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

Association of phthalate metabolites with periodontitis: a population-based study

BackgroundWidespread exposure to phthalates may raise the probability of various diseases. However, the association of phthalate metabolites with periodontitis remains unclear.MethodsTotally 3402 participants from the National Health and Nutrition Examination Survey (NHANES) 2009 to 2014 cycles were enrolled in the cross-sectional investigation. We utilized weighted logistic regression to evaluate the association of ten phthalate metabolites with periodontitis. Restricted cubic spline analysis was applied to investigate potential nonlinear relationships.ResultsThe weighted prevalence of periodontitis in the study was 42.37%. A one standard deviation (SD) rise in log-transformed levels of mono-2-ethyl-5-carboxypenty phthalate (MECPP), mono-n-butyl phthalate (MnBP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-isobutyl phthalate (MiBP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-benzyl phthalate (MBzP) was associated with higher odds of periodontitis, with odds ratios (95% confidence intervals) of 1.08 (1.02-1.14), 1.07 (1.02-1.11), 1.10 (1.05-1.15), 1.05 (1.01-1.09), 1.09 (1.04-1.14), and 1.08 (1.03-1.13), respectively. Individuals with the highest quartile concentrations of MECPP, MnBP, MEHHP, MEOHP, and MBzP were associated with 32%, 20%, 30%, 25%, and 26% increased odds of periodontitis, respectively, compared to those with the lowest quartile. Additionally, mono-(3-carboxypropyl) phthalate (MCPP) demonstrated an interesting inverted J-shaped relationship with periodontitis.ConclusionsThe findings indicate an association of certain phthalate metabolites with periodontitis among US adults.

Gender associations between phthalate exposure and biomarkers of oxidative stress: A prospective cohort study.

Previous epidemiologic research has shown that phthalate exposure in pregnant women is related to adverse birth outcomes in a sex-specific manner. However, the biological mechanism of phthalate exposure that causes these birth outcomes remains poorly defined. In this research, we investigated the association between phthalate exposure and placental oxidative stress in a large population-based cohort study, aiming to initially explore the relationship between phthalate exposure and gene expression in placental oxidative stress in a sex-specific manner. Quantitative PCR was performed to measure the expression of placental inflammatory mRNAs (HO-1, HIF1α, and GRP78) in 2469 placentae. The multiple linear regression models were used to investigate the associations between mRNA and urinary phthalate monoesters. Phthalate metabolites monomethyl phthalate (MMP) and mono-n-butyl phthalate (MBP) were positively correlated with higher HIF1α expression in placentae of male fetuses (p < .05). Mono-benzyl phthalate (MBzP) increased the expression of HO-1, HIF1α, and GRP78 in placentae of male fetuses, and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) up-regulated the expression of HIF1α and GRP78. Additionally, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively correlated with HO-1, HIF1α, and GRP78 in placentae of female fetuses. Maternal phthalate exposure was associated with oxidative stress variations in placental tissues. The associations were closer in the placentas of male fetuses than in that of female ones. The placenta oxidative stress is worth further investigation as a potential mediator of maternal exposure-induced disease risk in children.

Phthalate metabolites and sex steroid hormones in relation to obesity in US adults: NHANES 2013-2016.

Obesity and metabolic syndrome pose significant health challenges in the United States (US), with connections to disruptions in sex hormone regulation. The increasing prevalence of obesity and metabolic syndrome might be associated with exposure to phthalates (PAEs). Further exploration of the impact of PAEs on obesity is crucial, particularly from a sex hormone perspective. A total of 7780 adult participants in the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2016 were included in the study. Principal component analysis (PCA) coupled with multinomial logistic regression was employed to elucidate the association between urinary PAEs metabolite concentrations and the likelihood of obesity. Weighted quartiles sum (WQS) regression was utilized to consolidate the impact of mixed PAEs exposure on sex hormone levels (total testosterone (TT), estradiol and sex hormone-binding globulin (SHBG)). We also delved into machine learning models to accurately discern obesity status and identify the key variables contributing most to these models. Principal Component 1 (PC1), characterized by mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) as major contributors, exhibited a negative association with obesity. Conversely, PC2, with monocarboxyononyl phthalate (MCNP), monocarboxyoctyl phthalate (MCOP), and mono(3-carboxypropyl) phthalate (MCPP) as major contributors, showed a positive association with obesity. Mixed exposure to PAEs was associated with decreased TT levels and increased estradiol and SHBG. During the exploration of the interrelations among obesity, sex hormones, and PAEs, models based on Random Forest (RF) and eXtreme Gradient Boosting (XGBoost) algorithms demonstrated the best classification efficacy. In both models, sex hormones exhibited the highest variable importance, and certain phthalate metabolites made significant contributions to the model's performance. Individuals with obesity exhibit lower levels of TT and SHBG, accompanied by elevated estradiol levels. Exposure to PAEs disrupts sex hormone levels, contributing to an increased risk of obesity in US adults. In the exploration of the interrelationships among these three factors, the RF and XGBoost algorithm models demonstrated superior performance, with sex hormones displaying higher variable importance.

Prenatal phthalate exposure and neurodevelopmental differences in twins at 2 years of age

BackgroundPrevious studies of singletons evaluating prenatal phthalate exposure and early neurodevelopment reported mixed results and the associations could be biased by parental, obstetrical, and genetic factors.MethodsA co-twin control design was employed to test whether prenatal phthalate exposure was associated with children’s neurocognitive development. We collected information from 97 mother-twin pairs enrolled in the Wuhan Twin Birth Cohort between March 2016 and October 2018. Fourteen phthalate metabolites were measured in maternal urine collected at each trimester. Neurodevelopmental differences in twins at the age of two were examined as the outcome of interest. Multiple informant model was used to examine the covariate-adjusted associations of prenatal phthalate exposure with mental development index (MDI) and psychomotor development index (PDI) scores assessed at 2 years of age based on Bayley Scales of Infant Development (Second Edition). This model also helps to identify the exposure window of susceptibility.ResultsMaternal urinary levels of mono-2-ethyl-5-oxohexyl phthalate (MEOHP) (β = 1.91, 95% CI: 0.43, 3.39), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) (β = 1.56, 95% CI: 0.33, 2.79), and the sum of di-(2-ethylhexyl) phthalate metabolites (∑DEHP) (β = 1.85, 95% CI: 0.39, 3.31) during the first trimester showed the strongest and significant positive associations with intra-twin MDI difference. When stratified with twin chorionicity, the positive associations of monoethyl phthalate (MEP), monoisobutyl phthalate (MiBP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), individual DEHP metabolites, and ∑DEHP exposure during pregnancy with intra-twin neurodevelopmental differences were more significant in monochorionic diamniotic (MCDA) twins than those in dichorionic diamniotic (DCDA) twins.ConclusionsNeurodevelopmental differences in MCDA twins were strongly associated with prenatal phthalate exposure. Our findings warrant further confirmation in longitudinal studies with larger sample sizes.

Telomere length as a modifier in the relationship between phthalate metabolites exposure and glucose homeostasis

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 A1C (HbA1C), 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, HbA1C, fasting insulin, SPISE, and HOMA-IR). The quantile of g-calculation analysis also supported the positive associations with HbA1C, 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.

Associations between Phthalate Metabolite Concentrations in Follicular Fluid and Reproductive Outcomes among Women Undergoing in Vitro Fertilization/Intracytoplasmic Sperm Injection Treatment.

Phthalates have been reported to impair fertility in various studies. However, evidence exploring the associations between phthalate metabolites in follicular fluid (FF) and reproductive outcomes is lacking. To investigate the associations between phthalate metabolite concentrations in FF and in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes among women recruited from a fertility clinic. We included 641 women undergoing IVF/ICSI treatment from December 2018 to January 2020. The levels of eight phthalate metabolites, including monoethyl phthalate (MEP), mono-isobutyl phthalate (MiBP), mono--butyl phthalate (MBP), monobenzyl phthalate (MBzP), 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 quantified in FF collected on the oocyte retrieval day. Associations between quartiles of individual phthalate metabolite concentrations and nine IVF/ICSI outcomes, including oocyte yield, mature oocyte number, two distinct pronuclei (2PN) zygote number, fertilization rate, blastocyst formation rate, implantation, clinical pregnancy, miscarriage, and live birth, were estimated with generalized linear models. The effects of phthalate mixtures on IVF/ICSI outcomes were assessed using Bayesian kernel machine regression (BKMR) models. After adjusting for relevant confounders, elevated quartiles of MBzP, MEHHP, and MEHP in FF were inversely associated with the numbers of retrieved oocytes, mature oocytes, and 2PN zygotes (all for trends ). In comparison with the lowest quartile, the highest quartile of molar sum of di(2-ethylhexyl) phthalate metabolites () was associated with a reduction of 9.1% [95% confidence interval (CI): , ] and 10.3% (95% CI: , ) in yielded oocyte and mature oocyte numbers, respectively. Furthermore, the BKMR models revealed inverse associations between phthalate mixtures and the numbers of retrieved oocytes and mature oocytes. We generally found null results for implantation, clinical pregnancy, miscarriage, and live birth. Certain phthalate metabolites in FF are inversely associated with the numbers of retrieved oocytes, mature oocytes, and 2PN zygotes among women undergoing IVF/ICSI treatment. https://doi.org/10.1289/EHP11998.

Long-term exposure to exogenous phthalate, masculinity and femininity trait, and gender identity in children: a Chinese 3-year longitudinal cohort study

BackgroundPhthalate esters (PAEs) are known to have hormone-like properties, and there is a growing trend of children expressing a gender identity different from assigned sex. However, there has been limited research in the potential links between PAEs exposure and gender identity.MethodsA total of 571 children (278 boys) completed the follow-up from Oct 2017 to Oct 2020 in Childhood Blood Pressure and Environmental Factors (CBPEF) cohort in Xiamen, China. Urinary PAE metabolites were measured at three time of visits using ultraperformance liquid chromatography-tandem mass spectrometry. The Children’s Sex Role Inventory scale was used to assess gender identity (masculinity, femininity, androgyny and undifferentiated), and Tanner definition was used to define puberty timing. Generalized linear models and log-binomial regression were used to assess the relationships between PAEs exposure, gender trait scores and gender identity.ResultsOverall, the concentration of most PAEs in more than 90% of participants was above the limit of detection values. In visit 1, there were 10.1% boys with femininity and 11.3% girls with masculinity; while these figures increased to 10.8% and 12.3% during follow-up, respectively. Early puberty onset accounted for 24.8% and 25.6% among boys and girls. Long-term exposure to mono-2-ethylhexyl phthalate (MEHP) (β = 1.20, 95%CI = 0.13, 2.28), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP) (β = 1.25, 95%CI = 0.22, 2.28) and mono-2-ethyl-5-oxohexyl phthalate (MEOHP) (β = 1.40, 95%CI = 0.24, 2.56) was associated with the increased differences of femininity trait scores in boys who enter puberty earlier, prolonged exposure to di(2-ethylhexyl) phthalate (DEHP) might also have such a positive impact (β = 1.38, 95%CI = 0.36, 2.41). For gender identity, persistent exposure to low molecular weight phthalates (LMWP) was negatively associated with undifferentiated type among boys entering puberty earlier (RR = 0.18, 95%CI = 0.05, 0.75, P < 0.05), and most of the PAE metabolites exposures showed risk ratios > 1 for their femininity.ConclusionLong-term exposure to PAEs increase the femininity trait scores in boys with early onset of puberty. Although the mechanisms remain to be determined, environmental pollution might have subtle, yet measurable effects on childhood gender identity. Reducing these chemicals exposure has important public implications on gender development.

Association between urinary phthalate metabolites and chronic obstructive pulmonary disease incidence in US adults: results from NHANES 2007-2018.

Despite associations between urinary phthalates and respiratory symptoms and disorders have been investigated, knowledge about their impact on COPD incidence remains limited. Using data of 8242 adults (aged 20-80years) from the 2007-2018 National Health and Nutrition Examination Survey (NHANES), the association of mixed urinary phthalate metabolites with COPD incidence was evaluated. Among them, 789 were COPD patients, and the rest were non-COPD participants. In the single-pollutant models, a variety of phthalate metabolites were identified as independent positive factors for COPD incidence, including mono-(carboxynonyl) phthalate (MCNP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-n-butyl phthalate (MnBP), mono-(3-carboxylpropyl) phthalate (MCPP), mono-ethyl phthalate (MEP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-benzyl phthalate (MBzP). Multi-pollutant models, including weighted quantile sum (WQS) regression, quantile-based g computation (qgcomp), and Bayesian kernel machine regression (BKMR) approaches consistently revealed the positive association between phthalates co-exposure and COPD incidence, and MCPP was recognized as the dominant positive driver. The positive association was more evident in the youth group and the male group. The interactions between certain phthalate metabolites in COPD were also observed. Given the limitations of the cross-sectional design of NHANES study, well-designed longitudinal studies are needed to verify or disprove these findings.

Associations of urinary di(2-ethylhexyl) phthalate metabolites with lipid profiles among US general adult population

BackgroundDi(2-ethylhexyl) phthalate (DEHP) a parent compound that is metabolized into 4 phthalate metabolites, which correlate to adverse cardio-metabolic risk factors. This study aimed to explore the links between urinary DEHP metabolites and serum lipids in the U.S. general adult population. MethodsIn this cross-sectional study, data on 11 urinary phthalate metabolites from the 2005–2018 National Health and Nutrition Examination Surveys (NHANES) were analyzed. Multivariate linear regression and restricted cubic spline (RCS) were used to examine the relationship between phthalate metabolites [specific DEHPs: mono-(2-ethyl-5-carboxy-pentyl) phthalate (MECPP), mono-(2-ethyl-5-hydroxy-hexyl) phthalate (MEHHP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-oxo-hexyl) phthalate (MEOHP)] and serum lipids (triglycerides [TG], total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], and high-density lipoprotein cholesterol [HDL-C]). To identify mixed exposure effects of phthalate metabolites, quantile g-computation (QG-C) and weighted quantile sum (WQS) regression were employed for the lipid profiles. ResultsA total of 9141 adults were included in the analysis. MECPP, MEHHP, MEHP, and MEOHP in the highest quartile had a negative relationship with HDL-C compared to the lowest quartile (All P for trend <0.05). TG showed a significant positive relation with MECPP, MEHHP, and MEOHP (All P for trend <0.05), but there was no notable association with MEHP. RCS demonstrated a linear relationship of DEHP metabolites with HDL-C, TC, TG, and LDL-C (all P for nonlinearity >0.05). The WQS index of DEHP metabolites showed independent correlations with HDL-C [β = −0.26, 95%CI (−0.43, −0.09), P = 0.002], TC [β = 0.55, 95%CI (0.13, 0.98), P = 0.011], and TG [β = 2.40, 95%CI (0.85, 3.96), P = 0.003]. ConclusionOur study suggests that environmental DEHP exposure may affect serum HDL-C and TG levels in the general adult population. Further research is warranted to confirm these findings and illuminate the underlying mechanisms of DEHP exposure on lipids.

Association of urinary phthalate metabolites with all-cause and cardiovascular disease mortality among adults with diabetes mellitus: National Health and Nutrition Examination Survey 2005-2014.

The study regarding phthalate metabolites and mortality among diabetes mellitus (DM) is limited. We aimed to examine the association of urinary phthalate metabolites with all-cause and cardiovascular disease (CVD) mortality among adults with DM. This study included 8,931 adults from the National Health and Nutrition Examination Survey (NHANES) from 2005-2006 to 2013-2014. Mortality data were linked to National Death Index public access files through December 31, 2015. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidences (CIs) for mortality. We identified 1,603 adults with DM [mean ± SE age, 47.08 ± 0.30 years; 50.5% (833) were men]. Mono-(carboxynonyl) phthalate (MCNP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP), and the sum of Di (2-ethylhexyl) phthalate (DEHP) metabolites (∑DEHP) were positively associated with DM (MCNP: OR = 1.53, 95%CI = 1.16-2.01; MECPP: OR = 1.17, 95% CI = 1.03-1.32; ∑DEHP: OR = 1.14, 95% CI = 1.00-1.29). Among DM patients, mono-(3-carboxypropyl) phthalate (MCPP) was associated with a 34% (HR 1.34, 95% CI 1.12-1.61) increased risk of all-cause mortality while the HRs (95%CI) of CVD mortality were 2.02 (1.13-3.64) for MCPP, 2.17 (1.26-3.75) for mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), 2.47 (1.43-4.28) for mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), 2.65 (1.51-4.63) for MECPP, and 2.56 (1.46-4.46) for ∑DEHP, respectively. This study is an academic exploration of the association between urinary phthalate metabolites and mortality among adults with DM, suggesting that exposure to phthalates might be associated with an increased risk of all-cause and CVD mortality in DM. These findings suggest that patients with DM should carefully use plastics products.

Exposure of preterm neonates receiving total parenteral nutrition to phthalates and its impact on neurodevelopment at the age of 2 months

This prospective study assessed the exposure to phthalates of preterm neonates who received total parenteral nutrition (TPN) during their stay in the neonatal intensive care unit (NICU) and the risk of neurodevelopment delays at the age of 2 months. Our study recruited 33 preterm neonates who required TPN upon NICU admission. Urine samples for analyzing phthalate metabolites were obtained at admission and then daily until the last day of receiving TPN. Phthalates in the daily TPN received by the preterm neonates were analyzed. The neurodevelopment of the neonates was assessed using the Ages and Stages Questionnaire Edition 3 (ASQ-3). Diethyl phthalate and butyl benzyl phthalate were found in all TPN samples, while 27% and 83% contained dibutyl phthalate and di-(2-ethylhexyl) phthalate (DEHP), respectively. Yet, the daily dose of each phthalate that our preterm neonates received from TPN was much lower than the recommended tolerable limit. Urinary levels of monobenzyl phthalate and four metabolites of DEHP [i.e., mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP)] and the sum of four DEHP metabolites (∑4DEHP) increased significantly in preterm neonates before discharge. However, these levels were not correlated with their phthalate parent compounds in TPN, suggesting other sources of exposure in the NICU. At 2 months, we found that urinary levels of mono-iso-butyl phthalate (MiBP), MECPP, MEHP, and ∑4DEHP were inversely related to fine motor skills. After adjusting for head circumference, the inverse relationships remained significant, suggesting direct effects from phthalates. Given the extreme vulnerability of our population, it is critical to minimize exposure to phthalates during their NICU stay.

Urinary Phthalate Metabolites and Slow Walking Speed in the Korean Elderly Environmental Panel II Study.

Previous epidemiological studies have suggested that phthalate exposure may contribute to neurocognitive and neurobehavioral disorders and decreased muscle strength and bone mass, all of which may be associated with reduced physical performance. Walking speed is a reliable assessment tool for measuring physical performance in adults age 60 y and older. We investigated associations between urinary phthalate metabolites and slowness of walking speed in community-dwelling adults ages 60-98 y. We analyzed 1,190 older adults [range, 60-98 y of age; , ] from the Korean Elderly Environmental Panel II study and measured repeatedly up to three times between 2012 and 2014. Phthalate exposure was estimated using the following phthalate metabolites in urine samples: mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-n-butyl phthalate (MnBP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), and mono-benzyl phthalate (MBzP). Slowness was defined as a walking speed of . We used logistic and linear regression models to evaluate the association between each urinary phthalate metabolite and slowness or walking-speed change. We also used Bayesian kernel machine regression (BKMR) to examine overall mixture effects on walking speed. At enrollment, MBzP levels were associated with an increased odds of slowness [odds ratio (OR) per doubling increase: 1.15, 95% confidence interval (CI): 1.02, 1.30; OR for the highest vs. lowest quartile: 2.20 (95% CI: 1.12, 4.35) with p-trend across ]. In longitudinal analyses, MEHHP levels showed an increased risk of slowness [OR per doubling increase: 1.15 (95% CI: 1.02, 1.29), OR for the highest vs. lowest quartile: 1.47 (95% CI: 1.04, 2.06), ]; whereas those with higher MnBP showed a reduced risk of slowness [OR per doubling increase: 0.84 (95% CI: 0.74, 0.96), OR in the highest (vs. lowest) quartile: 0.64 (95% CI: 0.47, 0.87), ]. For linear regression models, MBzP quartiles were associated with slower walking speed () at enrollment, whereas MEHHP quartiles were associated with slower walking speed, and MnBP quartiles were associated with faster walking speed in longitudinal analysis ( and , respectively). Further, the BKMR analysis revealed negative overall trends between the phthalate metabolite mixtures and walking speed and DEHP group (MEHHP, MEOHP, and MECPP) had the main effect of the overall mixture. Urinary concentrations of prevalent phthalates exhibited significant associations with slow walking speed in adults ages 60-98 y. https://doi.org/10.1289/EHP10549.

Oxidative stress mediates the associations between phthalate exposures and thyroid cancer/benign nodule risk

Epidemiological studies have suggested that phthalate exposures are associated with increased risks of thyroid cancer and benign nodule, while the underlying mechanisms are largely unknown. Here, we explored the mediation effects of oxidative stress (OS) biomarkers in the associations between phthalate exposures and the risks of thyroid cancer and benign nodule. Urine samples collected from 143 thyroid cancer, 136 nodule patients, and 141 healthy controls were analyzed for 8 phthalate metabolites and 3 OS biomarkers [8-hydroxy-2-deoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA), and 8-iso-prostaglandin F2α (8-isoPGF2α)]. Multivariable linear or logistic regression models were used to explore the associations of OS biomarkers with phthalate metabolite concentrations and the risks of thyroid cancer and nodule. The mediation role of OS biomarkers was also investigated. Urinary monoethyl phthalate (MEP), monomethyl phthalate (MMP), mono (2-ethyl-5-oxohexyl) phthalate (MEOHP), mono (2-ethylhexyl) phthalate (MEHP), and mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) were positively associated with at least 2 OS biomarkers (all P-values<0.01), and part of these positive associations varied in different subgroups. All 3 OS biomarkers were positively associated with the risks of thyroid nodule and cancer (P-values<0.001). The mediation analysis showed that OS biomarkers significantly mediated the associations between urinary MEHOP concentration and nodule, as well as between urinary MMP, MEHP, and MEHHP concentrations and cancer and nodule, with the estimated proportions of mediation ranging from 15.8% to 85.6%. Our results suggest that OS is a potential mediating mechanism through which phthalate exposures induce thyroid carcinogenesis and nodular formation.

Associations between exposure to phthalates and subclinical hypothyroidism in pregnant women during early pregnancy: A pilot case-control study in China

Phthalates are environmental endocrine disruptors with thyroid-disrupting properties; however, the association between phthalate exposure and subclinical hypothyroidism (SCH) during pregnancy is unknown. We recruited a study population from a cohort of pregnant women in Beijing, China, and conducted the present pilot case-control study of 42 SCH cases and 84 non-SCH controls matched with age and body mass index (BMI). Serum levels of thyroid peroxidase antibody, free thyroxine (FT4), thyroid-stimulating hormone (TSH), and urinary levels of ten phthalate metabolites during early pregnancy were measured. Urinary monoethyl phthalate (MEP) levels in SCH cases were observably higher than those in controls (p = 0.01). Conditional logistic regression analysis revealed that mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), MEP, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and di-(2-ethylhexyl) phthalate (ΣDEHP) were significantly associated with a higher risk of SCH during early pregnancy (adjusted odds ratios = 1.89, 1.42, 1.81, and 1.92, respectively). Concomitantly, multiple linear regression analysis showed that MECPP, MEOHP, and ΣDEHP were positively associated with TSH and FT4 × TSH in the entire study population. Bayesian kernel machine regression analysis and stratified analysis by BMI revealed upward tendencies in the serum levels of TSH and FT4 × TSH. In summary, exposure to phthalates, especially DEHP, may be associated with a higher risk of SCH during early pregnancy, and a possible mechanism is the disruption of the hypothalamus-pituitary-thyroid axis.

Relationship between shellfish consumption and urinary phthalate metabolites: Korean National Environmental Health Survey (KoNEHS) cycle 3 (2015-2017).

Phthalates are endocrine disrupting chemicals that are widely used in the production of items of daily life such as in polyvinylchloride plastics, insecticides, and medical devices. This study aimed to determine the association between phthalate exposure and shellfish consumption using data from the Korean National Environmental Health Survey (KoNEHS) cycle 3 (2015-2017), which is a nationally representative survey. In this study, we analyzed the KoNEHS cycle 3 data of 3,333 (1,526 men and 1,807 women) adults aged more than 19 years. Data related to the variables of sociodemographic factors, health-related behaviors, dietary factors, seafood consumption frequency, and urinary phthalate metabolites concentrations were collected. The concentrations of urinary phthalate metabolites of all the participants were divided into quartiles to define high and low concentration groups based on the 75th percentile concentration. A χ2 test was conducted to analyze the distribution of independent variables. To analyze the relationship between shellfish consumption and phthalate exposure, the odds ratios (ORs) were calculated using logistic regression analysis. Total adults with shellfish consumption frequency of over once a week showed the following adjusted ORs for high concentrations of the following metabolites compared with the group that consumed shellfish once a week or less: 1.43 (95% confidence interval [CI]: 1.01-2.06) for mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), 1.43 (95% CI: 1.01-2.03) for mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), 1.57 (95% CI: 1.10-2.24) for ∑di-2-ethylhexyl phthalate (∑DEHP), 2.01 (95% CI: 1.46-2.77) for mono-carboxyoctyl phthalate (MCOP), 1.56 (95% CI: 1.11-2.18) for mono-carboxy-isononly phthalate (MCNP), and 2.57 (95% CI: 1.85-3.56) for mono (3-carboxypropyl) phthalate (MCPP). The concentrations of urinary phthalate metabolites (MEOHP, MECPP, ∑DEHP, MCOP, MCNP, and MCPP) were higher in adults with a higher frequency of shellfish consumption.

Exposure to a mixture of personal care product and plasticizing chemicals in relation to reproductive hormones and menarche timing among 12-19 years old girls in NHANES 2013-2016.

The effects of co-exposure to personal care product and plasticizing chemicals (PCPPCs) on reproductive hormones and menarche timing has rarely been studied. We used Bayesian kernel machine regression (BKMR), adaptive least absolute shrinkage and selection operator (adaptive LASSO), and generalized linear model (GLM) to explore the mixture effects of 16 PCPPCs on reproductive hormones and early menarche among 297 girls aged 12-19 years in the National Health and Nutrition Examination Survey (NHANES) 2013-2016. In the BKMR, the mixture of PCPPCs was negatively and positively associated with testosterone (TT) and sex hormone-binding globulin (SHBG), respectively. In the adaptive LASSO, 2,5-dichlorophenol (2, 5-DCP), Mono (carboxyisoctyl) phthalate (MCOP), and Mono-benzyl phthalate (MBzP) were positively associated with estrogen (E2), whereas Mono-ethyl phthalate (MEP), Monoisobutyl phthalate (MiBP) and Mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) were inversely associated with E2. Bisphenol A (BPA) and MBzP were positively associated with SHBG, whereas Mono (carboxyisonony) phthalate (MCNP) and Mono (2-ethyl-5-carboxypentyl) phthalate (MECPP) were inversely associated with SHBG. In GLM, Benzophenone-3 (BZP) and MECPP were negatively associated with TT, whereas 2,4-dichlorophenol (2,4-DCP) revealed a positive association with early menarche onset. In conclusion, PCPPCs in the mixture and individually are associated with reproductive hormones and early menarche onset in girls.

Urinary phthalate metabolites and the risk of endometrial polyp: A pilot study from the TREE cohort

Phthalates, as endocrine disrupting chemicals that can alter the endogenous hormones, may be involved in the incidence of endometrial polyp, a benign hormone-dependent condition. We conducted a pilot case-control study from the Tongji Reproductive and Environmental (TREE) cohort to investigate the associations between phthalate exposures and the risk of endometrial polyp. A total of 40 endometrial polyp patients were matched to 80 controls by age and body mass index in the ratio of 1:2. Two spot urine samples from each subject were quantified for eight phthalate metabolites to enhance exposure assessment. The conditional logistic regression and quantile-based g-computation models were separately used to explore the associations between individual and mixture of urinary phthalate metabolites and the risk of endometrial polyp. After adjusting for covariates, individual chemical analyses showed that urinary monobenzyl phthalate (MBzP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethylhexyl) phthalate (MEHHP) and the sum of di(2-ethylhexyl) phthalate (ΣDEHP) were associated with increased risks of endometrial polyp, with adjusted odds ratios ranging from 2.62 (95% CI: 0.88, 7.84) for MECPP to 6.96 (95% CI: 1.87, 25.87) for ΣDEHP comparing the extreme exposure categories (all P for trends <0.05 or = 0.057). These associations still persisted when these exposures were modeled as continuous variables. Chemical mixture analyses showed that a simultaneous one-quartile increase in concentrations of eight phthalate metabolites was associated with an elevated odds ratio of 3.14 (95% CI: 1.49, 6.60) in endometrial polyp. Our data suggests that exposure to individual benzylbutyl phthalate (BBzP) and DEHP, as well as mixture of phthalates is associated with increased risk of endometrial polyp. This may inform public health recommendations and policies to avoid phthalate exposures for improving female reproductive health.

The Potential Biomarker of Di(2-ethylhexyl) Phthalate Exposure during Catheterization.

Di(2-ethylhexyl) phthalate (DEHP) may produce toxicity, posing a risk to human health. Medical devices composed of DEHP are frequently used in catheterization, but few studies have investigated DEHP exposure during catheterization. The aim of this prospective series was to characterize the exposure pattern of DEHP during catheterization. We enrolled 16 patients with congenital heart disease undergoing catheterization. Collection of urine was done to measure DEHP metabolites on hospitalization, before catheterization, after catheterization, and at discharge. The following DEHP metabolites were measured: mono-(2-ethylhexyl) phthalate (MEHP), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and the ratio of MEHP to overall metabolites (MEHP%) was determined. DEHP exposure from polyvinyl chloride (PVC)-containing catheter and infusion systems were recorded in detail. Differences in DEHP levels before and after catheterization were analyzed. Urinary levels of MEHP, MEHHP, and MEOHP significantly decreased from before catheterization to after catheterization (all p < 0.01), but did not change significantly from initial hospitalization to before catheterization. Urinary MEHP% significantly decreased from initial hospitalization to before catheterization (p < 0.001), then increased after catheterization (p < 0.001), and decreased gradually at discharge (p = 0.03). Urinary MEHP% after catheterization and at discharge was significantly positively related to the duration of using PVC-containing catheter systems. There was a significant positive correlation between urinary MEHP% and the duration of using PVC-containing infusion system before catheterization, and a borderline significant correlation at both post-catheterization time slots. Our results demonstrated that urinary MEHP% may be a potential biomarker of DEHP contamination from the use of PVC-containing catheters or infusion systems.

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.

Sex-specific associations between prenatal exposure to phthalates and neurocognitive development in Taiwanese children: Application of environmental mixture methods to small study sample

BACKGROUND AND AIM: Few studies have examined the sex-specific effect of phthalates as a mixture by applying multiple mixture methods to a small study sample. This study, therefore, examined sex-specific associations of prenatal exposure to urinary phthalates with neurocognitive development in Taiwanese children aged two to three years old. METHODS: The study included 127 children who were followed up at the ages two-three years in the Taiwanese Maternal and Infant Cohort Study. The Mental Development Index (MDI) and Psychomotor Development Index (MDI) were measured in children using the Bayley Scales of Infant Development-II (BSID-II). The monomethyl phthalate, monoethyl phthalate, mono-butyl phthalate (MBP), mono-benzyl phthalate, mono-2-ethylhexyl phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate, mono (2-ethyl-5-oxohexyl) phthalate (MEOHP) were measured in urine samples collected from mothers during pregnancy. Multivariable linear regression (MLR), Weighted Quantile Sum (WQS) regression, quantile g-computation (qgcom), Bayesian Kernel Machine Regression (BKMR), the Super Learner with g-computation were applied and compared to examine the sex-specific effects of the phthalate mixture on MDI and PDI. RESULTS: The mediation MDI and PDI were 94.0 and 99.0, respectively. The spearman correlation ranged between -0.01 and 0.74. None of these methods could detect any sex-specific associations between phthalates and MDI. Results suggest that WQS and qgcomp were able to detect inverse associations between phthalates and PDI with a stronger effect in boys. BKMR and Super Learner with g-computation were unable to detect any precise associations of phthalates with PDI. However, mixture methods detected mixtures&amp;#x27; negative directionality and linear dose-response effects on neurocognitive development. MBP, MEHP, and MEOHP dominated these associations with PDI. CONCLUSIONS: Mixture methods outperformed MLR. However, flexible approaches like BKMR and Super Learner with g-computation may perform better with larger samples. Therefore, the study recommends using multiple mixtures methods for getting comprehensive results from mixture studies. KEYWORDS: Mixture; Neurodevelopment; WQS; BKMR; G-computation