those who performed other tasks (GM 70.8 μg/L) (p =.012). The GM concentration of firefighters who were active ≤ 50 m from the fire was 119.0 μg/L, and 37.6 μg/L for those who were > 50 m away (p =.012). The GM concentration was significantly different (p =.039) in firefighters with subjective symptoms after fire suppression (151.9 μg/L) compared to those without symptoms (81.6 μg/L). This study showed that firefighters were exposed to phthalate. [ABSTRACT FROM AUTHOR]

Phthalates, widely utilized in industrial products, are classified as endocrine-disrupting chemicals (EDCs). Although certain phthalate and their metabolites have been implicated in cancer development, the reported findings have exhibited inconsistencies. Therefore, we conducted the comprehensive literature search to assess the association between phthalate and their metabolites and cancer risk by identifying original studies measuring phthalates or their metabolites and reporting their correlation with cancer until July 4, 2023. The Odds Ratios (ORs) and corresponding 95% confidence intervals (CIs) were extracted and analyzed to estimate the risk. Pooled data from eleven studies, including 3101 cancer patients and 6858 controls, were analyzed using a fixed- or random-effects model based on heterogeneity tests. When comparing extreme categories of different phthalates and their metabolites, we observed a significant association between urinary phthalates and phthalate metabolites (MEHHP, MECPP, DBP and MBzP) and cancer risk. The findings of our meta-analysis reinforce the existing evidence that urinary phthalates and phthalate metabolites is strongly associated with cancer development. Further investigations are warranted to elucidate the underlying mechanisms of this association. These results may offer novel insights into cancer development.

Background: People are constantly exposed to phthalates, but few reliable studies have focused on the connection between phthalate exposure and latent tuberculosis infection (LTBI). Methods: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) database (2011–2012). The LTBI was assessed by QuantiFERON®-TB Gold-In-Tube (QFT) or tuberculin skin testing (TST). The odds ratios (ORs) and 95% confidence intervals (CIs) per log10 unit change in the concentration of phthalate metabolites were calculated using crude and adjusted logistic regression models. The relationships between mixed phthalate concentrations and LTBI were assessed using Bayesian kernel machine regression (BKMR) models. Results: According to the results of the multivariable logistic regression, in a fully adjusted model, only monobenzyl phthalate (MBZP) was negatively associated with LTBI in Q3 (OR (95% CI): 0.485 (0.286,0.823), P = 0.007). According to the restricted cubic spline (RCS) model, there was a linear dose‒response association between all 11 phthalate metabolites and LTBI (p for nonlinearity >0.05). We found a significant positive correlation between mixed phthalate metabolites and LTBI by using fully adjusted BKMR model. Conclusions: Our analysis demonstrated that LTBI in the general U.S. population is linearly linked with exposure to single or combined phthalates.

The baby disposable diapers were investigated as a sampling material for urine collection and validated for the evaluation of the exposure of children to xenobiotics. Phthalate metabolites detected in urine samples were chosen as proof-of-concept analytes. For the determination of phthalate metabolites in children’s urine samples, high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) was used. Two sampling approaches were compared, namely sterile containers and baby disposable diapers. Thirty urine samples from infants and toddlers were analyzed by both methods in parallel and the results were compared. It was found that for diaper sampling, lower concentrations of the metabolites were observed, however, the general distribution for particular metabolites remains the same for both methods. For most of the metabolites high determination coefficients were obtained, namely 0.9929 for MEHHP, 0.9836 for MMP, 0.9796 for MECPP, and 0.9784 for 2-cx-MMHP. For MEOHP the determination correlation coefficient was 0.9154, while for MBP was – 0.7771 and MEHP was – 0.5228. In general, for diaper sampling an underestimation for 2-cx-MMHP and MEOHP was observed, while for MMP diaper-based approach provides overestimation. However, the proposed procedure confirms the possibility of using baby disposable diapers as a material for the collection of urine samples for biomonitoring purposes and fast screening of phthalates exposure.

Purpose: Phthalate esters have been a research hotspot recently owing to potential obesogenic activity, but conflicting results have been reported. This case-control study was designed to investigate whether there was an association between phthalate metabolites and childhood obesity in China. Methods: A total of 240 pairs of obese/overweight children and age- (±3 months) and gender-matched controls were recruited. Nine phthalate metabolites were analyzed in the first morning urine sample. Physical activity and dietary intake were recorded using validated questionnaires. Results: In monofactor analysis, the levels of monomethyl phthalate (MMP) and monobutyl phthalate (MnBP) in controls were significantly higher than those of overweight/obese children (p < 0.05). Moderate physical activity (p = 0.004), consumption of vegetables, fruits, and tonic were significantly higher in controls (all p < 0.05), and consumption of fried food, western fast food, carbonated drinks, and juice were higher in cases (all p < 0.05). After adjusting for physical activity and dietary intake, neither MMP [OR = 0.825, (95% CI: 0.559–1.217)] nor MnBP [(OR = 0.808, 95% CI: 0.556–1.176)], were significantly associated with obesity. In all models, moderate physical activity was negatively associated and high glucose high fat dietary patterns were positively associated with the risk of childhood obesity (p < 0.01). Conclusion: Diet and physical activity, but not phthalate metabolites were associated with childhood obesity. Further studies are needed to verify our findings. The trial was registered at clinicaltrials.gov as NCT05622513. [ABSTRACT FROM AUTHOR]

Background: Early onset of puberty could have significant impacts on childhood health, but the extent to which it was affected by phthalate esters (PAEs) and sex hormone disruption was not understood. The aim of this study is to investigate the associations between exposure to PAEs and sex hormone disruption and early onset of puberty in children. Methods: A longitudinal cohort study was conducted in China from May 2017 to Oct 2020, involving 740 children during consecutive visits. The onset of puberty was evaluated using Tanner definition, and early puberty was defined as an onset age less than the first 25 %, with cut-offs of 10.33 and 8.97 years for boys and girls, respectively. Serum testosterone (TT), estradiol (E2) and urinary PAE metabolites were measured during three visits. Generalized linear models were used to explore the associations between PAE and sex hormones with the age of puberty onset, while log-binomial regressions were applied to assess the associations of persistent exposure to PAEs and sex hormones with early pubertal onset. Results: Approximately 86.0 % of boys and 90.2 % of girls completed puberty onset from pre-puberty, and more than 95 % of participants had PAE concentrations higher than the limit of detection. Boys showed higher exposure to PAE pollutants and higher TT levels. Persistent exposure to PAEs was positively associated with early pubertal onset in girls (ARR = 1.97, 95 %CI = 1.12, 3.46). Moreover, persistent exposure to PAEs and E2 had synergistic associations with early pubertal onset in both boys (ARR = 4.77, 95 %CI = 1.06, 21.54) and girls (ARR = 7.07, 95 %CI = 1.51, 33.10). However, PAEs and TT had antagonistic associations only in boys (ARR = 0.44, 95 %CI = 0.07, 2.58). Conclusion: Long-term exposure to PAEs might increase the risk of early pubertal onset, and it appears to work in synergy with E2, while in antagonism with TT in boys’ early pubertal onset. Reducing PAEs exposure might promote pubertal health.

Although phthalate esters contribute to airway remodeling by increasing bronchial cells' migration and proliferation, the relationship between human exposure to phthalates and asthma is not understood. We measured phthalate exposure in the human body and evaluated its effect on asthma. Asthma (n = 123) and asthma-free (n = 139) participants were, respectively, recruited from an asthma clinic and the community in Taiwan. The urine levels of six phthalate metabolites were determined by liquid chromatography tandem mass spectrometry. Compared with the controls, male asthma patients had higher means of mono-(2-ethylhexyl) phthalate (MEHP) (116.3 nmol/g), monobutyl phthalate (MBP) (850.3 nmol/g) and monoethyl phthalate (MEP) (965.8 nmol/g), and female patients had greater MBP (2902.4 nmol/g). Each 10-fold increase in the level of these phthalate metabolites was correspondingly associated with a 5.0-, 5.8-, 4.2- and 5.3-fold risk of contracting asthma. Male asthma patients were identified to have a higher proportion of MEHP exposure (32.5%) than the controls (25.3%). In asthma patients, an increase in urine MEHP levels and the total phthalate metabolite concentration were notably linked to increased risks of emergency room visits and being hospitalized. For the occurrence and acute clinical events of adult asthma, phthalate exposures and MEHP retention may contribute to higher risks of contracting this respiratory disorder. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BackgroundPhthalates (PAEs) are important synthetic substances in plastics, attracting much attention due to their potential effects on the cardiovascular system.MethodsIn this study, urine and blood samples from 39 individuals were collected in Tianjin, China. Phthalates and phthalate metabolites (mPAEs) were analyzed using gas chromatography-mass spectrometry (GC-MS) and high-performance liquid chromatography-mass spectrometry (HPLC-MS), respectively. The polymerase chain reaction (PCR) products from bisulfite-treated mitochondrial DNA (mtDNA) samples were analyzed using pyrosequencing technology.ResultsThe detection frequencies for 9 PAEs varied from 2.56 to 92.31%, and those for 10 mPAEs varied from 30.77 to 100%. The estimated daily intakes (EDIs) and cumulative risk of PAEs were calculated based on the experimental statistics of urinary PAEs and mPAEs. For PAEs, the HIRfD (hazard index corresponding to reference doses) values of 10.26% of participants and the HITDI (hazard index corresponding to tolerable daily intake) values of 30.77% of participants were estimated to exceed 1, suggesting a relatively high exposure risk. The mtDNA methylation levels in the MT-ATP8 and MT-ND5 were observed to be lower than in the MT-ATP6. Mono-ethyl phthalate (MEP) and MT-ATP8 were positively correlated with triglyceride levels (p < 0.05). Based on the association of PAEs, mtDNA methylation, and triglycerides, the mediating role of mtDNA methylation between PAEs and cardiovascular diseases (CVDs) was analyzed in this study, but no mediated effect was observed.ConclusionThe effects of PAE exposure on cardiovascular diseases (CVDs) should be investigated further.

Humans are often exposed to phthalates and their alternatives, on account of their widespread use in PVC as plasticizers, which are associated with harmful human effects. While targeted biomonitoring provides quantitative information for exposure assessment, only a small portion of phthalate metabolites has been targeted. This results in a knowledge gap in human exposure to other unknown phthalate compounds and their metabolites. Although the non-targeted analysis (NTA) approach is capable of screening a broad spectrum of chemicals, there is a lack of harmonized workflow in NTA to generate reproducible data within and between different laboratories. The objective of this study was to compare two different NTA data acquisition modes, the data-dependent (DDA) and independent (DIA) acquisition (DDA), as well as two data analysis approaches, based on diagnostic ions and Compound Discoverer software for the prioritization of candidate precursors and identification of unknown compounds in human urine. Liquid chromatography coupled to high-resolution mass spectrometry was used for sample analysis. The combination of three-diagnostic-ion extraction and DDA data acquisition was able to improve data filtering and data analysis for prioritizing phthalate metabolites. With DIA, 25 molecular features were identified in human urine, while 32 molecular features were identified in the same urine samples using DDA data. The number of molecular features identified with level 1 confidence was 11 and 9 using DIA and DDA data, respectively. The study demonstrated that besides sample preparation, the impact of data acquisition must be taken into account when developing a NTA method and a consistent protocol for evaluating such an impact is necessary. [ABSTRACT FROM AUTHOR]

Background: School-aged children living near plastics–producing factories may have higher risk of exposure to phthalates released during the manufacturing processes. Objectives: We aimed to investigate the urinary concentrations of phthalate metabolites in school-aged children living near a petrochemical complex and estimate the cumulative risk of phthalate exposure. Methods: We used a well-established cohort (Taiwan Petrochemical Complex Cohort for Children, TPE3C) of school-aged children (6–13 years old) living near polyvinyl chloride (PVC) and vinyl chloride monomer (VCM) factories in central Taiwan from October 2013 to September 2014. A total of 257 children were included from five elementary schools: Syu-Cuo Branch (n = 58, school A, ~0.9 km), Feng-An (n = 40, school B, ~2.7 km), Ciao-Tou (n = 58, school C, ~5.5 km), Mai-Liao (n = 37, school D, ~6.9 km), and Lung-Feng (n = 57, school E, ~8.6 km). We analyzed 11 metabolites of seven phthalates (including di-2-ethylhexyl phthalate (DEHP) and di-n-butyl phthalate (DnBP)) in urine. Daily intakes (DIs) were compared with acceptable intake levels to calculate the hazard quotient (HQ) for individual phthalates, and the cumulative risk for each child was assessed using a hazard index (HI), which was the sum of the the individual HQs. Results: The geometric mean and proportion of participants with HIs exceeding one for hepatic (HIhep) and reproductive (HIrep) effects were 0.33 (13.2%) and 0.24 (7.8%), respectively. The major contributors to phthalate exposure risk were DEHP, di-iso-butyl phthalate (DiBP) and DnBP in all children. Moreover, we observed a U shaped distribution of DEHP exposure by school distance from the PVC and VCM factories (school A: 7.48 μg/kg/day and school E: 80.44 μg/kg/day). This may be due to emissions (closest) and and being located downwind of PVC scrap incineration (farthest). Conclusions: Our findings suggest that children living near a petrochemical complex were at a greater risk of phthalate exposure than normal school-aged children and that phthalate exposure was mainly attributed to DEHP, DiBP and DnBP. In addition, inhalation may have been a risk factor for people living near to PVC and VCM factories. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the relationship between phthalate metabolites and renal function. Methods: We analyzed data from 9989 participants who took part in the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. Renal function was reflected by estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and hypertension. We used generalized linear regression to estimate the correlation between covariate-adjusted creatinine-normalized phthalate metabolites and renal function. In addition, subgroup analysis was used to further compare the effect differences between various populations. Results: In the adjusted model, we found differential associations between phthalates and plasticizers metabolites and renal function. We found that Mono-benzyl phthalate, Mono-(3-carboxypropyl) phthalate, and Mono-(2-ethyl-5-oxohexyl) phthalate were positively associated with lower eGFR with odds ratios (95% confidence intervals) of 1.38 (1.14, 1.67), 1.30 (1.09, 1.57), and 1.27 (1.04, 1.53). While Mono-ethyl phthalate, Mono-(2-ethyl)-hexyl phthalate, Mono-isononyl phthalate and Mono-isobutyl phthalate were negatively associated with lower eGFR with OR values of 0.79 (0.69, 0.90), 0.64 (0.52, 0.78), 0.65 (0.51, 0.82) and 0.80 (0.63, 1.00), respectively. In addition, we found that Mono(carboxyoctyl) phthalate and Mono-isobutyl phthalate were negatively associated with hypertension with ORs of 0.86 (0.78, 0.96) and 0.84 (0.72, 0.98). But phthalates and plasticizers metabolites were not associated with UACR. Conclusion: This study found differences in the effects of phthalates and plasticizers metabolites on kidney function, which may raise concerns about possible changes in kidney function resulting from exposure to current levels of plasticizers.

Although phthalate esters contribute to airway remodeling by increasing bronchial cells’ migration and proliferation, the relationship between human exposure to phthalates and asthma is not understood. We measured phthalate exposure in the human body and evaluated its effect on asthma. Asthma (n = 123) and asthma-free (n = 139) participants were, respectively, recruited from an asthma clinic and the community in Taiwan. The urine levels of six phthalate metabolites were determined by liquid chromatography tandem mass spectrometry. Compared with the controls, male asthma patients had higher means of mono-(2-ethylhexyl) phthalate (MEHP) (116.3 nmol/g), monobutyl phthalate (MBP) (850.3 nmol/g) and monoethyl phthalate (MEP) (965.8 nmol/g), and female patients had greater MBP (2902.4 nmol/g). Each 10-fold increase in the level of these phthalate metabolites was correspondingly associated with a 5.0-, 5.8-, 4.2- and 5.3-fold risk of contracting asthma. Male asthma patients were identified to have a higher proportion of MEHP exposure (32.5%) than the controls (25.3%). In asthma patients, an increase in urine MEHP levels and the total phthalate metabolite concentration were notably linked to increased risks of emergency room visits and being hospitalized. For the occurrence and acute clinical events of adult asthma, phthalate exposures and MEHP retention may contribute to higher risks of contracting this respiratory disorder.

Phthalates have been studied due to their linkages with adverse developmental effects; however, metabolites of this class of compounds are undercharacterized and are poorly captured by traditional targeted analysis. In this study, we developed a nontargeted analysis approach for identifying and classifying phthalate metabolites based on a comprehensive study of their fragmentation pathways in electrospray ionization (ESI) quadrupole-time-of-flight mass spectrometry (QTOF-MS). This approach identifies molecular features in the data as phthalate metabolites via the detection of three structurally significant fragment ions. Then phthalate metabolites are classified into four types based on the presence of additional fragment ions specific to each type. Cleavage mechanisms for each class of phthalate metabolite are proposed based on fragmentation patterns generated at various collision energies (CE). All of the tested phthalate metabolites including oxidative and nonoxidative metabolites produced a fragment ion at m/z 121.0295, representing the deprotonated benzoate ion [C6H5COO]−. Most tested phthalate metabolites can produce a specific ion at m/z 147.0088, the deprotonated o-phthalic anhydride ion. However, phthalate carboxylate metabolites can only produce the [M–H–R]− ion at m/z 165.0193 and do not produce the fragment at m/z 147.0088. Other phthalate oxidative metabolites (hydroxyl- and oxo-) follow a different fragmentation pathway than nonoxidative metabolites. With this workflow, eight unknown phthalate metabolites were putatively identified in pooled urine, with one identified as a previously unreported metabolite by a combination of the MS/MS spectrum and the predicted retention time. Method detection limits for phthalate metabolites in urine were also estimated. [ABSTRACT FROM AUTHOR]

Phthalate metabolites and bisphenols can cause adverse pregnancy outcomes. However, there is no study to evaluate the associations of prenatal exposure to phthalate metabolites and bisphenols with non-syndromic cleft lip and/or palate (NSCL/P) risk in offspring. A population-based case-control study was conducted in a multicenter setting from 2005 to 2021, enrolling 448 pregnant women. Seven phthalate metabolites and six bisphenols were quantified in placenta using liquid chromatography-tandem mass spectrometry. In the logistic regression analysis, high levels of mono-ethyl phthalate, mono-cyclohexyl phthalate, mono-octyl phthalate, bisphenol A, bisphenol AF, bisphenol AP, and fluorene-9-bisphenol were associated with increased NSCL/P risk with odds ratios (95% confidence intervals) of 1.86(1.07,3.25), 6.56(3.47,12.39), 8.49(4.44,16.24), 8.34(4.32,16.08), 3.19(1.81,5.62), 2.78(1.59,4.86), and 5.16(2.82,9.44). The Bayesian kernel machine regression model revealed that co-exposure to phthalate metabolites and bisphenols was associated with increased NSCL/P risk. Similarly, quantile-based g-computation analysis indicated that each quantile increase in mixture concentration was positively related to higher risk for NSCL/P [odds ratio (95% confidence interval) = 2.98(1.97,4.51)]. This study provides novel evidence that prenatal single and co-exposure to phthalate metabolites and bisphenols were associated with increased NSCL/P risk, suggesting that exposure to phthalate metabolites and bisphenols during pregnancy should be minimized to reduce the incidence of NSCL/P in offspring. [Display omitted] • Prenatal exposure to mPAEs and BPs was associated with increased risk for NSCL/P. • The BKMR and qgcomp models were used to evaluate the joint effect of mPAEs and BPs. • This study used placental mPAEs and BPs as biomarkers of in vivo exposure. [ABSTRACT FROM AUTHOR]

Phthalate esters (PAEs) possess endocrine-disrupting properties. Studies in humans have indicated that in utero phthalate exposure affects maternal thyroid hormones, which are essential for fetal growth and development. However, these studies also reported inconsistent results on the relationship between phthalates and thyroid hormones. This prospective cohort study aimed to assess phthalate exposure across the three trimesters of pregnancy and its association with thyroid hormone levels. From 2019 to 2022, we recruited 672 pregnant women, and two urine samples and one blood sample were collected from each participant during the pregnancy. We examined the urine samples from 663, 335, and 294 women in the first, second, and third trimester, respectively, for the following seven phthalate metabolites: monoethyl phthalate (MEP) from diethyl phthalate (DEP); mono-n-butyl phthalate (M n BP) and mono-iso-butyl phthalate (M i BP) from dibutyl phthalate (DBP); monobenzyl phthalate (MB z P) from butyl benzyl phthalate; and three di(2-ethylhexyl) phthalate (DEHP) metabolites, mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP). Additionally, we examined the levels of free thyroxine (FT4), thyroid-stimulating hormone (TSH), and total triiodothyronine (TT3) in the serum samples of the following participants: 596, 627, and 576 in the first trimester; 292, 293, and 282 in the second trimester; and 250, 250, and 248 in the third trimester, respectively. Other than MBzP, which was detected in 25%–33% of the samples, other metabolites were detectable in >86% of urine samples, indicating widespread exposure to DEP, DBP, and DEHP. The detected phthalate exposure levels in our cohort were significantly higher than those reported in other countries. Metabolite levels varied across the trimesters, implying changes in exposure and metabolism throughout pregnancy. The observed variability in urinary concentrations of phthalate metabolites, which ranged from poor to moderate, underscores the importance of taking multiple measurements during pregnancy for precise exposure assessment. Using a linear mixed model, we analyzed the effects of repeated phthalate exposure on thyroid hormone levels while adjusting for potential confounders. We observed significant linear trends in FT4, TSH, and, to a lesser extent, TT3 across quartiles of specific phthalate metabolites. Comparing the highest to the lowest quartiles, we found a significant increase in FT4 levels, ranging from 2 to 3.7%, associated with MEP; MECPP; MEHHP; and the sum of seven metabolites (∑ 7 PAE), three DEHP metabolites (∑ 3 DEHP), two DBP metabolites (∑DBP), and both low molecular weight (∑LMW) and high molecular weight metabolites. Increased TSH levels (5%–16%) were observed for all phthalate metabolites (except MEHHP) and their molar sums, including ∑ 7 PAE. For TT3, a significant increase was observed with MEP (2.2%) and a decrease was observed with ∑DBP (−2.7%). A higher TSH/FT4 ratio was observed with the highest quartiles (third or fourth) of several phthalate metabolites: MEP (8.8%), M i BP (8.7%), M n BP (22.2%), ∑ 7 PAE (15.3%), ∑DBP (16.4%), and ∑LMW (18.6%). These hormonal alterations, most notably in the second and third trimesters, suggest that phthalate exposure may impact fetal growth and development by affecting maternal thyroid function. • Phthalates are linked to endocrine disruption, affecting fetal development. • Pregnant women in Saudi Arabia demonstrated widespread phthalate exposure. • Phthalate levels fluctuated across the trimesters, altering thyroid hormones. • High phthalate exposure is associated with increased FT4 and TSH levels. • These findings raise concerns for pregnancy outcomes and fetal health. [ABSTRACT FROM AUTHOR]

Background: The PPARα gene may be crucial to the neurotoxic effect of phthalates. However, epidemiological studies considering the neurodevelopmental influence of phthalates interacting with genetic susceptibility are limited. We hypothesized phthalates could interact with the PPARα gene, synergistically affecting neurocognitive development. Methods: A total of 961 mother-infant pairs were involved in this study. The concentrations of phthalate metabolites in maternal urine during pregnancy were detected. Children's neurocognitive development was estimated with the Bailey Infant Development Inventory (BSID). Genetic variations in PPARα were genotyped with the Illumina Asian Screening Array. We applied generalized linear regression models to estimate genotypes and phthalate metabolites' association with children's neurocognitive development. Results: After adjusting for potential confounders, the mono-n-butyl phthalate (MnBP) concentration was negatively associated with Psychomotor Development Index (PDI) (β = −0.86, 95% CI: −1.67, −0.04). The associations between MnBP and neurocognitive development might be modified by PPARα rs1800246. Compared with low-MnBP individuals carrying rs1800246 GG genotypes, high-MnBP individuals with the AG + AA genotype had a higher risk of neurocognitive developmental delay, with the odds ratio of 2.76 (95% CI:1.14, 6.24). Conclusions: Our current study revealed that prenatal exposure to MnBP was negatively correlated with children's neurocognitive development, and PPARα rs1800246 might modify the association. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The PPARα gene may be crucial to the neurotoxic effect of phthalates. However, epidemiological studies considering the neurodevelopmental influence of phthalates interacting with genetic susceptibility are limited. We hypothesized phthalates could interact with the PPARα gene, synergistically affecting neurocognitive development.Methods: A total of 961 mother-infant pairs were involved in this study. The concentrations of phthalate metabolites in maternal urine during pregnancy were detected. Children’s neurocognitive development was estimated with the Bailey Infant Development Inventory (BSID). Genetic variations in PPARα were genotyped with the Illumina Asian Screening Array. We applied generalized linear regression models to estimate genotypes and phthalate metabolites’ association with children’s neurocognitive development.Results: After adjusting for potential confounders, the mono-n-butyl phthalate (MnBP) concentration was negatively associated with Psychomotor Development Index (PDI) (β = −0.86, 95% CI: −1.67, −0.04). The associations between MnBP and neurocognitive development might be modified by PPARα rs1800246. Compared with low-MnBP individuals carrying rs1800246 GG genotypes, high-MnBP individuals with the AG + AA genotype had a higher risk of neurocognitive developmental delay, with the odds ratio of 2.76 (95% CI:1.14, 6.24).Conclusions: Our current study revealed that prenatal exposure to MnBP was negatively correlated with children’s neurocognitive development, and PPARα rs1800246 might modify the association.

Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Phthalates are used in industry as plasticizers or additives in everyday products and they have been considered as endocrine disrupting chemicals. Maternal exposure during pregnancy has been associated with neonatal exposure, preterm birth and impacts in the reproductive and respiratory systems. The aim of this study is to determine six phthalate metabolites (mono isobutyl phthalate, miBP, mono n-butyl phthalate, mnBP, mono benzyl phthalate, mBzP, mono ethylhexyl phthalate, mEHP, mono 2-ethyl-5-hydroxyhexyl phthalate, mEHHP, mono 2-ethyl-5-oxohexyl-phthalate, mEOHP) in amniotic fluid and urine from 100 pregnant women. Participants answered questionnaires for the use of plastics and cosmetics, dietary habits, health effects, pregnancy problems, health and infant development. Positive amniotic fluid samples ranged from 1% to 21% and urine from 27% to 54%. The median levels for amniotic fluid were 2.3 μg/L - 10.7 μg/L and for urine 4.9 μg/L - 46.7 μg/L. The major results include significant correlations between urinary phthalates indicating their common sources of exposure, the frequent use of deodorant was significantly associated with higher urinary miBP (p = 0.050) and mnBP (p = 0.028) and a weak inverse association was found for the use of make-up products with mBzP (p = 0.053). The frequent use of plastic food containers was significantly associated with urinary mEHP (p = 0.026), and a positive trend was noticed for mEHP in amniotic fluid (p = 0.093). An association although weak was found between urinary mEHP and lower birth length (rs = 0.396, p = 0.062). No other associations were found for infant health problems or development. The daily intake of the total phthalates was calculated 5.4 μg/kg body weight/day which corresponds to hazard index 0.10 and exposure follows the declining trend that has been observed the last decades.

Background: School-aged children living near plastics–producing factories may have higher risk of exposure to phthalates released during the manufacturing processes. Objectives: We aimed to investigate the urinary concentrations of phthalate metabolites in school-aged children living near a petrochemical complex and estimate the cumulative risk of phthalate exposure. Methods: We used a well-established cohort (Taiwan Petrochemical Complex Cohort for Children, TPE3C) of school-aged children (6–13 years old) living near polyvinyl chloride (PVC) and vinyl chloride monomer (VCM) factories in central Taiwan from October 2013 to September 2014. A total of 257 children were included from five elementary schools: Syu-Cuo Branch (n = 58, school A, ~0.9 km), Feng-An (n = 40, school B, ~2.7 km), Ciao-Tou (n = 58, school C, ~5.5 km), Mai-Liao (n = 37, school D, ~6.9 km), and Lung-Feng (n = 57, school E, ~8.6 km). We analyzed 11 metabolites of seven phthalates (including di-2-ethylhexyl phthalate (DEHP) and di-n-butyl phthalate (DnBP)) in urine. Daily intakes (DIs) were compared with acceptable intake levels to calculate the hazard quotient (HQ) for individual phthalates, and the cumulative risk for each child was assessed using a hazard index (HI), which was the sum of the the individual HQs. Results: The geometric mean and proportion of participants with HIs exceeding one for hepatic (HIhep) and reproductive (HIrep) effects were 0.33 (13.2%) and 0.24 (7.8%), respectively. The major contributors to phthalate exposure risk were DEHP, di-iso-butyl phthalate (DiBP) and DnBP in all children. Moreover, we observed a U shaped distribution of DEHP exposure by school distance from the PVC and VCM factories (school A: 7.48 μg/kg/day and school E: 80.44 μg/kg/day). This may be due to emissions (closest) and and being located downwind of PVC scrap incineration (farthest). Conclusions: Our findings suggest that children living near a petrochemical complex were at a greater risk of phthalate exposure than normal school-aged children and that phthalate exposure was mainly attributed to DEHP, DiBP and DnBP. In addition, inhalation may have been a risk factor for people living near to PVC and VCM factories.

Given the rising concern over the potential impact of environmental factors on metabolic heath, we conducted a cross-sectional analysis among 645 adults aged 20 and older in the National Health and Nutrition Examination Survey (NHANES), examining the association between nine phthalate metabolites (Mono-n-butyl phthalate (MBP), Mono-ethyl phthalate (MEP), Mono-(2-ethyl)-hexyl phthalate (MEHP), Mono-benzyl phthalate (MBzP), Mono-n-methyl phthalate (MnMP), Mono-(3-carboxy propyl) phthalate (MCPP), Mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), Mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), Mono-isobutyl phthalate (MiBP)) and six glucose homeostasis indices (fasting glucose, fasting insulin, hemoglobin A 1C (HbA 1C), homeostatic model assessment of insulin resistance (HOMA-IR), single Point Insulin Sensitivity Estimator (SPISE), and HOMA-β). Latent Class Analysis identified three phthalate metabolites exposure patterns: high MEP-low MEOHP (n = 282), high MBzP-low MEHHP (n = 214), and high MEHHP, MEOHP (n = 149). The high MBzP-low MEHHP and high MEHHP, MEOHP, versus the high MEP-low MEOHP, exposure groups showed significantly higher levels of fasting insulin (β = 0.126, 95% CI: 0.023–0.228), SPISE (β = 0.091, 95% CI: 0.018–0.164), and HOMA-IR (β = 0.091, 95% CI: 0.018–0.164). In the shorter telomere length group, high MEHHP, MEOHP exposure showed an increase in SPISE levels (β = 0.153, 95% CI: 0.037–0.269), while in the overweight/obese subgroup, high MEHHP, MEOHP exposure was significantly positively associated with HOMA-IR (β = 0.392, 95% CI: 0.150–0.735). Bayesian kernel machine regression analyses showed positive associations between higher combined phthalate exposure and increased glucose homeostasis indices (fasting glucose, HbA 1C , fasting insulin, SPISE, and HOMA-IR). The quantile of g-calculation analysis also supported the positive associations with HbA 1C , HOMA-IR, and fasting insulin. Our findings indicate that phthalate exposure was positively associated with glucose homeostasis indices, which strengthen the call for proactive measures to reduce phthalate exposure and mitigate potential risks to glucose metabolism. [Display omitted] • Sharp global rise in diabetes highlights need to explore its various determinants. • We examined association between nine phthalate metabolites and glucose homeostasis. • Three phthalate metabolites exposure patterns identified. [ABSTRACT FROM AUTHOR]

The baby disposable diapers were investigated as a sampling material for urine collection and validated for the evaluation of the exposure of children to xenobiotics. Phthalate metabolites detected in urine samples were chosen as proof-of-concept analytes. For the determination of phthalate metabolites in children's urine samples, high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) was used. Two sampling approaches were compared, namely sterile containers and baby disposable diapers. Thirty urine samples from infants and toddlers were analyzed by both methods in parallel and the results were compared. It was found that for diaper sampling, lower concentrations of the metabolites were observed, however, the general distribution for particular metabolites remains the same for both methods. For most of the metabolites high determination coefficients were obtained, namely 0.9929 for MEHHP, 0.9836 for MMP, 0.9796 for MECPP, and 0.9784 for 2-cx-MMHP. For MEOHP the determination correlation coefficient was 0.9154, while for MBP was – 0.7771 and MEHP was – 0.5228. In general, for diaper sampling an underestimation for 2-cx-MMHP and MEOHP was observed, while for MMP diaper-based approach provides overestimation. However, the proposed procedure confirms the possibility of using baby disposable diapers as a material for the collection of urine samples for biomonitoring purposes and fast screening of phthalates exposure. [Display omitted] • Disposable baby diapers (DBDs) were investigated as a sampling material for urine collection. • Phthalate metabolites (PMs) detected in urine samples were chosen as proof-of-concept analytes. • 30 urine samples from infants and toddlers were analyzed by two methods in parallel. • PMs determination in children's urine samples by LC-MS/MS was performed. • Proposed procedure confirms the possibility of using DBDs for the urine samples collection for biomonitoring purposes. [ABSTRACT FROM AUTHOR]

Many hazardous substances can be released during incineration of municipal solid waste (MSW), which pose a potential threat to human health. As additives, phthalates (PAEs) and bisphenols (BPs), which are widely used in daily goods, are likely to be present in the released hazardous substances. In the present study, we investigated the urinary levels of phthalate metabolites (mPAEs) and BPs in workers in an MSW incineration plant (the exposed group) and in residents 8 km away (the control group) in Shenzhen, China. The results showed that the median total urinary concentration of mPAEs in workers was significantly higher than that in residents (1.02 × 103 vs. 375 ng/mL). However, there was no significant difference between workers and residents for BPs. Among the mPAEs measured, the most abundant compound was mono-n-butyl phthalate in both exposed and control groups. Monoethyl phthalate and monomethyl phthalate might be potential markers for MSW incineration because of significantly high levels in the exposed group. The workers engaged in different types of workshops showed no significant differences in the urinary levels of mPAEs, also for BPs. It was worth noting that 70.8% of workers were at risk of the non-carcinogenic effects caused by PAEs with diethylhexyl phthalate having the highest risk. Actions should be taken to reduce the risks caused by these hazardous chemicals.

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.

Background: People are constantly exposed to phthalates, but few reliable studies have focused on the connection between phthalate exposure and latent tuberculosis infection (LTBI)., Methods: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) database (2011-2012). The LTBI was assessed by QuantiFERON®-TB Gold-In-Tube (QFT) or tuberculin skin testing (TST). The odds ratios (ORs) and 95% confidence intervals (CIs) per log10 unit change in the concentration of phthalate metabolites were calculated using crude and adjusted logistic regression models. The relationships between mixed phthalate concentrations and LTBI were assessed using Bayesian kernel machine regression (BKMR) models., Results: According to the results of the multivariable logistic regression, in a fully adjusted model, only monobenzyl phthalate (MBZP) was negatively associated with LTBI in Q3 (OR (95% CI): 0.485 (0.286,0.823), P  = 0.007). According to the restricted cubic spline (RCS) model, there was a linear dose‒response association between all 11 phthalate metabolites and LTBI ( p for nonlinearity >0.05). We found a significant positive correlation between mixed phthalate metabolites and LTBI by using fully adjusted BKMR model., Conclusions: Our analysis demonstrated that LTBI in the general U.S. population is linearly linked with exposure to single or combined phthalates., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Fuqiang Wen reports financial support was provided by 10.13039/501100013365West China Hospital of 10.13039/501100004912Sichuan University., (© 2024 The Authors.)

Background: Exposure to phthalate esters may be linked to the risk of high blood pressure (HBP), but limited evidence is available in Chinese children. Objective: To investigate the associations between nine phthalate metabolites (mPAEs) and systolic/diastolic BP, pulse pressure (PP), mean arterial pressure (MAP), and the risk of HBP. Methods: In this cross-sectional study, a total of 1044 primary school children (6–8 years old) were enrolled from Shenzhen, China, between 2016 and 2017. Nine mPAEs were analyzed from urine using ultra-performance liquid chromatography and tandem mass spectrometry. A multivariable linear regression model was used to explore the associations between phthalate exposure and systolic/diastolic BP, PP, and MAP. A binary logistic regression model was used to examine the associations between phthalate exposure and the risk of HBP. Results: Monomethyl phthalate (MMP) concentrations were significantly higher in HBP children than normal BP children. MMP, monoisobutyl phthalate (MiBP), monobutyl phthalate (MnBP), mono(5-carboxy-2-ethylpentyl) phthalate, mono-[(2-carboxy methyl)hexyl] phthalate (MCMHP), the sum of four short-chain mPAEs (∑LMW), and the sum of all nine mPAEs (∑9mPAEs) were significantly positively associated with increases in systolic BP z-score, while only MMP was significantly positively associated with diastolic BP z-score. MMP, MiBP, MnBP, MCMHP, ∑LMW, and ∑9mPAEs were significantly associated with increases in PP, while MMP and MnBP were significantly associated with increases in MAP. MMP was significantly associated with the risk of HBP, with an odds ratio of 1.87 (95% CI: 1.23, 2.85). Conclusions: The present study suggests that dimethyl phthalate exposure increases the risk of HBP. And some types of phthalates are associated with elevations in systolic/diastolic BP z scores, PP, and MAP in Chinese children.

Increasing number of consumer chemicals have been associated with chronic kidney disease (CKD) in human populations. However, many studies that investigated estimated glomerular filtration rate (eGRF) as an outcome reported inconsistent associations. In the present study, we employed a subset (n = 1292) of a nationally representative adult population participating in Korean National Environmental Health Survey (KoNEHS) 2015–2017, and assessed associations of major phthalates, bisphenol A (BPA), and parabens with both eGRF and albuminuria. In order to address a potential collider issue, a covariate-adjusted standardization method was applied, in addition to the conventional creatinine-correction, for adjusting urine dilution. Regardless of adjustment method, urinary DEHP metabolites showed significant positive associations with albumin to creatinine ratio (ACR). In addition, urinary metabolites of other heavy molecular weight phthalates such as MCOP and MCNP showed significant positive associations with ACR in the female population, but only following the covariate-adjusted standardization. For eGFR, conventional creatinine-correction resulted in positive associations with most of measured phthalate metabolites. However, with the covariate-adjusted standardization, most of positive associations with eGFR disappeared, and instead, significant negative associations were observed for MnBP, BPA, and EtP. Secondary analysis following stratification by CKD status, as well as principal component analysis (PCA), generally supported the observed associations. The present observations highlight the importance of urine dilution adjustment method for association studies on eGFR, and suggest potential effects of several consumer chemicals on adverse kidney function among humans.

A gas chromatography-mass spectrometry (GC–MS) method to determine polar and thermally unstable phthalate metabolites [monomethyl phthalate–MMP, monoethyl phthalate–MEP, mono-n-butyl phthalate–MnBP, mono-(2-ethylhexyl) phthalate–MEHP] has been developed. This is the first report presenting the separation of monophthalates without derivatization step and any additional equipment or special injection port. Injection parameters (temperature, pressure, time, and volume of injection), chromatographic separation (retention gap, temperature program), and MS detection/identification (working parameters, ion selection) were investigated. Mechanisms and phenomena occurring under different conditions in the GC injector were evaluated and discussed. The limits of detection (LODs) of MMP, MEP, MnBP, MEHP in the protocol were 0.049, 0.036, 0.038, and 0.029 ng (per 2 μL of injection), respectively. The response of the monophthalates was found to be linear in the tested concentration range (for MMP: 0.15–100 ng, MEP and MnBP: 0.11–100 ng, MEHP: 0.087–100 ng per 2 μL) with the coefficient of determination higher than 0.9817 and inter-day precision in the range of 1.4–5.4%. The developed method is fast, easy and repeatable. Moreover, it allows for the elimination of derivatization agents, reduction of toxic waste production and simplification of analytical procedure.

In the following work, a new method for the analysis of the phthalate monoesters in human urine was reported. Phthalate monoesters are metabolites generated as a result of phthalate exposure. In compliance with the dictates of Green Analytical Chemistry, a rapid and simple protocol was developed and optimized for the quantification of phthalate monoesters (i.e., monoethyl phthalate, monoisobutyl phthalate, mono‐n‐butyl phthalate, mono‐(2‐ethylhexyl) phthalate, mono‐n‐octyl phthalate, monocyclohexyl phthalate, mono‐isononyl phthalate) in human urine, which entails preceding derivatization with methyl chloroformate combined with the use of commercial solid phase microextraction and the analysis by gas chromatography‐triple quadrupole mass spectrometry. The affinity of the derivatized analytes toward five commercial coatings was evaluated, and in terms of analyte extraction, the best results were reached with the use of the divinylbenzene/carboxen/polydimethylsiloxane fiber. The multivariate approach of experimental design was used to seek for the best working conditions of the derivatization reaction and the solid phase microextraction, thus obtaining the optimum response values. The proposed method was validated according to the guidelines issued by the Food and Drug Administration achieving satisfactory values in terms of linearity, sensitivity, matrix effect, intra‐ and inter‐day accuracy, and precision. [ABSTRACT FROM AUTHOR]

The extensive production and use of phthalates means that these compounds are now ubiquitous in the environment and various biota, which raises concerns about potential harmful health effects. In this study, phthalate metabolites (mPAEs) were measured in breast milk (n = 100) collected from mothers of southern China between 2014 − 2022. Of the nine target mPAEs, five were detected in all of the samples, including mono-methyl phthalate (MMP), mono-ethyl phthalate (MEP), mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), and mono-(2-ethylhexyl) phthalate (MEHP). The total levels of mPAEs in breast milk ranged from 4.76 to 51.6 ng/mL, with MiBP and MnBP being the predominant isomers (MiBP + MnBP > 48.3%). Increasing trends were observed in MMP (5.7%/year) and MEHP (7.1%/year) levels during the study period, while a decreasing trend were observed in MiBP (−6.6%/year); no clear temporal trends were found for the other metabolites and total mPAE levels. The results indicate that exposure to phthalates is still prevalent in southern China. Breastfeeding was found to contribute to estimated daily phthalate intakes of 0.383–6.95 μg/kg-bw/day, suggesting insignificant health risks to infants based on dietary exposure. However, the increasing exposure to MMP and MEHP calls for more research into the possible sources and potential risks. [Display omitted] • The first evidence of temporal trends in phthalate occurrence in Chinese breast milk. • MMP and MEHP concentrations in breast milk increased between 2014 and 2022. • MiBP concentrations in breast milk decreased between 2014 and 2022. • Intake of phthalates by breastfeeding poses no health risks for nursing infants. [ABSTRACT FROM AUTHOR]

Evidence suggests that endocrine disrupting chemicals (EDCs), commonly used in plastics and personal care products, may be associated with reduced levels of vitamin D. Therefore, this study examined the relationship between phthalate metabolites, 5-chloro-2-(2,4-dichlorophenoxy)phenol (triclosan; TCS) and bisphenols (BPs) with vitamin D 3 (25(OH)D 3) and active 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3), and their relationship to calcium homeostasis. 57 female participants (age 31.8 ± 4.6 years; BMI 25.6 ± 3.7 kg/m2) were analyzed for urinary levels of phthalate metabolites, TCS and BPs, and serum levels of 25(OH)D 3 and 1,25(OH) 2 D 3, determined by isotope-dilution liquid chromatography tandem mass spectrometry. Serum calcium/calmodulin-dependent (CaM) associated proteins were determined by Slow Off-rate Modified Aptamer (SOMA)-scan. In the study cohort, 25(OH)D 3 and 1,25(OH) 2 D 3 levels were 22.9 ± 11.2 ng/mL and 0.05 ± 0.02 ng/mL, respectively: mono-3-carboxypropyl-phthalate (MCPP) correlated negatively with 25(OH)D 3 (ρ = −0.53, p = 0.01). 28 of the 57 women recruited were 25(OH)D 3 deficient, <20 ng/mL (50 nmol/L): in this group, mono-iso-butylphthalate (MiBP) and mono-butylphthalate (MBP) negatively correlated with 25(OH)D 3 ; (ρ = −0.47, p = 0.049) and (ρ = −0.64, p = 0.005), respectively. EDCs did not correlate with 1,25(OH) 2 D 3 , measures of renal function or CaM proteins. These putative data indicate that MCPP is related to 25(OH)D 3 , while MiBP and MBP were related to vitamin D deficiency; however, no correlations were observed with TCS and BPs. No phthalate metabolites correlated with 1,25(OH) 2 D 3 , CaM associated proteins or renal function, suggesting that effects occur earlier in the vitamin D pathway and not through modulation of cellular calcium flux. The observed correlations are surprisingly strong compared to other predictors of 25(OH)D 3 , and larger studies adjusting for potential confounders are warranted. [Display omitted] • Phthalates are proposed to impact CYP enzymes involved in 1,25(OH) 2 D 3 metabolism. • The relationship between phthalate metabolites and 25(OH)D 3 in women was examined. • MCPP negatively correlated with 25(OH)D 3 in the study cohort. • In deficient 25(OH)D 3 women, MiBP and MBP negatively correlated with 25(OH)D 3. • Observed correlations are remarkably strong compared to other predictors of 25(OH)D 3. [ABSTRACT FROM AUTHOR]

Urinary phthalate metabolite (mPAEs) analysis is a reliable tool for assessing human exposure to phthalates. With growing interest in urinary biomonitoring of these metabolites, there is a need for fast and sensitive analytical methods. Therefore, a simple, rapid procedure for simultaneous determination of fifteen phthalate metabolites in human urine samples by liquid chromatography-tandem mass spectrometry was developed. The novelty of the present procedure is based on the use of diethyl carbonate as a green biobased extraction solvent and air-assisted liquid-liquid microextraction (AALLME) as a sample preparation step. A Plackett-Burman design was used for screening the factors that influence the AALLME extraction efficiency of mPAEs. The effective factors were then optimized by response surface methodology using a central composite rotatable design. Under the optimized conditions, good linearity can be achieved in a concentration range of 1.0–20.0 ng mL-1 with correlation coefficients higher than 0.99. The repeatability and reproducibility precision were in the range of 2–12% and 1–10% respectively. Recoveries ranging from 90% to 110%. This, and the low limits of detection, ranging from 0.01 to 0.05 ng mL-1, make the proposed procedure sensitive and suitable for human biomonitoring of phthalate exposures. For proof-of-principle, the new method was used to measure the urinary concentrations of mPAEs in 20 urine samples from Brazilian women. The high frequency of detections and in part high concentrations of mPAEs indicate to widespread exposure to several phthalates among Brazilian women. [Display omitted] • A simple, rapid, sensitive and accurate method for 15 phthalate metabolites determination in human urine is proposed. • The proposed method is eco-friendly, as a green bio-based extraction solvent was used. • The method is based on air-assisted liquid-liquid microextraction and liquid chromatography coupled to mass spectrometry. • The proposed method was successfully applied for the analysis of Brazilian women urine samples. [ABSTRACT FROM AUTHOR]

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Environmental exposure to phthalates may contribute to an increased risk of asthma in children and adults. We aimed to assess the direction and strength of the association between urinary phthalates metabolites and current asthma in children and adults that participated in the National Health and Nutrition Examination Survey (NHANES) 2007–2012. Data on ten urinary phthalate metabolites, self-reported questionnaires, spirometry measures, and covariates were obtained from 7765 participants (28.1% were children aged 6–17 years) taking part in the NHANES 2007–2012. Asthma was assessed using self-reported questionnaires for children and adults, and via spirometry measures for adults alone. We used crude and adjusted logistic regression models to estimate the odds ratios (ORs) and 95% confidence interval (CI) per one log10 unit change in the concentration of phthalate metabolites. We further modeled the effect modification by sex. Out of 10 metabolites, only mono-benzyl phthalate (MBzP) was positively associated with the prevalence of self-reported asthma in children, after adjusting for a range of potential confounders (odds ratio 1.54; 95% confidence interval 1.05–2.27). No significant relationship was observed for adults. The association of mono-ethyl phthalate (MEP) was modified by sex, with significantly increased odds of asthma among males [boys (2.00; 1.14–3.51); adult males (1.32; 1.04–1.69)]. While no other phthalates showed a positive relationship with current asthma in males, mono-(carboxynonyl) phthalate (MCNP) and mono-(3-carboxylpropyl) phthalate (MCPP) were inversely associated with spirometrically defined asthma in adult females. A sex-specific relationship in adults was evident when spirometry, but not self-reported measures were used to define asthma. We found no clear association between exposure to phthalates and current asthma, except for a significant relationship between MBzP metabolites and self-reported asthma in children. As a result, exposure to phthalates and asthma development and/or exacerbations remains controversial, suggesting a need for a well-designed longitudinal study. [ABSTRACT FROM AUTHOR]

The ubiquity and potential toxicity of phthalates make their exposure on humans a matter of great concern. Measuring the targeted phthalate metabolites using liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a commonly used approach for human biomonitoring of phthalates. However, the targeted LC-MS/MS methods have been unable to meet the desire to comprehensively and rapidly screen and identify for as many known and potentially unknown phthalate metabolites in human samples. Instead, non-targeted screening methods, allowing the rapid detection and identification of unknown compounds in a wide variety of environmental and human samples are complementary to the targeted methods. In this study, 23 phthalate metabolites were analyzed using liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS) for development of a non-targeted screening method. The fragmentation patterns of the 23 phthalate metabolites were investigated using collision-induced dissociation experiments at 10, 20, and 40 eV. And three common specific product ions at m/z 121.0297, m/z 147.0088, and m/z 165.0193 corresponding to C 7 H 5 O 2 -, C 8 H 3 O 3 -, and C 8 H 5 O 4 -, respectively were observed in their mass spectra. Based on the three common product ions, a new strategy was proposed for non-targeted screening of the new phthalate metabolites as exposure biomarkers for human biomonitoring. It can greatly reduce the time spent on data processing for potential precursor ions. Additionally, the correlation of the retention time and logKow of the phthalate metabolites was explored, which provides a useful tool to reduce the number of identified candidates in the non-targeted screening. Image 1 • 23 native phthalate metabolites standards were analyzed by HPLC-QTOF-MS/MS. • A strategy for identification of phthalate metabolites has been proposed. • A simpler retention prediction model was plotted. • The strategy is useful for non-targeted screening of new biomarkers of phthalates exposure for human biomonitoring. [ABSTRACT FROM AUTHOR]

Phthalates, bisphenol A (BPA) and triclosan (TCS) are detectable in the vast majority of people. Most humans are continuously exposed to these chemicals due to their presence in food or in everyday consumer products. The measurement of these compounds in family members may help to explore the impact of major lifestyle factors on exposure. Mothers and (young) children are especially interesting to study, as they mostly share considerable parts of daily life together. Phthalate metabolites, bisphenol A (BPA) and triclosan (TCS) were measured in first morning void urine, collected in mother-child pairs (n = 129) on the same day. The mothers (27-45y) and their children (6-11y) were recruited in the Brussels agglomeration and rural areas of Belgium in the context of the European COPHES-DEMOCOPHES human biomonitoring project. Face-to-face questionnaires gathered information on major exposure sources and lifestyle factors. Exposure determinants were assessed by multiple linear regression analysis. The investigated compounds were detectable in nearly all mothers (92.8–100%) and all children (95.2–100%). The range (P 90 vs. P 10) of differences in urinary concentrations within each age group was for most compounds around 10–20 fold, and was very high for TCS up to 35 and 350-fold in children and mothers respectively. Some participants exceeded the tolerable daily intake guidelines as far as they were available from the European Food Safety Authority (EFSA). Overall, for BPA, the urinary concentrations were similar among both age groups. Most urinary phthalate metabolites were higher in children compared to the mothers, except for monoethyl phthalate (MEP). TCS levels were generally higher in the mothers. Despite the difference in mothers' and children's urinary concentrations, the creatinine-corrected levels were correlated for all biomarkers (Spearman rank r = 0.32 to 0.66, p < 0.001). Furthermore, for phthalates, similar home and lifestyle factors were associated with the urinary concentrations in both age groups: home renovation during last two years or redecoration during the last year for di-ethyl phthalate (DEP); PVC in home for di-n-butyl phthalate (DnBP), di-iso-butyl phthalate (DiBP) and butyl benzyl phthalate (BBzP), and personal care products use for DiBP and DnBP. Based on questionnaire information on general food type consumption patterns, the exposure variability could not be explained. However, comparing the phthalate intake from the current study with earlier assessed Belgian food intake calculations for both ages, food in general was estimated to be the major intake source for di-ethyl hexyl phthalate (DEHP), with diminishing importance for BBzP, DiBP and DnBP. Our results confirm, that children and their mothers, sharing diets and home environments, also share exposure in common consumer products related chemicals. By collecting morning urine levels on the same day, and using basic questionnaires, suspected exposure routes could be unraveled. Phthalates (BBzP, DEP, DnBP, DiBP, DEHP) and phenols (BPA, TCS) exposure takes place via food and/or everyday consumer products. These compounds were detected in nearly all morning urine samples collected in Belgian mother-child pairs sharing home environments. The levels were clearly correlated among both age groups. Personal care products use, housing and/or food intake were the main determinants of exposure associated with the urinary levels. Image 1 • Phthalates, BPA and TCS were measurable in urine of nearly all mother-child pairs. • Analysing morning urine of family members facilitated exploring common exposure patterns. • All urinary levels, especially TCS and MEP were highly variable within both age groups. • Sharing home environments implies sharing exposure in consumer product chemicals. [ABSTRACT FROM AUTHOR]

Phthalates are a group of widely used chemicals and humans are exposed to them in their daily life. Some phthalates may affect the hormonal balance in both children and adults. The aim of this study was to assess the phthalate exposure and its determinants among children at age of 7 years from the Polish Mother and Child Cohort Study (REPRO_PL). 250 urine samples collected in 2014–2015 were analysed for 21 metabolites of 11 parent phthalates using on-line high performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). This represents the most extensive set of phthalate metabolites ever determined for Poland. Ten metabolites were quantifiable in 100% of the samples, another eight in >90%. The highest median concentrations were found for the primary monoester metabolites of di-iso-butyl (MiBP, 72.4 μg/l), di-n-butyl (MnBP, 56.3 μg/l) and diethyl (MEP, 42.0 μg/l) phthalate, followed by the sum of di-2-ethylhexyl (ΣDEHP, 89.3 μg/l) and di-iso-nonyl (ΣDiNP, 21.9 μg/l) phthalate metabolites. Metabolite concentrations were higher in children at 7 years than in the same children at age 2 or in their mothers during pregnancy. Generally, phthalate exposures in this study were much higher than exposures reported in other European populations. Multivariate regression models showed that body mass index, place of residence, breastfeeding duration, socio-economic status and parental education were associated with the metabolite levels in the 7-year old children. Daily intake and hazard index calculations revealed that a small percentage of children (around 3–10%) exceeded the tolerable daily intakes established by international institutions such as EFSA and U.S. EPA indicating that these children might be at risk of anti-androgenic effects from the individual and cumulative exposure to phthalates. Thus, further monitoring of this population, by educational programs and follow-up interventions, is required. Unlabelled Image • Phthalate exposures in children from Poland ranked among the highest. • The most prevalent phthalate metabolites were MEP, MiBP, MnBP, ΣDEHP and ΣDiNP. • BMI, place of residence and breastfeeding are associated with phthalate body burdens. • Exposures in the upper percentiles exceeded levels that cannot be regarded as safe. [ABSTRACT FROM AUTHOR]

Abstract Human exposure to phthalates is ubiquitous and has received considerable attention due to their association with adverse health outcomes, including type 2 diabetes mellitus (T2DM). Nevertheless, earlier studies that link phthalate exposure to T2DM yielded ambiguous results. Furthermore, studies that associate phthalate exposure with oxidative stress and then with T2DM are scant. In this diabetic case-control study, urine samples collected from 101 individuals aged 28–68 years from Jeddah, Saudi Arabia, were analyzed to determine 20 phthalate metabolites (PhMs) and seven oxidative stress biomarkers (OSBs). Unconditional logistic regression was used to estimate odds ratios for the association between diabetes and urinary PhMs and OSBs in participants, stratified by age, gender, nationality, smoking status, occupation, and urinary creatinine. Twelve PhMs and five OSBs were found at detection rates above 50%, with geometric mean concentrations of 0.61–100 and 0.35–10.7 ng/mL (1.04–171 and 0.61–18.6 μg/g creatinine), respectively. Almost all exposures were significantly higher in diabetic cases than in controls. The 12 PhMs were positively associated with higher urinary concentrations of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 8-iso-prostaglandin F 2α (8-PGF 2α). Individuals in the 3rd and/or 4th quartile(s) for urinary concentrations of PhMs and OSBs showed 3.7- and 7.3-fold increase, respectively, in the odds of having diabetes compared with those in the 1st quartile. The rank order of association of PhMs/OSBs with diabetes followed the order of: mEP ≈ mBP > mEHP > mCPP > mECPP ≈ mEOHP ≈ mEHHP ≈ mIBP ≈ mMP > mCMHP ≈ mBzP and 8-OHdG > 8-PGF 2α ≈ 15-PGF 2α. The relationship between phthalate exposure and risk of developing T2DM was mediated in part by phthalate-induced oxidative stress, especially 8-OHdG. Our study suggests that human exposure to phthalates is associated with increased oxidative stress which mediates the development of T2DM. Graphical abstract Unlabelled Image Highlights • 20 PhMs and 7 OSBs were analyzed in urine of diabetic case-control population. • 12 PhMs were positively associated with 8-OHdG and 8-PGF 2α levels in urine. • Urinary mEP, mBP and mEHP levels were strongly associated with diabetes. • Odds ratios for diabetes were significant for 8-OHdG, 8-PGF 2α and 15-PGF 2α. • Mediation effect of 8-OHdG was significant between phthalate exposure and T2DM. [ABSTRACT FROM AUTHOR]

Abstract Prostatic enlargement might affect up to 30% of men and can cause signs and symptoms in the lower urinary tract in the elderly. Imbalanced estrogen and androgen secretions are important in prostatic physiopathology. Phthalates-environmental endocrine disruptors-affect androgen secretion and disrupt sexual organs, including testes and the prostate, but the underlying mechanisms are unclear. Using European Association of Urology (EAU) guidelines, we recruited from urology clinics in southern Taiwan 207 elderly men diagnosed with benign prostatic hyperplasia (BPH) and prostatic enlargement between 2015 and 2017. We took blood and urine samples from all patients on the same day. We used multivariate linear regression, associations, and potential interactions after we had measured and analyzed oxidative stress (OS) markers, steroidal hormones, and 11 urinary phthalate metabolites, and then we adjusted for confounders. Di(2-ethylhexyl) phthalate (DEHP) metabolite levels, particularly urinary mono-(2-ethylhexyl) phthalate, were positively associated with androgen, estrogen, hormone ratios, inducible nitric oxide synthetase (iNOS), 8-hydroxy-2′-deoxyguanosine (8-OHdG), prostate specific antigen (PSA), and prostate volume (PV) (p < 0.05). PV and PSA were positively associated with androgen, estrogen, hormone ratios and OS markers (p < 0.05). The estimated percentages of exposure to phthalates in prostatic enlargement mediated by androgen, estrogen, and OS markers ranged from 3.5% to 63.1%. Exposure to DEHP promoted the progress of BPH by increasing dihydrotestosterone (DHT), estradiol (E 2), the converted enzymes aromatase and 5α reductase, and reactive oxygen species (ROS) (8-OHdG and iNOS) production. Sex hormones and OS might be important hyperplasia-promoters after a patient has been exposed to phthalates, especially to DEHP. Graphical abstract Unlabelled Image Highlights • Androgens and estrogens have agonistic and antagonistic effects that stimulate prostate development and progression. • Increasing ROS production was positively associated with prostatic hyperplasia. • Sex hormones and ROS mediate phthalate-induced effects in the development and progression of prostatic hyperplasia. [ABSTRACT FROM AUTHOR]

Early-life phthalate exposures may adversely affect children's neurodevelopment by disrupting thyroid function, reducing gonadal hormone levels, or altering fatty acid concentrations in the brain. This study aimed to identify periods of heightened susceptibility during gestation, infancy, and childhood to the impact of phthalates on children's cognitive abilities. We used data from 253 mother-child pairs in the Health Outcomes and Measures of the Environment (HOME) Study (Cincinnati, Ohio), a longitudinal pregnancy and birth cohort. We quantified urinary concentrations of 11 phthalate metabolites in samples collected twice during gestation and 6 times during study visits when children were aged 1–8 years using a modified method of on-line solid phase extraction coupled with isotope dilution-high performance liquid chromatography-tandem mass spectrometry. We assessed children's intelligence (IQ) at ages 5 and 8 years using the Wechsler Preschool and Primary Scale of Intelligence-III and Wechsler Intelligence Scale for Children-IV, respectively. We estimated covariate-adjusted associations between a 1-standard deviation increase in log 10 -transformed urinary phthalate metabolite concentrations at each visit and children's IQ, adjusting for demographic, perinatal, and child factors; we tested for differences in these associations across visits using multiple informant models. Associations between some phthalate metabolites and IQ varied by visit (phthalate x visit interaction p-values<0.20). The sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP), mono(3-carboxypropyl) phthalate, and monoethyl phthalate at age 3 years, and monobenzyl phthalate at 16 weeks gestation and child ages 3, 5, and 8 years were inversely associated with children's full-scale IQ. For example, each 1-standard deviation increase in ΣDEHP at age 3 was associated with a 1.9-point decrease in full-scale IQ (95% confidence interval: -3.7, -0.2). Mono-n-butyl phthalate and mono-isobutyl phthalate at age 4 years were positively associated with children's full-scale IQ. Urinary concentrations of several phthalate metabolites at age 3 years, compared to other time periods, were more strongly associated with decreased cognitive abilities in these children. • Urinary ΣDEHP, MEP and MCPP at age 3 years were inversely associated with child IQ. • Gestational and childhood urinary MBzP levels were inversely associated with child IQ. • Age 3 years may be a susceptible period of neurodevelopment to several phthalates. • Phthalate exposure at age 3 years was more strongly related to decreased child IQ. [ABSTRACT FROM AUTHOR]