Phthalate Metabolites Research Articles

The Association between Maternal Urinary Phthalate Concentrations and Blood Pressure in Pregnancy: A Systematic Review and Meta-Analysis.

Phthalates are commonly found in a wide range of environments and have been linked to several negative health outcomes. While earlier research indicated a potential connection between phthalate exposure and blood pressure (BP) during pregnancy, the results of these studies remain inconclusive. The objective of this meta-analysis was to elucidate the relationship between phthalate exposure and BP in pregnancy. A comprehensive literature search was carried out with PubMed, EMBASE, and Web of Science, and pertinent studies published up until 5 March 2023 were reviewed. Random-effects models were utilized to consolidate the findings of continuous outcomes, such as diastolic and systolic BP, as well as the binary outcomes of hypertensive disorders of pregnancy (HDP). The present study included a total of 10 studies. First-trimester MBP exposure exhibited a positive association with mean systolic and diastolic BP during both the second and third trimesters (β = 1.05, 95% CI: 0.27, 1.83, I2 = 93%; β = 0.40, 95% CI: 0.05, 0.74, I2 = 71%, respectively). Second-trimester monobenzyl phthalate (MBzP) exposure was positively associated with systolic and diastolic BP in the third trimester (β = 0.57, 95% CI: 0.01, 1.13, I2 = 0; β = 0.70, 95% CI: 0.27, 1.13, I2 = 0, respectively). Conversely, first-trimester mono-2-ethylhexyl phthalate (MEHP) exposure demonstrated a negative association with mean systolic and diastolic BP during the second and third trimesters (β = -0.32, 95% CI: -0.60, -0.05, I2 = 0; β = -0.32, 95% CI: -0.60, -0.05, I2 = 0, respectively). Additionally, monoethyl phthalate (MEP) exposure was found to be associated with an increased risk of HDP (OR = 1.12, 95% CI: 1.02, 1.23, I2 = 26%). Our study found that several phthalate metabolites were associated with increased systolic and diastolic BP, as well as the risk of HDP across pregnancies. Nevertheless, given the limited number of studies analyzed, additional research is essential to corroborate these findings and elucidate the molecular mechanisms linking phthalates to BP changes during pregnancy.

Associations between urinary phthalate metabolite concentrations and rheumatoid arthritis in the U.S. adult population

Phthalates are ubiquitous environmental contaminants. Nevertheless, limited data is available about the impacts of phthalates on rheumatoid arthritis (RA). The purpose of this study was to use National Health and Nutrition Examination Survey (NHANES) data from 2005 to 2018 to assess the individual and combined effects of exposure to phthalate mixtures on RA in adults. A total of 8240 participants with complete data participated in the study, of whom 645 had RA. The levels of ten phthalate metabolites were detected in urine samples. In the single-pollutant models, independent associations were identified between urinary mono-(carboxyoctyl) phthalate (MCOP), mono-(3-carboxylpropyl) phthalate (MCPP), mono-isobutyl phthalate (MiBP) and mono-benzyl phthalate (MBzP) with the incidence of RA. The results of multi-pollutant models, including weighted quantile sum (WQS) regression, quantile-based g computation (qgcomp), and Bayesian kernel machine regression (BKMR) approaches consistently revealed that co-exposure to phthalates was positively associated with RA incidence. Such association was more pronounced in adults over 60 years of age, where MCOP was identified as the dominant positive driver. Overall, our findings add novel evidence that co-exposures to phthalates might be positively associated with RA incidence. Given the limitations of the NHANES study, well-designed longitudinal studies are required to verify or disprove these results.

Adolescent endocrine disrupting chemical exposure and academic achievement

BackgroundEpidemiologic studies support associations of exposure to endocrine disrupting chemicals (EDCs), such as some phthalates, phenols, and parabens with a wide range of cognitive and behavioral traits. While many of these traits are associated with academic achievement, the relationship of EDC exposure specifically with academic achievement in adolescence has not yet been studied. ObjectiveWe assessed the association of urinary biomarker concentrations of EDCs with academic achievement in adolescents as well as the potential for psychosocial factors to modify associations. MethodsWe quantified urinary concentrations of select EDCs in 205 adolescent participants from the New Bedford Cohort (NBC), a prospective birth cohort of children born to mothers residing near the New Bedford Harbor Superfund site in Massachusetts, and estimated associations between EDCs and adolescent academic achievement assessed with the Wide Range Achievement Test (WRAT). Measures of socioeconomic status and the home environment were used to estimate psychosocial stress. ResultsUrinary concentrations of antiandrogenic phthalates were inversely associated with Math Computation scores. For example, each doubling of the concentration of antiandrogenic phthalate metabolites in urine was associated with a 1.94 point decrease (95% CI: 3.84, −0.05) in Math Computation scores, indicating poorer performance. For the most part, associations were stronger in adolescents with more, as compared to less, social disadvantage, but most of these differences did not achieve statistical significance. ConclusionOur findings support the potential for adolescents’ exposure to antiandrogenic phthalates to correlate with poorer academic achievement in math, particularly among participants with greater psychosocial stress.

Calcium supplementation and body mass index modify associations between prenatal phthalate exposure and perinatal bone ultrasound measures among pregnant women

Phthalates have endocrine activity that may interfere with bone health, particularly during pregnancy and the early postpartum period, when bone resorption increases. We evaluated associations between prenatal phthalate exposure and perinatal bone health among 289 mothers in the ELEMENT birth cohort in Mexico City who were randomized upon recruitment to receive 1,200 mg daily calcium supplementation or placebo throughout pregnancy. Spot urine samples at up to three timepoints during pregnancy were assayed for 9 phthalate metabolites. Bone integrity was assessed by quantitative ultrasound speed of sound (SOS) measurements of the phalange and distal radius at 3, 6, and 8 months of pregnancy and 1, 3, 7, and 12 months postpartum. Geometric means of specific gravity-corrected phthalate concentrations were used as overall measures of prenatal exposure. Linear mixed effect models estimated associations between phthalate exposure and repeated perinatal bone SOS measures, adjusting for age, pre-pregnancy body mass index (BMI), education, parity, calcium supplementation, and month of pregnancy/postpartum. Effect modification by calcium supplementation and BMI were assessed in sensitivity analyses. An interquartile range increase in MEP and MiBP increased pregnancy phalange z-scores (β: 0.11; 95%CI: 0.003, 0.31 and β: 0.15; 95%CI: 0.00,0.42, respectively). Higher concentrations of several phthalate metabolites resulted in lower SOS measures among women who received calcium supplements (compared to placebo group) but higher SOS measures among women with a BMI≥25 (compared to BMI<25). These results suggest that phthalate exposure may interfere with bone remodeling during pregnancy, and that consideration of effect modifiers is paramount to fully understand the effects of environmental exposures on bone health.

Associating phthalate exposure during pregnancy with preschooler's FMI, ABSI and BRI trajectories via putative mechanism pathways

Phthalates are well-known obesogens, but a few studies have explored their impacts on the childhood fat mass index (FMI), body shape index (ABSI) and body roundness index (BRI). Information from 2950 participants recruited in the Ma'anshan Birth Cohort was analyzed. The relationships between six maternal phthalate metabolites and their mixture and childhood FMI, ABSI and BRI were investigated. FMI, ABSI and BRI in children aged 3.5 y, 4.0 y, 4.5 y, 5.0 y, 5.5 y and 6.0 y were calculated. The latent class trajectory modeling categorized the FMI trajectories into “rapidly increasing FMI” (4.71%) and “stable FMI” (95.29%) groups; ABSI trajectories were categorized as “decreasing ABSI” (32.74%), “stable ABSI” (46.55%), “slowly increasing ABSI” (13.26%), “moderately increasing ABSI” (5.27%) and “rapidly increasing ABSI” (2.18%) groups; BRI trajectories were categorized as “increasing BRI” (2.82%), “stable BRI” (19.85%), and “decreasing BRI” (77.34%) groups. Prenatal MEP exposure was associated with repeated measurements of FMI (β = 0.111, 95% CI = 0.002–0.221), ABSI (β = 0.145, 95% CI = 0.023–0.268) and BRI (β = 0.046, 95% CI = −0.005–0.097). Compared with each stable trajectory group, prenatal MEP (OR = 0.650, 95% CI = 0.502–0.844) and MBP (OR = 0.717, 95% CI = 0.984–1.015) were linked to a decreased risk of “decreasing BRI” in children; there was a negative relationship between MBP and the “decreasing ABSI” group (OR = 0.667, 95% CI = 0.487–0.914), and MEP increased the risks of “slowly increasing ABSI” (OR = 1.668, 95% CI = 1.210–2.299) and “rapidly increasing ABSI” (OR = 2.522, 95% CI = 1.266–5.024) in children. Phthalate mixture during pregnancy showed significant relationships with all anthropometric indicator trajectories, with MEP and MBP always being of the largest importance. In conclusion, this study suggested that prenatal phthalate coexposure increased the childhood probability of being in higher ABSI and BRI trajectory groups. That is, children were more likely to be obese when they were exposed to higher levels of some phthalate metabolites and their mixture. The low-molecular weight phthalates, including MEP and MBP, contributed the greatest weights.

O-090 Endocrine disruptors

Abstract Female mammals, including women, are exposed to endocrine disrupting chemicals (EDCs) on a daily basis. This is of concern because many EDCs inhibit ovarian follicle growth and steroidogenesis, processes that are critical for maintaining female fertility. Our research focuses on the effects of EDCs known as phthalates on female fertility. Phthalates are of interest because they are ubiquitous synthetic chemicals used as plasticizers and stabilizers in a myriad of consumer products, including everything from shower curtains to children’s toys to cosmetics and personal care products such as perfumes, nail polish, deodorants, and lotions. Phthalates are also used in pesticides, wood finishes, adhesives, solvents, lubricants, defoaming agents, and in medical devices including tubing, blood bags, surgical gloves, and dialysis equipment. Despite the widespread use of phthalates and ubiquitous human exposure, limited information is available about the effects of environmentally relevant phthalate mixtures on female reproduction. Thus, we tested the hypothesis that prenatal exposure to an environmentally relevant phthalate mixture affects female reproduction in the F1, F2, and F3 generations of mice. To test this hypothesis, pregnant CD-1 mice were orally dosed with vehicle control (corn oil) or a phthalate mixture (20µg/kg/day-500mg/kg/day) daily from gestational day 10 to birth. The mixture was based on urinary phthalate metabolite levels measured pregnant women in the United States, and consisted of 35% diethyl phthalate, 21% di(2-ethylhexyl) phthalate, 15% dibutyl phthalate, 15% di-isononyl phthalate, 8% diisobutyl phthalate, and 5% benzylbutyl phthalate. Adult F1 females born to these dams were used to create the F2 generation by mating them with unexposed males and F2 females were used to create the F3 generation by mating them with unexposed males. At selected times, estrous cyclicity and fertility indices were monitored and ovaries and sera were collected for analysis. Our data indicate that prenatal exposure to the phthalate mixture significantly decreases anogenital distance, testosterone levels, and litter size, but it significantly increases abnormal estrous cyclicity, uterine weight, the number of cystic ovaries, follicle-stimulating hormone levels, and luteinizing hormone levels compared to control in the F1 generation. Further, our data indicate that prenatal exposure to the phthalate mixture increases body weight, uterine weight, the number of cystic ovaries, and time to pregnancy and it decreases testosterone levels compared to control in the F2 generation. In addition, our data indicate that prenatal exposure to the phthalate mixture increases body weight, uterine weight, the number of cystic ovaries, and abnormal cyclicity and it decreases anogenital distance and the number of live pups compared to control in the F3 generation. Collectively, these data suggest that prenatal exposure to an environmentally relevant mixture of phthalates adversely affects reproductive function in a multi- and transgenerational manner in female mice. These findings have increased our understanding of the mechanisms by which EDCs cause female reproductive toxicity. This information eventually may lead to the development of novel targets for the prevention or treatment of infertility induced by EDCs.

Associations of urinary phthalate metabolites with household environments among mothers and their preschool-age children

Phthalates have become a matter of public health concern due to their extensive use worldwide and negative health effects. The evaluation of potential sources of phthalate exposure is crucial to design prevention strategies, especially for vulnerable populations. This study included 528 mother-child pairs in the Taiwan Mother Infant Cohort Study who were followed up at ages 3–6 years between 2016 and 2020. Each mother was interviewed by using a structured questionnaire containing questions on demographic characteristics and household environment factors, such as the use of plastic food packaging, residential visible mold, insecticide sprays, and electric mosquito repellents. Eleven phthalate metabolites were analyzed in urine samples simultaneously collected from the mother-child pairs. The phthalate metabolite urinary concentrations were higher among the children than among their mothers, except those of mono-ethyl phthalate (MEP) and mono-2-ethylhexyl phthalate (MEHP). Multiple linear regression analyses showed that urine samples collected during the summer showed higher concentrations of phthalate metabolites than those collected during the winter. Family income levels had negative associations with the concentrations of MnBP and metabolites of di-2-ethylhexyl phthalate (DEHP) in children. The use of plastic food packaging was positively associated with mono-n-butyl phthalate (MnBP) and metabolites of DEHP in mothers. Residential visible mold or mold stains were significantly associated with higher MnBP and DEHP metabolite concentrations in children. The use of insecticide sprays was positively associated with MnBP concentrations in children. Significant associations between household environmental factors and phthalate exposure were mostly found in children, potentially indicating different exposure pathways between mothers and their children. Findings from this study provide additional information for the design of prevention strategies to protect the health of children and women.

180-LB: Associations of Phthalate Metabolites with Glycemic Parameters and Fetal Growth in Type 1 Diabetes (T1D) Pregnancies

Background: The risk of delivering a large for gestational age (LGA) infant is higher in pregnant individuals with T1D compared to individuals without diabetes, despite advances in managing T1D in pregnancy. Exposure to endocrine disrupting chemicals (e.g., phthalates) can affect both glucose homeostasis and fetal growth. Objective: To estimate associations of urinary phthalate metabolite levels with continuous glucose monitoring (CGM) data in pregnancy and birthweight. Methods: We analyzed urinary levels of 14 phthalate metabolites and derived trimester-specific CGM summary measures in 32 pregnant women with T1D. We estimated associations of log2-transformed urinary metabolite levels with continuous CGM outcomes and infant weight (GROW percentile) using linear regression, and estimated associations between metabolite levels and odds of LGA (GROW percentile ≥90) vs. AGA (&amp;lt;90) using logistic regression. Models were adjusted for maternal age and gestational week of study visit. Results: Participants were primarily white (85%), nulliparous (53%), with a mean age of 33 years, and 50% had LGA infants. Concentrations of mono-benzyl phthalate (mBzP) and mono-carboxy octyl phthalate (mCNP), were associated with glycemia in the 3rd trimester. Specifically, each doubling of mBzP and mCNP concentration was associated with 8.5 mg/dL (95% CI: 1.4, 15.6) and 8.9 mg/dL (-1.3, 19.0) higher average glucose, -6.0% (-10.9, -1.0) and -8.9% (-15.1, -2.7) less time spent in range (63-140mg/dL), and 5.9% (0.7, 11.2) and 7.4% (0.3, 14.5) more time spent above range (&amp;gt;140 mg/dL). Phthalates were not associated with continuous GROW percentile. Conclusion: Exposure to certain phthalates in later pregnancy may affect glycemic control in pregnant individuals with T1D. However, effects of phthalate exposure on birthweight are unclear. Future studies may disentangle the extent to which phthalate exposure and its effects on glycemic control may impact fetal growth. Disclosure E. V. Preston: None. F. M. Brown: Other Relationship; Dexcom, Inc. G. A. Hansbury: None. J. C. O'connell: None. D. Wolfs: None. J. Dreyfuss: None. S. Wolpowitz: None. Z. Wang: None. T. James-todd: None. E. M. Isganaitis: None. Funding National Institute of Environmental Health Sciences; National Institute of Diabetes and Digestive and Kidney Diseases

Longitudinal association of prepubertal urinary phthalate metabolite concentrations with pubertal progression among a cohort of boys

BackgroundEpidemiological studies have reported associations of anti-androgenic phthalate metabolite concentrations with later onset of male puberty, but few have assessed associations with progression. ObjectivesWe examined the association of prepubertal urinary phthalate metabolite concentrations with trajectories of pubertal progression among Russian boys. MethodsAt enrollment (ages 8–9 years), medical history, dietary, and demographic information were collected. At entry and annually to age 19 years, physical examinations including testicular volume (TV) were performed and spot urines collected. Each boy's prepubertal urine samples were pooled, and 15 phthalate metabolites were quantified by isotope dilution LC-MS/MS at Moscow State University. Metabolites of anti-androgenic parent phthalates were included: butylbenzyl (BBzP), di-n-butyl (DnBP), diisobutyl (DiBP), di(2-ethylhexyl) (DEHP) and diisononyl (DiNP) phthalates. We calculated the molar sums of DEHP, DiNP, and all AAP metabolites. We used group-based trajectory models (GBTMs) to identify subgroups of boys who followed similar pubertal trajectories from ages 8–19 years based on annual TV. We used multinomial and ordinal regression models to evaluate whether prepubertal log-transformed phthalate metabolite concentrations were associated with slower or faster pubertal progression trajectories, adjusting for covariates. Results304 boys contributed a total of 752 prepubertal urine samples (median 2, range: 1–6) for creation of individual pools. The median length of follow-up was 10.0 years; 79% of boys were followed beyond age 15. We identified three pubertal progression groups: slower (34%), moderate (43%), and faster (23%) progression. A standard deviation increase in urinary log-monobenzyl phthalate (MBzP) concentrations was associated with higher adjusted odds of being in the slow versus faster pubertal progression trajectory (aOR 1.47, 95% CI 1.06–2.04). None of the other phthalate metabolites were associated with pubertal progression. ConclusionsOn average, boys with higher concentrations of prepubertal urinary MBzP had a slower tempo of pubertal progression, perhaps attributable to the disruption of androgen-dependent biological pathways.

Exposure to phthalate metabolites, bisphenol A, and psychosocial stress mixtures and pregnancy outcomes in the Atlanta African American maternal-child cohort

BackgroundConsumer products are common sources of exposure for phthalates and bisphenol A (BPA), which disrupt the endocrine system. Psychosocial stressors have been shown to amplify the toxic effects of endocrine disruptors but, information is limited among African Americans (AAs), who experience the highest rates of adverse pregnancy outcomes and are often exposed to the highest levels of chemical and non-chemical stressors. We examined the association between an exposure mixture of phthalate metabolites, BPA, and psychosocial stressors with gestational age at delivery and birthweight for gestational age z-scores in pregnant AA women. Study designParticipants were enrolled in the Atlanta African American Maternal-Child Cohort (N = 247). Concentrations of eight phthalate metabolites and BPA were measured in urine samples collected at up to two timepoints during pregnancy (8–14 weeks gestation and 20–32 weeks gestation) and were averaged. Psychosocial stressors were measured using self-reported, validated questionnaires that assessed experiences of discrimination, gendered racial stress, depression, and anxiety. Linear regression was used to estimate individual associations between stress exposures (chemical and psychosocial) and birth outcomes. We leveraged quantile g-computation was used to examine joint effects of chemical and stress exposures on gestational age at delivery (in weeks) and birthweight for gestational age z-scores. ResultsA simultaneous increase in all phthalate metabolites and BPA was associated with a moderate reduction in birthweight z-scores (mean change per quartile increase = −0.22, 95% CI = −0.45, 0.0). The association between our exposure mixture and birthweight z-scores became stronger when including psychosocial stressors as additional exposures (mean change per quantile increase = −0.35, 95% CI = −0.61, −0.08). Overall, we found null associations between exposure to chemical and non-chemical stressors with gestational age at delivery. ConclusionsIn a prospective cohort of AA mother-newborn dyads, we observed that increased prenatal exposure to phthalates, BPA, and psychosocial stressors were associated with adverse pregnancy outcomes.

Distribution of phthalate metabolites, benzophenone-type ultraviolet filters, parabens, triclosan and triclocarban in paired human hair, nail and urine samples

In this study, the distribution of nineteen ingredients of personal care product (PCPs), including seven metabolites of phthalates (mPAEs), five benzophenone-type ultraviolet filters (BPs), and seven antimicrobial agents (AAs), were investigated in paired human hair, nail and urine samples. The median concentrations of ΣmPAEs, ΣBPs and ΣAAs were 135, 2.76 and 179 ng/g in hair, 37.3, 2.95 and 297 ng/g in nails, and 345, 4.03 and 50.1 ng/mL in urine, respectively. Mono-methyl phthalate (49%), 2,4-dihydroxybenzophenone (45%) and triclosan (71%) were the most abundant mPAE, BP and AA in hair samples, respectively, and had similar abundance in nail samples. In contrast, mono-n-butyl phthalate (45%), 4-hydroxy benzophenone (29%) and methyl paraben (54%) were the predominant mPAE, BP and AA in urine samples, respectively. Significant differences in the concentrations of some target compounds were observed between male and female but inconsistent across different matrices. Moreover, most compounds with significant correlations had quite different correlation coefficients in each matrix. No significant correlations were found between hair, nail and urine samples for most of the target analytes. These results suggest these analytes have matrix-specific distribution, and it is necessary to use multiple matrices to comprehensively assess the risk of ingredients of PCPs to human health.

#3383 ASSOCIATION BETWEEN MELAMINE AND PHTHALATES AND URINARY RENAL INJURY MARKERS AMONG CHILDREN AGED 4 YEARS

Abstract Background and Aims Chronic kidney disease (CKD) is a global public health issue and the prevalence and incidence of CKD and end-stage renal disease (ESRD) in Taiwan are among the highest in the world. The pathophysiology of renal function downhill is complex and multifactorial, and previous studies suggest that we should be concerned about the effects of low-dose environmental exposure to melamine and phthalate in increasing the risk of renal injury in susceptible populations such as children. However, the sex difference in renal injury related to environmental exposure among children is unknown. The aim of this study is to investigate the relationship between early renal injury biomarkers and melamine and phthalate exposure among boys and girls aged 4 years in Taiwan. Method In total, 1,676 pregnant women were enrolled in the original Taiwan Maternal and Infant Cohort Study (TMICS), a multicenter birth cohort study conducted at 9 hospitals in northern, central, southern, and eastern Taiwan from October 2012 to May 2015. Of those, 694 children aged 4 years participated in follow-up questionnaire interviews, received physical examinations and blood and urine tests from August 2016 to February 2020. After excluding 142 participants with missing data, the final statistical analysis of follow-up data included 552 children. One-spot overnight urine specimens were used to simultaneously measure melamine, 11 phthalate metabolites, and two markers of renal injury, microalbumin and N-acetyl-beta-D-glucosaminidas (NAG). Average daily intake (ADI) levels of melamine and six parental phthalates, including DEHP (di-2-ethylhexylphthalate), DiBP (Dibutyl phthalate), DnBP (Di-n-butyl phthalate), BBzP (Butyl benzyl phthalate), and DEP (Diethyl phthalate), were estimated using a creatinine excretion-based model from urine melamine and phthalate metabolites. We used a weighted quantile sum (WQS) regression model to select the most important exposure variables of ADI levels of phthalates and melamine associated with urine microalbumin to creatinine ratio (ACR) and NAG; Furthermore, to examine effects of those most important exposure variables on ACR and NAG in multivariable linear regression models. The significance was set as two-sided p &amp;lt; 0.05. Results Of them, 319 (57.8%) and 223(42.2%) were boys and girls, respectively, with a median age of 4.0±0.8 years old. Median ADI levels (µg/kg bw/day) were 5.73 for DEHP, 1.75 for DEP, 3.23 for DnBP, 0.07 for BBzP, 1.37 for DiBP, and 1.18 for melamine and there is not significantly different between boys and girls. Using the WQS regression model to examine the association between ADI levels of melamine and phthalates and urine ACR and NAG, we found that a significant and positive association between the WQS score and ACR (β1 = 0.083, p = 0.023). ADI levels of melamine had the highest weight (0.650). Furthermore, we found that the highest (quartile 4) of ADI levels of melamine had the significantly higher ACR in all children (adjusted β = 0.131, p = 0.036), compared to other quartiles (quartile 1, 2 and 3). In subgroup analysis, the significant association between melamine intake and urine ACR was found in boys (adjusted β = 0.249, p = 0.003), not in girls. Conclusion Environmental exposure to melamine may be associated with urine ACR among children aged 4 years in Taiwan, and boys may be easily affected by melamine exposure.

Prenatal exposure to phthalates and gender-specific play behavior at seven years of age in the SELMA study

BackgroundA growing body of evidence shows that prenatal exposure to phthalates affects child development. Since many phthalates have been shown to alter endocrine signaling, they may influence reproductive development, neurodevelopment, and child behavior. Indeed, a few studies reported associations between prenatal phthalate exposure and gender-specific play behavior. However, evidence for this relationship is limited, and previous findings are based on single phthalates, while human exposure entails mixtures of chemicals. ObjectiveWe aimed to investigate the associations between prenatal exposure to single phthalates, as well as a phthalate mixture, and gender-specific play behavior. MethodsA total of 715 mother–child pairs from the Swedish Environmental Longitudinal, Mother and Child, Asthma and Allergy (SELMA) study were included. In the median week 10 of pregnancy, phthalate metabolites were measured in urine. Gender-specific play behavior was measured with Preschool Activities Inventory at the age of seven years. Linear and weighted quantile sum regressions were used; data was stratified by sex. Models were adjusted for child and maternal age, maternal education, parental attitudes toward play behavior, and urinary creatinine concentration. ResultsFor boys, single compound analyses revealed negative associations of prenatal exposure to di-isononyl phthalate (DINP) concentrations with masculine (β = −1.44; 95% CI = −2.72, −0.16) and composite (β = −1.43; 95% CI = −2.72, −0.13) scores. Suggestive associations were also observed with a mixture approach identifying DINP as the main contributor of the association of decreased masculine play. Among girls, higher urinary concentrations of 2,4-methyl-7-oxyooctyl-oxycarbonyl-cyclohexane carboxylic acid (MOiNCH) was associated with decreased feminine (β = −1.59; 95% CI = −2.62, −0.57) and masculine scores (β = −1.22; 95% CI = −2.14, −0.29), whereas the mixture analyses did not yield conclusive results for girls. ConclusionOur findings suggest associations of prenatal exposure to DINP with decreased masculine play behavior in boys while the results for girls were not fully conclusive.

Oxidatively generated DNA damage mediates the associations of exposure to phthalates with uterine fibroids and endometriosis: Findings from TREE cohort

BackgroundEpidemiological studies on phthalate exposures in associations with uterine fibroids (UF) and endometriosis (EMT) are inconsistent. The underlying mechanisms are poorly understood. ObjectivesTo investigate the relationships of urinary phthalate metabolites with UF and EMT risks, and further to examine the mediating role of oxidative stress. MethodsThis study included 83 and 47 women separately diagnosed with UF and EMT, as well as 226 controls from the Tongji Reproductive and Environmental (TREE) cohort. Two spot urine samples from each woman were analyzed for two oxidative stress indicators and eight urinary phthalate metabolites. Unconditional logistic regression models or multivariate regression models were fitted to evaluate the associations among phthalate exposures, oxidative stress indicators, and the risks of UF and EMT. The potential mediating role of oxidative stress was estimated by the mediation analyses. ResultsWe observed that each ln-unit increase in urinary mono-benzyl phthalate (MBzP) concentrations was associated with increased UF risk [adjusted OR (aOR): 1.56, 95% CI: 1.20, 2.02], and that each ln-unit increase in urinary MBzP (aOR: 1.48, 95% CI: 1.09, 1.99), mono-isobutyl phthalate (MiBP) (aOR: 1.83, 95% CI: 1.19, 2.82), and mono-2-ethylhexyl phthalate (MEHP) (aOR: 1.66, 95% CI: 1.19, 2.31) concentrations were associated with increased EMT risk (all FDR-adjusted P < 0.05). Moreover, we observed that all tested urinary phthalate metabolites were positively associated with two oxidative stress indicators [4-hydroxy-2-nonenal-mercapturic acid (4-HNE-MA) and 8-hydroxy-2-deoxyguanosine (8-OHdG)], in which 8-OHdG was associated with increased risks of UF and EMT (all FDR-adjusted P < 0.05). The mediation analyses showed that 8-OHdG mediated the positive relationships of MBzP with UF risk, and of MiBP, MBzP, and MEHP with EMT risk, with the estimated intermediary proportion ranging from 32.7% to 48.1%. ConclusionsOxidatively generated DNA damage may mediate the positive associations of certain phthalate exposures with the risks of UF and EMT. However, further investigation is warranted to confirm these findings.

Exposure of Swedish adolescents to elements, persistent organic pollutants (POPs), and rapidly excreted substances - The Riksmaten adolescents 2016-17 national survey.

Adolescence is a period of significant physiological changes, and likely a sensitive window to chemical exposure. Few nation-wide population-based studies of chemical body burdens in adolescents have been published. In the national dietary survey Riksmaten Adolescents (RMA) 2016-17, over 13 chemical substance groups, including elements, chlorinated/brominated/fluorinated persistent organic pollutants (POPs) were analysed in blood, and in urine metabolites of phthalates/phthalate alternatives, phosphorous flame retardants, polycyclic aromatic hydrocarbons (PAHs), and pesticides, along with bisphenols and biocide/preservative/antioxidant/UV filter substances (N=1082, ages 11-21). The aim was to characterize the body burdens in a representative population of adolescents in Sweden, and to compare results with human biomonitoring guidance values (HBM-GVs). Cluster analyses and Spearman's rank order correlations suggested that concentrations of substances with known common exposure sources and similar toxicokinetics formed obvious clusters and showed moderate to very strong correlations (r≥0.4). No clusters were formed between substances from different matrices. Geometric mean (GM) concentrations of the substances were generally less than 3-fold different from those observed among adolescents in NHANES (USA 2015-16) and GerES V (Germany 2014-17). Notable exceptions were brominated diphenyl ethers (PBDEs) with >20-fold lower GM concentrations, and the biocide triclosan and ultraviolet (UV) filter benzophenone-3 with >15-fold lower mean concentrations in RMA compared to NHANES. Exceedance of the most conservative HBM-GVs were observed for aluminium (Al, 26% of subjects), perfluorooctanesulfonic acid (PFOS, 19%), perfluorooctanoic acid (PFOA, 12%), lead (Pb, 12%), MBP (dibutyl phthalate metabolite, 4.8%), hexachlorobenzene (HCB, 3.1%) and 3-phenoxybenzoic acid (PBA, pyrethroid metabolite, 2.2%). Males showed a higher proportion of exceedances than females for Pb, HCB and PFOS; otherwise no gender-related differences in exceedances were observed. A higher proportion of males than females had a Hazard Index (HI) of substances with liver and kidney toxicity and neurotoxicity >1. Industrialized countries with similarly high standards of living, with some exceptions, show comparable average body burdens of a variety of toxic chemicals among adolescents from the general population. The exceedances of HBM-GVs and HIs strongly suggests that further efforts to limit chemical exposure are warranted.

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.

Association between phthalate exposure and the risk of depressive symptoms in the adult population of the United States

Previous research has suggested an association between phthalate exposure and depressive symptoms, but the evidence is limited. Our study aimed to examine the association between phthalate exposure and the risk of depressive symptoms in the US adult population. We used data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018 to analyze the association between urinary phthalates and depressive symptoms. We included 11 urinary phthalate metabolites in our analysis and used the 9-item Patient Health Questionnaire (PHQ-9) to assess the presence of depression among study participants. Participants were divided into quartiles for each urinary phthalate metabolite, and we evaluated the association using a generalized linear mixed model with a logit link and binary distribution. A total of 7340 participants were included in the final analysis. After controlling for potential confounders, we found a positive association between the molar sum of di (2-ethylhexyl) phthalate (DEHP) metabolites and depressive symptoms, with an odds ratio of 1.30 (95% CI = 1.02–1.66) for the highest compared to the lowest quartile. In addition, we found positive associations of mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono (2-ethyl-5-carboxypentyl) phthalate (MECPP) with depressive symptoms, with odds ratios of 1.43 (95% CI = 1.12–1.81, p for trend = 0.02) and 1.44 (95% CI = 1.13–1.84, p for trend = 0.02), respectively, when comparing the highest quartile to the lowest quartile.. In conclusion, this study is the first to identify a positive association between DEHP metabolites and the risk of depressive symptoms in the general adult population in the United States.

Perinatal and postnatal exposure to phthalates and early neurodevelopment at 6 months in healthy infants born at term.

Phthalates are non-persistent chemicals largely used as plasticizers and considered ubiquitous pollutants with endocrine disrupting activity. The exposure during sensible temporal windows as pregnancy and early childhood, may influence physiological neurodevelopment. The aim of this study is to analyze the relationship between the urinary levels of phthalate metabolites in newborn and infants and the global development measured by the Griffiths Scales of Children Development (GSCD) at six months. Longitudinal cohort study in healthy Italian term newborn and their mothers from birth to the first 6 months of life. Urine samples were collected at respectively 0 (T0), 3 (T3), 6 (T6) months, and around the delivery for mothers. Urine samples were analyzed for a total of 7 major phthalate metabolites of 5 of the most commonly used phthalates. At six months of age a global child development assessment using the third edition of the Griffith Scales of Child Development (GSCD III) was performed in 104 participants. In a total of 387 urine samples, the seven metabolites analyzed appeared widespread and were detected in most of the urine samples collected at any time of sampling (66-100%). At six months most of the Developmental Quotients (DQs) falls in average range, except for the subscale B, which presents a DQ median score of 87 (85-95). Adjusted linear regressions between DQs and urinary phthalate metabolite concentrations in mothers at T0 and in infants at T0, T3 and T6 identified several negative associations both for infants' and mothers especially for DEHP and MBzP. Moreover, once stratified by children's sex, negative associations were found in boys while positive in girls. Phthalates exposure is widespread, especially for not regulated compounds. Urinary phthalate metabolites were found to be associated to GSCD III scores, showing inverse association with higher phthalate levels related to lower development scores. Our data suggested differences related to the child's sex.

Phthalates exposure and pubertal development in a 15-year follow-up birth cohort study in Taiwan.

Phthalates are ubiquitous endocrine disruptors that can affect pubertal development in children. The association of fetal and childhood levels of phthalates with pubertal development were explored. We conduct a population-based birth cohort study to investigate the association between prenatal and childhood exposure to phthalates and pubertal development. Initially, a total of 445 children were recruited from 2000 to 2001, of which 90 children were followed for 15 years which measurements of urine and development assessed at 2, 5, 8, 11, and 14 years. We defined higher Tanner stage as the 14-year-old Tanner stage ≥ 4 and 5 for boys and girls, respectively. A logistic regression analysis was conducted to estimate the crude and adjusted odds ratio of a higher Tanner stage at 14 years old. The Pearson correlation coefficient and multiple linear regression were used to estimate the association of testicular volume, uterine volume, ovarian volume, and blood hormones at 14 years of age with the log-transformed concentration of phthalates at 2, 5, 8, 11, and 14 years. In boys, a significantly different geometric mean of mono-benzyl phthalate (MBzP) was observed in 11-year-olds; 6.82 and 2.96 in the lower Tanner stage group and higher Tanner stage group. In girls, a significant difference in the geometric mean of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) in 11-year-olds and mono-ethyl phthalate (MEP) in 2-year-olds was observed; MEHHP was 32.97 and 18.13 in the lower Tanner stage group and higher Tanner stage group, and MEP was 26.54 and 65.74 in the lower Tanner stage group and higher Tanner stage group, respectively. Uterine volume at 14 years old was negatively associated with several phthalate metabolites (MEHP at 8 years old, MnBP at 8 years old, MBzP at 14 years old, MMP prenatally, MMP at 8 years old, and MEP at 8 years old) after adjusting for covariates. However, no significant correlations were found between phthalate metabolites and ovarian or testicular volume. Phthalate exposure at certain time points may influence the reproductive development of children during puberty; however, further studies should be conducted to determine the causal nature of this association.

Supporting legislative action: Urinary levels of phthalates and phenols among influencers in the ‘Plastics in the spotlight’ advocacy initiative

BackgroundSociety-wide initiatives to prevent human exposure to plastic residues include laws and policies. Such measures require citizens’ support, which can be increased by honest advocacy and pedagogic projects. These efforts must have a scientific basis. ObjectiveTo assist the ‘Plastics in the spotlight’ advocacy initiative raise awareness among the general public of the presence of plastic residues in the human body, and to increase citizens' support for legislation on plastic control in the European Union. MethodsSpot urine samples of 69 volunteers with cultural and political influence from Spain, Portugal, Latvia, Slovenia, Belgium, and Bulgaria were collected. Concentrations of 30 phthalate metabolites and phenols were determined through a high-performance liquid chromatography with tandem mass spectrometry and ultra-high-performance liquid chromatography with tandem mass spectrometry, respectively. ResultsAt least 18 compounds were detected in all urine samples. The maximum number of compounds detected per participant was 23, and the mean, 20.5. Phthalates were detected more frequently than phenols. Median concentrations were highest for monoethyl phthalate (41.6 ng/mL, adjusted for specific gravity), and maximum concentrations were highest for mono-iso-butyl phthalate (1345.1 ng/mL), oxybenzone (1915.1 ng/mL), and triclosan (949.6 ng/mL). Most reference values were not exceeded. Women had higher concentrations of the 14 phthalate metabolites and oxybenzone than men. Urinary concentrations were not correlated with age. DiscussionThe study had three main limitations: method of subject selection (volunteers), small sample size, and limited data on determinants of exposure. Studies on volunteers do not pretend to be representative of the general population and are no substitute for biomonitoring studies in representative samples of the populations of interest. Studies as ours can only illustrate the existence and some aspects of the problem, and can raise awareness among citizens concerned by the evidence that the studies provide in a group of subjects who are humanly appealing. ConclusionsThe results illustrate that human exposure to phthalates and phenols is widespread. All countries appeared to be similarly exposed to these contaminants, with higher levels in females. Most concentrations did not exceed reference values. The effects of this study on the objectives of the ‘Plastics in the spotlight’ advocacy initiative deserve a specific analysis from policy science.