Mono-isobutyl Phthalate Concentrations Research Articles

A Comprehensive Assessment of Associations between Prenatal Phthalate Exposure and the Placental Transcriptomic Landscape.

Background:Phthalates are commonly used endocrine-disrupting chemicals that are ubiquitous in the general population. Prenatal phthalate exposure may alter placental physiology and fetal development, leading to adverse perinatal and childhood health outcomes.Objective:We examined associations between prenatal phthalate exposure in the second and third trimesters and the placental transcriptome at birth, including genes and long noncoding RNAs (lncRNAs), to gain insight into potential mechanisms of action during fetal development.Methods:The ECHO PATHWAYs consortium quantified 21 urinary phthalate metabolites from 760 women enrolled in the CANDLE study (Shelby County, TN) using high-performance liquid chromatography–tandem mass spectrometry. Placental transcriptomic data were obtained using paired-end RNA sequencing. Linear models were fitted to estimate separate associations between maternal urinary phthalate metabolite concentration during the second and third trimester and placental gene expression at birth, adjusted for confounding variables. Genes were considered differentially expressed at a Benjamini-Hochberg false discovery rate (FDR) . Associations between phthalate metabolites and biological pathways were identified using self-contained gene set testing and considered significantly altered with an FDR-adjusted .Results:We observed significant associations between second-trimester phthalate metabolites mono (carboxyisooctyl) phthalate (MCIOP), mono-2-ethyl-5-carboxypentyl phthalate, and mono-2-ethyl-5-oxohexyl phthalate and 18 genes in total, including four lncRNAs. Specifically, placental expression of NEAT1 was associated with multiple phthalate metabolites. Third-trimester MCIOP and mono-isobutyl phthalate concentrations were significantly associated with placental expression of 18 genes and two genes, respectively. Expression of genes within 27 biological pathways was associated with mono-methyl phthalate, MCIOP, and monoethyl phthalate concentrations.Discussion:To our knowledge, this is the first genome-wide assessment of the relationship between the placental transcriptome at birth and prenatal phthalate exposure in a large and diverse birth cohort. We identified numerous genes and lncRNAs associated with prenatal phthalate exposure. These associations mirror findings from other epidemiological and in vitro analyses and may provide insight into biological pathways affected in utero by phthalate exposure. https://doi.org/10.1289/EHP8973

Gestational phthalate exposures and bone mineral density in early adolescence: the HOME Study

Background/Aim: Phthalate exposures have been associated with lower areal bone mineral density (aBMD) and osteoporosis in adults. Although early life may be a period of heightened susceptibility to environmental osteotoxicants, we are unaware of any studies of phthalate exposures in utero and aBMD in children. Thus, we examined gestational phthalate exposures and early adolescent aBMD in a prospective birth cohort study. Methods: We used data from 225 pregnant mothers and their children enrolled in a Cincinnati, OH area cohort from 2003-2006. We measured monobutyl phthalate (MnBP), monobenzyl phthalate (MBzP), mono-(3-carboxypropyl) phthalate (MCPP), monoethyl phthalate (MEP), monoisobutyl phthalate (MiBP), and four metabolites of di-2-ethylhexyl phthalate (DEHP) in maternal urine collected at 16- and 26-weeks gestation and calculated the average of creatinine-adjusted concentrations. We measured children’s femoral neck, distal forearm (1/3 radius), spine, total hip, and total body (excluding head) aBMD with dual x-ray absorptiometry at 12 years of age and calculated height-, age-, sex-, and race-specific aBMD z-scores. We estimated covariate-adjusted associations per 2-fold increase in maternal urinary phthalate concentrations and assessed effect measure modification (EMM) by child’s sex using sex-stratified models. Results: In adjusted analyses, higher MCPP and MEP concentrations were associated with greater aBMD at all sites with estimates generally stronger for MCPP. For example, associations of MCPP and MEP concentrations with total hip aBMD z-score were 0.16 (95% CI: 0.01, 0.32) and 0.09 (95% CI: 0.01, 0.17), respectively. Sex modified urinary MEP and MiBP concentration’s associations with spine aBMD. Higher MEP concentrations were associated with greater spine aBMD z-score in males (β = 0.19, 95% CI: 0.09, 0.30; EMM p-value 0.06) while higher MiBP concentrations were associated with greater spine aBMD z-score in females (β = 0.24, 95% CI: 0.07, 0.41; EMM p-value 0.07). Conclusions: Gestational phthalate exposures may increase bone mineral density in early adolescence.

Urinary Concentrations of Phthalate Metabolite Mixtures in Relation to Serum Biomarkers of Thyroid Function and Autoimmunity among Women from a Fertility Center.

Background:Although previous epidemiological studies have explored associations of phthalate metabolites with thyroid function, no studies to date have assessed associations of mixtures with thyroid function and autoimmunity among potentially susceptible subgroups such as subfertile women.Objective:We aimed to explore associations of mixtures of urinary phthalate metabolites with serum markers of thyroid function and autoimmunity.Methods:This cross-sectional study included 558 women attending a fertility center who provided one spot urine and one blood sample at enrollment (2005–2015). We quantified urinary concentrations of eight phthalate metabolites using mass spectrometry, and biomarkers of thyroid function [thyroid-stimulating hormone (TSH), free and total thyroxine (, ) and triiodothyronine (, ), and autoimmunity [thyroid peroxidase and thyroglobulin antibodies (TPOAb and TgAb, respectively)] in serum using electrochemiluminescence assays. We applied principal component analysis (PCA) and Bayesian kernel machine regression (BKMR) to identify the main patterns of urinary phthalate metabolites. We used linear mixed models to assess the association between PCA-derived factor scores in quintiles and serum thyroid function and autoimmunity, adjusting for age, body mass index (BMI), specific gravity (SG), and, for the PCA, other factor scores.Results:We observed two factors using PCA, one representing the di(2-ethylhexyl) (DEHP) and another non-DEHP metabolites. Compared to women in the lowest quintile of the DEHP factor scores, women in the highest quintile had significantly lower serum concentrations of , , , and [absolute difference: ; 95% confidence interval (CI): , ; ; absolute difference: ; 95% CI: , ; ; absolute difference: ; 95% CI: 0.54, ; ; and absolute difference: ; 95% CI: , ; , respectively]. Using BKMR, we observed that mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) was the primary contributor to these negative associations. DEHP and non-DEHP factor scores were not associated with serum TSH, TgAb, or TPOAb.Conclusions:Mixtures of urinary DEHP metabolites were inversely associated with serum biomarkers of thyroid function but not with autoimmunity, which were within normal ranges for healthy adult women. https://doi.org/10.1289/EHP6740

Pregnancy intention and phthalate metabolites among pregnant women in The Infant Development and Environment Study cohort.

Preconception life style and health play a pivotal role in positively impacting the health of a pregnancy, and this includes the reduction of exposure to endocrine-disrupting chemicals such as phthalates. We have previously demonstrated that women planning a pregnancy with assisted reproductive technology (ART) have lower phthalate metabolite concentrations than their non-ART-using counterparts. To determine whether women who intended to become pregnant had lower phthalate metabolite concentrations than those who had an unintended pregnancy, or whether change in phthalate exposure across pregnancy differed between these two groups. A total of 721 women enrolled in The Infant Development and Environment Study (TIDES), a multicentre US prospective pregnancy cohort; 513 (71%) indicated their pregnancy was planned. Urine samples from first- and third-trimester visits were analysed for 10 specific-gravity-adjusted, natural-log-transformed phthalate metabolites. Simple and multivariable linear regression, adjusting for centre, race, age, income, marital status, and parity, were employed to determine whether phthalate metabolite concentrations differed by pregnancy intention. In bivariate analyses, the geometric mean concentrations of all first-trimester and most third-trimester phthalates were higher in women with unplanned pregnancies. However, after covariate adjustment, only first-trimester monoisobutyl phthalate (MiBP) remained associated with pregnancy intention, and the association changed direction such that unplanned pregnancies had lower MiBP concentrations (ß -0.18, 95% CI -0.35, -0.02). We did not find evidence of a difference in phthalate exposure between pregnancy planners and non-planners.

Urinary levels of phthalate metabolites in women associated with risk of premature ovarian failure and reproductive hormones.

Phthalates, a class of high production-volume chemicals widely used as plasticizers, have been shown to impair ovarian functions in female animals, but epidemiological evidence is very limited. In this case-control study, the associations between phthalate exposure and premature ovarian failure (POF) in women were assessed. A total of 173 POF cases and 246 control women were recruited in Zhejiang, China. The urinary concentrations of 8 phthalate metabolites and the serum levels of ovary-related hormones were determined. Mono-isobutyl phthalate (MiBP) was the metabolite with the highest median concentration of 27.23 μg/g of creatinine in the whole group. Compared with the lowest quartile, higher urinary concentrations of MiBP were significantly associated with increased odds of POF (OR = 1.38, 95% CI: 0.73-2.61 for the fourth quartile; p for trend = 0.01). The estradiol/FSH ratio, a marker of ovarian function, in control women was significantly negatively associated with the urinary concentrations of most tested phthalate metabolites. Our results suggest that exposure to some phthalates may impair ovarian function and increase the odds of POF in women.

Unhealthy Levels of Phthalates and Bisphenol A in Mexican Pregnant Women with Gestational Diabetes and Its Association to Altered Expression of miRNAs Involved with Metabolic Disease.

Several studies indicate that bisphenol A (BPA) and phthalates may have a role in the development of metabolic diseases using different molecular pathways, including epigenetic regulatory mechanisms. However, it is unclear whether exposure to these chemicals modifies serum levels of miRNAs associated with gestational diabetes mellitus (GDM) risk. In the present study, we evaluated the serum levels of miRNAs associated with GDM (miR-9-5p, miR-16-5p, miR-29a-3p and miR-330-3p) and urinary levels of phthalate metabolites (mono-n-butyl phthalate (MBP), mono-isobutyl phthalate (MiBP), mono-benzyl phthalate (MBzP) and mono(2-ethyl hexyl) phthalate (MEHP)) and bisphenol A in GDM patients and women without GDM during the second trimester of gestation. We observed higher levels of miR-9-5p, miR-29a-3p and miR-330-3p in sera of patients with GDM compared to non-diabetic subjects. Phthalates were detected in 97–100% of urine samples, while BPA only in 40%. Urinary MEHP and BPA concentrations were remarkably higher in both study groups compared to previously reported data. Unadjusted MEHP levels and adjusted BPA levels were higher in non-diabetics than in GDM patients (p = 0.03, p = 0.02). We found positive correlations between adjusted urinary MBzP levels and miR-16-5p expression levels (p < 0.05), adjusted MEHP concentrations and miR-29a-3p expression levels (p < 0.05). We also found negative correlations between unadjusted and adjusted MBP concentrations and miR-29a-3p expression levels (p < 0.0001, p < 0.05), unadjusted MiBP concentrations and miR-29a-3p expression levels (p < 0.01). Urinary MEHP levels reflect a striking exposure to di(2-ethylhexyl) phthalate (DEHP) in pregnant Mexican women. This study highlights the need for a regulatory strategy in the manufacture of several items containing endocrine disruptors in order to avoid involuntary ingestion of these compounds in the Mexican population.

Urinary phthalate metabolites and metabolic syndrome in U.S. adolescents: Cross-sectional results from the National Health and Nutrition Examination Survey (2003-2014) data.

There is limited research on the association between phthalates and metabolic syndrome (MetS). Among adolescents, phthalate exposure, which can occur from multiple sources, has been linked to several risk factors for MetS. The objective was to investigate the association between urinary phthalate metabolite concentrations (i.e., mono-ethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), mono-benzyl phthalate (MBzP), mono-(3-carboxylpropyl) phthalate (MCPP), and di(2-ethylhexyl phthalate (DEHP)) and MetS in adolescents aged 12-19 years using the National Health and Nutrition Examination Survey (NHANES) data (2003-2014). A secondary aim was to assess if observed associations varied by a measure of socioeconomic status, economic adversity, which was defined using parental income and educational attainment as well as household food security. We used NHANES data which included physical examination, laboratory urinalysis and fasting blood profiles, and self-reported health characteristics and demographics. Physical examination and laboratory data were used to obtain values of MetS components and urinary phthalate metabolites. We created age-, sex-, and survey year-specific tertiles of creatinine-corrected urinary phthalate metabolites. Analysis was performed using appropriate weighting procedures that accounted for NHANES' complex sampling design. After univariate and bivariate analyses, we performed adjusted logistic regressions to test for associations between individual phthalate metabolites and MetS as well as MetS components and number of MetS components, separately, using the lowest tertile as the reference category. A cross-product term (phthalate metabolite*economic adversity) was subsequently added to adjusted models. Among 918 participants (mean age 16 years, 45% female, 18% with economic adversity), the prevalence of MetS was 5.3%. Prior to adjustment, adolescents with MetS had marginally higher concentrations of phthalate metabolites than adolescents without MetS. There was a suggestive positive association between intermediate concentrations of MnBP and odds of MetS after adjustment (T2: Odds Ratio (OR) = 2.66 (95% confidence interval: 0.98-7.24); T3: OR = 2.11 (0.71-6.27)). Males with higher MnBP concentrations had higher odds of dyslipidemia; however, associations were mostly non-significant for females. Relationships between MiBP concentrations and odds of MetS varied by sex. Males with higher concentrations of MnBP and MiBP had greater odds of having a higher number of MetS components. Relationships between phthalate metabolites and MetS did not vary by economic adversity. There was a suggestive positive association between MnBP and MetS among adolescents. Associations between phthalate metabolites and MetS as well as MetS components may vary by sex, but may not vary by economic adversity. Further research of the relationships between phthalate exposures, MetS, and potential interactions with socioeconomic factors is warranted.

Associations between Birthweight, Mono-isobutyl Phthalate Concentrations, Behaviors, Non-chemical Stressors and Overweight and Obesity in Young U.S. Adolescents

Associations between Birthweight, Mono-isobutyl Phthalate Concentrations, Behaviors, Non-chemical Stressors and Overweight and Obesity in Young U.S. Adolescents

Exposure To Select Phthalates And Phenols Through Use Of Personal Care Products Among Californian Adults And Their Children

Introduction: Certain phenols and phthalates are used in personal care products (PCPs). Aims: We aimed to study the associations between the use of PCPs and urinary concentrations of biomarkers of select phenols and phthalates among Californian adults and their children. Methods: Our study relied on a subsample of 90 adult-child pairs participating in the Study of Use of Products and Exposure Related Behavior (SUPERB). Each adult and child provided one to two urine samples in which we measured concentrations of the metabolites of 5 phenols and 3 low molecular weight phthalates. We used adjusted linear and Tobit regression models to study the associations between the use of PCPs in the past 24 hours and biomarker concentrations. Results: Benzophenone-3 (BP3) and paraben concentrations were higher in adults compared to their children. Conversely children had higher mono-n-butyl phthalate and mono-isobutyl phthalate concentrations. No significant difference was observed for the other compounds. In adults, the total number of different PCPs used was positively associated with urinary concentrations of methyl-, propyl- and butyl- parabens and the main metabolite of diethyl phthalate. Among children, the use of a few specific products including liquid soap, hair care products and sunscreen was positively associated with urinary concentrations of some phenols or phthalate metabolites. Discussion: These results strengthen the body of evidence suggesting that use of PCPs is an important source of exposure to parabens and diethyl phthalate in adults and provide data on exposure to selected phenols and phthalates through use of PCPs in children.

Exposure to select phthalates and phenols through use of personal care products among Californian adults and their children

IntroductionCertain phenols and phthalates are used in many consumer products including personal care products (PCPs). AimsWe aimed to study the associations between the use of PCPs and urinary concentrations of biomarkers of select phenols and phthalates among Californian adults and their children. As an additional aim we compared phenols and phthalate metabolites concentrations measured in adults and children urine samples collected the same day. MethodsOur study relied on a subsample of 90 adult–child pairs participating in the Study of Use of Products and Exposure Related Behavior (SUPERB). Each adult and child provided one to two urine samples in which we measured concentrations of selected phenols and phthalate metabolites. We computed Spearman correlation coefficients to compare concentrations measured in adults and children urine samples collected the same day. We used adjusted linear and Tobit regression models to study the associations between the use of PCPs in the past 24h and biomarker concentrations. ResultsBenzophenone-3 and parabens concentrations were higher in adults compared to their children. Conversely children had higher mono-n-butyl phthalate and mono-isobutyl phthalate concentrations. No significant difference was observed for the other compounds. The total number of different PCPs used was positively associated with urinary concentrations of methyl, propyl and butyl parabens and the main metabolite of diethyl phthalate in adults. Among children, the use of a few specific products including liquid soap, hair care products and sunscreen was positively associated with urinary concentrations of some phenols or phthalate metabolites. DiscussionThese results strengthen the body of evidence suggesting that use of PCPs is an important source of exposure to parabens and diethyl phthalate in adults and provide data on exposure to selected phenols and phthalates through use of PCPs in children.

Prenatal phthalate exposures and neurobehavioral development scores in boys and girls at 6-10 years of age.

Background: There is concern over potential neurobehavioral effects of prenatal phthalate exposures, but available data are inconsistent.Objectives: We examined associations between prenatal urinary concentrations of phthalate metabolites and neurobehavioral scores among children.Methods: We measured phthalate metabolite concentrations in urine samples from 153 pregnant participants in the Study for Future Families, a multicenter cohort study. Mothers completed the Child Behavior Checklist when the children were 6–10 years of age. We estimated overall and sex-specific associations between phthalate concentrations and behavior using adjusted multiple regression interaction models.Results: In boys, concentrations of monoisobutyl phthalate were associated with higher scores for inattention (β = 0.27; 95% CI: 0.04, 0.50), rule-breaking behavior (β = 0.20; 95% CI: 0.01, 0.38), aggression (β = 0.34; 95% CI: 0.09, 0.59), and conduct problems (β = 0.39; 95% CI: 0.20, 0.58), whereas the molar sum of di(2-ethylhexyl) phthalate metabolites was associated with higher scores for somatic problems (β = 0.15; 95% CI: 0.03, 0.28). Higher monobenzyl phthalate concentrations were associated with higher scores for oppositional behavior (β = 0.16; 95% CI: 0.01, 0.32) and conduct problems (β = 0.21; 95% CI: 0.06, 0.37) in boys, but with reduced anxiety scores in girls (β = –0.20; 95% CI: –0.39, –0.01). In general, the associations reported above were close to the null among girls. Model coefficients represent the difference in the square root–transformed outcome score associated with a 1-unit increase in log-transformed metabolites.Conclusions: Our results suggest associations between exposure to certain phthalates in late pregnancy and behavioral problems in boys. Given the few studies on this topic and methodological and population differences among studies, additional research is warranted.Citation: Kobrosly RW, Evans S, Miodovnik A, Barrett ES, Thurston SW, Calafat AM, Swan SH. 2014. Prenatal phthalate exposures and neurobehavioral development scores in boys and girls at 6–10 years of age. Environ Health Perspect 122:521–528; http://dx.doi.org/10.1289/ehp.1307063