Mono-n-butyl Phthalate Research Articles

Di-n-butyl phthalate, butylbenzyl phthalate and their metabolites induce haemolysis and eryptosis in human erythrocytes

Phthalates have been extensively used as plasticizers in various fields, including food, cosmetic, and pharmaceutical industry. Those compounds do not form covalent bonds to substances they are being added to, and thus they may migrate easily and penetrate various products used every day. They may reach organisms with air, food, or by a direct skin contact. Significant levels of phthalates and their metabolites are found in urine, breast milk, blood serum, venous blood, and cord blood.The purpose of this study was to assess the simple toxicity (haemolysis) and programmed death (eryptosis) caused by following phthalates: di-n-butyl phthalate (DBP), butylbenzyl phthalate (BBP) and their metabolites: mono-n-butyl phthalate (MBP) and mono-benzyl phthalate (MBzP) in vitro in human RBCs. RBCs were incubated with the above mentioned compounds at concentrations ranging between 0.5 and 500 μg/mL for 24 h.Obtained results demonstrated that DBP and BBP possess higher haemolytic properties compared to their metabolites. The lethal concentration (LC50) was determined. The value was 126.37 ± 5.94 μg/mL for DBP, and 103.65 ± 4.03 μg/mL for BBP, and for metabolites the LC50 value was over 500 μg/mL.All compounds induced eryptosis causing translocation of phosphatidylserine, increased cytosolic calcium ions level, increased caspase-3 and calpain activation in human erythrocytes. BBP caused translocation of phosphatidylserine at a lower concentration compared to DBP. In case of other parameters, more pronounced changes were evoked by DBP at lower concentrations. Metabolites showed a significantly lower toxicity compared to parent compounds.

Phthalate exposure in Thai children and adolescents

Abstract Background Phthalates are found in products made of plastic. Because of concerns regarding the hazards of phthalate exposure, including endocrine disruption, many countries have regulations to restrict their use in products used by children. However, in Thailand, no such restrictions exist, and data relating to phthalate exposure are scarce. Objectives To determine the level of exposure of Thai children and adolescents to phthalates, and study its associations with sociodemographic data and the exposure to potential sources of phthalates. Methods Healthy children aged 2–18 y were enrolled into the present cross-sectional study between January 2016 and December 2016 inclusive. Their anthropometric indices and Tanner staging were determined. Urinary concentrations of the phthalate metabolites, monomethyl phthalate (MMP) and mono-n-butyl phthalate (MBP), were determined in spot samples by high-performance liquid chromatography to estimate the level of phthalate exposure. Associations between sociodemographic data, exposure to potential sources of phthalates, and phthalate metabolite concentrations were analyzed. Results We included 103 boys and 118 girls with a mean age of 9.4 ± 3.64 (range 2.8–17.1) y and detected MMP in 28.5% and MBP in 88.6%. The geometric means (interquartile range) of urinary MMP and MBP were 3400 (2489, 4642) and 214.4 (164, 279) μg/g creatinine (Cr), respectively. Significant associations were found between exposure to floor cleaning products and Cr-adjusted urinary MMP level (P < 0.05), and paint and Cr-adjusted urinary MMP and MBP levels (P < 0.05). Prepuberty was significantly associated with urinary Cr-adjusted MMP level. Conclusion Urinary phthalate metabolite levels were high in a proportion of Thai children and adolescents. Exposure to floor cleaning products and paint is associated with phthalate exposure, and advanced Tanner stage is negatively associated with urinary Cr-adjusted MBP.

Simultaneous determination of primary and secondary phthalate monoesters in the Taihu Lake: Exploration of sources

While phthalates monoesters have been recognized as the bioactive metabolites of phthalates, the knowledge on their environmental occurrence and sources is limited. In this study, monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-iso-butyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), and mono-2-ethylhexyl phthalate (MEHP) were frequently detected in water samples from the Taihu Lake in China using an improved SPE-LC-MS-MS method. The mean concentrations for MMP, MEP, MiBP, MnBP, and MEHP were 51.7 ± 25.2, 6.0 ± 4.8, 19.6 ± 14.6, 42.2 ± 64.7, and 33.0 ± 37.4 ng/L, respectively, while those of their corresponding parent chemicals, DMP, DEP, DiBP, and DnBP and DEHP, were 36.54 ± 43.22, 42.64 ± 66.66, 246.8 ± 311.1, 524.7 ± 586.9, and 208.1 ± 223.5 ng/L, respectively. Three secondary monoesters of DEHP, mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono (2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono (2-ethyl-5-carboxypentyl) phthalate (MECPP) were for the first time detected with mean concentration of 1.27 ± 1.33, 1.33 ± 1.54, and 0.73 ± 0.79 ng/L, respectively. The percentage of the sum concentration of MEOHP, MEHHP, and MECPP relative to total concentration of DEHP metabolites was 5.3–12.4%. DEHP was identified to be biodegraded into secondary phthalate monoesters in water from the Taihu Lake, but their contribution to the total concentration of DEHP metabolites was 1.2–3.6%, lower than those in the Taihu Lake. Primary and secondary DEHP monoesters were also detected in influents and effluents of two sewage treatment plants adjacent to the Taihu Lake, the percentages of secondary DEHP monoesters in influents were 5.8% and 11.3%, similar with those in the Taihu Lake. Taken together with their relatively high concentrations in influents, the discharging of domestic wastewater may be an important contributor to the occurrence of phthalate monoesters in the Taihu Lake.

Screening of lactic acid bacteria strains for their ability to bind phthalate monoesters in vitro and the binding characteristics

In the present study, thirty lactic acid bacteria (LAB) strains were first screened for their ability to remove mono-n-butyl phthalate (MBP) in vitro, one representative of phthalate monoesters (PMEs), from the aqueous solution. Three Lactobacillus plantarum and two L. fermentum strains removed more than 25% MBP and were selected for further investigation of the binding characteristics. Consequently, five LAB strains were resistant to MBP, and the binding ability depends on initial MBP and bacterial cell concentrations. In particular, the removal was a fast and reversible process, and pH plays a major role in the binding capability. Both heat-treated and acid-treated bacteria were capable of removing the MBP, indicating the binding, not metabolism, is the mechanism by which MBP is removed from the aqueous solution. Acid treatment can increase the binding ability of LAB and also enhance the stability of MBP-LAB complex. In addition, these LAB strains could remove different percentages of other several common PMEs from the aqueous solution, especially exhibiting high binding capability on monoethylhexyl phthalate. These findings indicate that some specific LAB strains are able to detoxify phthalate monoesters and may be useful to protect humans and/or animals from the adverse health effects of PAEs.

Association between phthalate exposure and lower lung function in an urban elderly population: A repeated-measures longitudinal study

BackgroundLung function is a major predictor of morbidity and mortality. Only a few studies have explored the association between phthalate exposure and lung function. ObjectiveTo evaluate the association between phthalate exposure and lung function in the elderly. MethodsA total of 3 repeated-measures surveys were conducted in 559 elderly individuals aged ≥60 years in Seoul, Korea, at 1-year intervals (2012–2015). During each survey, urinary mono-(2-ethyl-5-hydrohexyl) phthalate (MEHHP) (geometric mean, 15.68 μg/L), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) (11.97 μg/L), and mono-n-butyl phthalate (MnBP) (2.09 μg/L) levels were measured; moreover, lung function tests and a structured questionnaire interview were performed. We constructed linear mixed models to assess the association between urinary phthalate metabolite levels and lung function. ResultsA doubling of creatinine-adjusted urinary phthalate metabolite levels was inversely associated with forced expiratory volume in 1 s (L) (β = −0.01, 95% confidence interval [CI]: −0.02, 0.004 for MEHHP; β = −0.02, 95% CI: −0.03, −0.01 for MEOHP; β = −0.01, 95% CI: −0.03, −0.003 for MnBP) and forced vital capacity (L) (β = −0.02, 95% CI: −0.03, −0.001 for MEHHP; β = −0.02, 95% CI: −0.03, −0.004 for MEOHP; β = −0.02, 95% CI: −0.03, −0.001 for MnBP). A doubling of creatinine-adjusted MnBP levels was associated with increased rates of annual decline in forced vital capacity (L/year) (β = −0.01, 95% CI: −0.02, −0.001). ConclusionsUrinary phthalate metabolite levels were associated with lower lung function and an increased rate of decline in lung function in an elderly population.

Association of phthalate exposures with urinary free cortisol and 8-hydroxy-2′-deoxyguanosine in early childhood

Several studies suggested potential links of phthalates to stress-related outcomes. However, limited evidence has been available for the relationships between phthalate metabolites and free cortisol and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in perinatal and postnatal environments. Therefore, we evaluated the relationships between phthalate metabolites and free cortisol and 8-OHdG in mother–child pairs. We repeatedly collected urine samples of 287 mother–child pairs from just before delivery to 15 months of age to measure the levels of four phthalate metabolites – mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-isobutyl phthalate (MiBP), and mono-n-butyl phthalate (MnBP) – and free cortisol and 8-OHdG. We used linear mixed effect models and generalized additive mixed models to estimate the relationship between the phthalate metabolites and free cortisol and 8-OHdG after adjusting for the child's gender, urine collection time, and maternal smoking status. The four phthalate metabolite levels were strongly correlated each other (all, p < .0001), and intra-class correlation for each metabolite in children ranged from 0.18 to 0.96. All four phthalate metabolites were positively associated with both free cortisol (MEHHP, β = 0.18 and p < .0001; MEOHP, β = 0.17 and p < .0001; MiBP, β = 0.13 and p = .0001; MnBP, β = 0.21 and p < .0001; and molar sum of metabolites, β = 0.21 and p < .0001) and 8-OHdG (MEHHP, β = 0.20 and p < .0001; MEOHP, β = 0.18 and p < .0001; MiBP, β = 0.23 and p < .0001; MnBP, β = 0.28 and p < .0001; and molar sum of metabolites, β = 0.29 and p < .0001) in childhood. Our findings suggest that phthalate exposures increase free cortisol and 8-OHdG levels in early childhood.

Phthalate Exposure is associated with Carotid Intima-Media Thickness in Adolescents and Young Adults

Background/Aim: Exposure to phthalates has been linked to cardiovascular risk factors. However, it is unclear regarding phthalates exposure and the risk of subclinical atherosclerosis. This study investigated the association between phthalates exposure and carotid intima-media thickness (CIMT) in young population. Methods: From a nationwide mass urine screening for renal health, conducted in 1992-2000 among school children 6 to 18 years of age in Taiwan, we recruited 789 subjects to participate the cardiovascular health examination in 2006-2008. Among them, 787 received measurements of 7 urinary phthalate metabolites and CIMT. Results: Both mean and maximal values of CIMT at all segments of carotid arteries significantly increased with the urinary mono-2-ethylhexyl phthalate (MEHP), ∑MEHP, and mono-n-butyl phthalate (MnBP) in a dose-response relationship after adjustment for multiple linear regression models. Multivariate logistic regression analysis showed that higher quartiles of urinary concentrations of MEHP, ∑MEHP, and MnBP were associated with a higher risk of thicker CIMT. Compared to subjects with the lowest quartile (Q1) of urinary MEHP, the adjusted odds ratios (aORs) (95% confidence interval (CI)) for thicker CIMT among subjects with higher urinary MEHP were 2.13(1.18-3.84) at Q2, 4.02(2.26-7.15) at Q3 and 7.39(4.16-13.12) at the highest Q4. Comparing those with lowest urinary MnBP, the corresponding aORs (95% CI) were 1.84 (1.08-3.15) for subjects at Q3, and 2.80 (1.65-4.75) for subjects at the highest Q4. Conclusions: Urinary phthalate metabolites of MEHP, ∑MEHP, and MnBP are strongly associated with CIMT in adolescents and young adults in Taiwan.

Urinary phthalate metabolites concentrations and symptoms of depression in an elderly population

BackgroundAnimal studies have reported an association between phthalates and depression, although there is limited evidence from epidemiological studies. We investigated the association between phthalate exposure and symptoms of depression in an elderly population. MethodsRepeated measures surveys up to three times were conducted during the study period (2012–2014) in the 535 elderly subjects. We measured the following urinary phthalate metabolite levels: mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-n-butyl phthalate (MnBP), and mono-benzyl phthalate (MBzP). MEHHP, MEOHP, and MECPP are metabolites of diethylhexyl phthalates (DEHP). MnBP and MBzP are metabolites of dibutyl phthalate and butyl benzyl phthalate, respectively. The phthalate metabolite concentrations were evaluated to identify associations with the symptoms of depression using the Korean version of the Geriatric Depression Scale-Short Form (SGDS-K). After factor analysis of the components of SGDS-K, we evaluated the association between phthalate exposure and SGDS-K subgroups to determine which symptoms of depression were affected by phthalate exposure. ResultsConcentrations of DEHP metabolites were positively associated with the risk of depressive symptoms in the elderly population (Odds ratio (95% confidence interval); 1.92 (1.17–3.13) for sum of three DEHP metabolites), while we found no significant association between depressive symptoms and either MnBP or MBzP. When we evaluated the associations between phthalate metabolite concentrations and the SDGS-K subgroup, we found that affective and spiritual symptoms were significantly associated with DEHP metabolite concentrations. ConclusionsOur study suggests that DEHP exposure is associated with depressive symptoms, particularly, the affective and spiritual symptoms, among the elderly population.

Personal care product use as a predictor of urinary concentrations of certain phthalates, parabens, and phenols in the HERMOSA study.

Use of personal care products, such as makeup, soaps, and sunscreen, may expose adolescent girls to potential endocrine disruptors, including phthalates, parabens, and other phenols. We evaluated the relationship between recent self-reported personal care product use and concentrations for urinary metabolites of phthalates, parabens, triclosan, and benzophenone-3 (BP-3) in 100 Latina adolescents. Girls who reported using makeup every day vs. rarely/never had higher urinary concentrations of monoethyl phthalate (MEP) (102.2 ng/mL vs. 52.4 ng/mL, P-value: 0.04), methyl paraben (MP) (120.5 ng/mL vs. 13.4 ng/mL, P-value < 0.01), and propyl paraben (PP) (60.4 ng/mL vs. 2.9 ng/mL, P-value < 0.01). Girls who reported recent use of specific makeup products, including foundation, blush, and mascara, had higher urinary concentrations of MEP, mono-n-butyl phthalate (MBP), MP, and PP. Use of Colgate Total toothpaste was associated with 86.7% higher urinary triclosan concentrations. Use of sunscreen was associated with 57.8% higher urinary concentrations of BP-3. Our findings suggest that personal care product use is associated with higher exposure to certain phthalates, parabens, and other phenols in urine. This may be especially relevant in adolescent girls who have high use of personal care products during a period of important reproductive development.

Association between prenatal bisphenol A and phthalate exposures and fetal metabolic related biomarkers: The Hokkaido study on Environment and Children's Health

Bisphenol A and phthalates are widely detected in human urine, blood, breast milk, and amniotic fluid. Both bisphenol A and phthalates have been suggested as playing a role in obesity epidemics. Exposure to these chemicals during fetal development, and its consequences should be concerning because they can cross the placenta. Thus, this study aimed to assess the association between prenatal exposure to bisphenol A and phthalates, and cord blood metabolic-related biomarkers. Maternal serum was used during the first trimester, to determine prenatal exposure to bisphenol A and phthalates. Levels of metabolic-related biomarkers in the cord blood were also determined. Linear regression models were applied to the 365 participants with both, exposure and biomarker assessments, adjusted for maternal age, pre-pregnancy body mass index, parity, education, and sex of the child. The level of bisphenol A was negatively associated with the leptin level (β = −0.06, 95% confidence interval [CI]: −0.11, −0.01), but was positively associated with the high-molecular-weight adiponectin level, with marginal significance (β = 0.03, 95%CI: 0.00, 0.06). The mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono-(2-ethylhexyl) phthalate (MEHP), and summation of MEHP and MECPP to represent DEHP exposure (∑DEHPm) levels were inversely associated with the leptin levels (β=−0.14, 95%CI: −0.27, −0.01; β = −0.12, 95%CI: −0.24, 0.00 with marginal significance; β=0.08, 95%CI: −0.14, −0.03; and β = −0.09, 95%CI: −0.16, −0.03, respectively). The present study provided some evidence that prenatal exposure to bisphenol A and certain phthalates may modify fetal adiponectin and leptin levels.

MiR-301b-3p/3584-5p enhances low-dose mono-n-butyl phthalate (MBP)–induced proliferation by targeting Rasd1 in Sertoli cells

To investigate the possible molecular mechanism of low concentration plasticizer mono-n-butyl phthalate (MBP) -induced juvenile Sertoli cells (SCs) proliferation, we evaluated global alterations of miRNA and mRNA expression in rat SCs treated with 0.1mM MBP. Microarray analysis revealed that miR-3584-5p and miR-301b-3p were up-regulated and their common target gene Dexamethasone-induced Ras-related protein 1 (Rasd1) was down-regulated. Further work suggested that SCs proliferation induced by low concentration MBP in vitro might be mediated by Rasd1 regulating ERK1/2 signaling pathway. The present study is first to investigate the effect of low-dose MBP on SCs proliferation and may enhance our understanding on the modes of action of low concentration MBP on male reproductive system. We hope the results will contribute to explain the causes of precocious puberty and testicular tumors induced by exogenous chemicals.

Risk assessment for phthalate exposures in the elderly: A repeated biomonitoring study

Recent studies indicated that exposure to phthalates affects the development of a variety of diseases in the elderly population. However, limited information was available about the variability of phthalate daily intakes (DIs) and the proportion of the population that is highly exposed to phthalates. Therefore, we measured the levels of three phthalate metabolites, mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-n-butyl phthalate (MnBP) in 4014 urine samples repeatedly collected from 1646 elderly people. The DIs of di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DnBP) were calculated using urinary MEHHP, MEOHP, and MnBP levels, and then the proportion of the population that was highly exposed to DEHP and DnBP was calculated. The intra-class correlation (ICC) for MEHHP, MEOHP, and MnBP levels was 0.07, 0.02, and 0.03, respectively, and exposures to DEHP and DnBP were strongly correlated with each other (correlation coefficient=0.89 and p-value<0.0001). The geometric mean of estimated DI was 8.8μg/kgbody-weight/day (range 0.005–3382.0) for DEHP and 1.5μg/kgbody-weight/day (range 0.0002–1076.8) for DnBP. The percentages of urine samples with DEHP > reference dose (RfD, 20μg/kgbody-weight/day) and DnBP > tolerable daily intake (TDI, 10μg/kgbody-weight/day) were 20.2% and 3.6%, respectively. The Korean elderly were co-exposed to DEHP and DnBP, and the variation of DEHP and DnBP metabolite levels was mainly attributed to intra-individual variation, rather than inter-individual variation. Furthermore, Korean elderly were exposed to the hazards of DEHP and DnBP based on the high level of the exceedance rate over TDI or RfD for DEHP and DnBP. Since the elderly are very susceptible to environmental pollutants, the harmful effects of DEHP and DnBP in the elderly population should be further studied in the future.

Prenatal Exposure to Nonpersistent Endocrine Disruptors and Behavior in Boys at 3 and 5 Years.

Background:Sex-specific associations have been reported between phthalates, bisphenol A (BPA), and child behavior. No data on large study populations are available for other phenols with possible endocrine-disrupting properties.Objectives:We aimed to study associations between prenatal exposure to phthalates and several phenols on behavior among male infants.Methods:We quantified 11 phthalate metabolites and nine phenols (four parabens, benzophenone-3, BPA, two dichlorophenols, triclosan) in spot urine samples collected during pregnancy among EDEN cohort mothers who delivered a boy. Mothers completed the Strength and Difficulties Questionnaire (SDQ) when their children were 3.1 () and 5.6 () y old.Results:BPA was positively associated with the relationship problems subscale at 3 y [incidence rate ratio (IRR): 1.11; 95% confidence interval (CI): 1.03, 1.20] and the hyperactivity–inattention subscale scores at 5 y (IRR: 1.08; 95% CI: 1.01, 1.14). Mono-n-butyl phthalate (MnBP) was positively associated with internalizing behavior, relationship problem, and emotional symptom scores at 3 y. Monobenzyl phthalate (MBzP) was positively associated with internalizing behavior and relationship problems scores at 3 y. After dichotomizing SDQ scores, triclosan tended to be positively associated with emotional symptom subscales at both 3 and 5 y.Conclusions:The observed associations between BPA, MnBP, and behavior in boys are consistent with previous findings. Further health impact assessment studies based on dose–response functions corrected for exposure misclassification are required to quantify the public health burden possibly entailed by such associations. https://doi.org/10.1289/EHP1314

Effects of the phthalate exposure during three gestation periods on birth weight and their gender differences: A birth cohort study in China

Phthalate has been widely used as a type of plasticiser in various consuming products in daily life. Recent studies have suggested that prenatal phthalate exposure may have adverse effects on fetal development. We aimed to identify the effects of in utero phthalate exposure on birth weight (BW). We evaluated a birth cohort comprising 3474 pregnant women and their single infants; 3103, 2975 and 2838 urine samples were collected in the first, second and third trimesters, respectively. Phthalate metabolites included monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEHHP), and mono-(2-ethyl-5-hydroxylhexyl) phthalate (MEOHP), which were analysed in the urine by using high performance liquid chromatography–tandem mass spectrometry. Mixed linear model was used in the statistical analysis. Generally, MMP and MEP exposure during pregnancy was associated with decreased birth weight of infants (MMP, β=−12.192, p=0.009; MEP, β=−11.876, p=0.014). Hierarchical analysis found that MMP and MEOHP exposure was associated with decreased infants' birth weight only in low birth weight groups (MMP, β=−42.538, p=0.005; MEOHP, β=−63.224, p=0.008); MEHP and MEHHP exposure was associated with decreased infants' birth weight in both low birth weight group (MEHP, β=−42.348, p=0.035; MEHHP, β=−50.485, p=0.006) and high birth weight group (MEHP, β=−16.580, p=0.034; MEHHP, β=−18.009, p=0.040), MBP and MEHP exposure were associated with increased infants' birth weight in male NBW group (MBP, β=10.438, p=0.039; MEHP, β=13.223, p=0.017). Moreover, the effect has sex difference. The reduction of birth weight associated with MEHP and MEOHP exposure was stronger in male infants, while MMP and MEP exposure was more significant in female infants.

Relationship of urinary phthalate concentrations to female infertility diagnosis

Endocrine disrupting compounds (EDC’s) are known to mimick or antagonize steroid hormone actions in animals. We sought to examine relationships between human female infertility diagnoses and urinary concentrations of 16 EDC’s. Cohort study of 94 women undergoing IVF at an academic medical center participating in the Sperm Epigenetics and Development Study (SEEDS). Urine was collected from women before egg retrieval. Urinary concentrations of phthalate EDC’s were measured by liquid chromatography, and urine specific gravity was measured by a handheld refractometer. Infertility diagnosis as reported to SART was collected. We performed logistic regression for each of 5 diagnoses (PCOS, anovulation, diminished ovarian reserve, unexplained infertility, and endometriosis) with 16 phthalate metabolites, and calculated odds ratios of a particular diagnosis versus.the others for 1 unit change in metabolite values, which were log transformed and corrected for specific gravity and BMI. With each unit increase in log exposure to monobenzyl phthalate (MBzP), there was a corresponding 1.79x increased risk for anovulation (p=0.04). With each unit increase in log exposure to mono-3-hydroxybutly phthalate (MHBP), there was a 2.32x increased risk for anovulation (p=0.06). Each unit increase in log exposure to monocarboxy-isononly phthalate (MCNP) resulted in a 1.87x increase in unexplained infertility (p=0.05). There was a trend toward increased unit log exposure to mono-n-butyl phthalate (MBP) in women with PCOS (1.80x, p=0.12) or with anovulation (1.93x, p = 0.15) compared to other diagnoses. With each unit increase in log exposure to mono-hydroxyiosbutyl phthalate (MHiBP), there was a 0.24x decreased risk for endometriosis (p=0.01). With each unit increase in log exposure to monocarbxylisooctyl phthalate (MCOP), there was a 0.67x decrease in odds for diminished ovarian reserve (p=0.11). Women with the diagnoses of anovulation or PCOS, endometriosis, unexplained infertility, and diminished ovarian reserve differ from each other in their environmental contaminant profile. Further studies are needed to confirm these findings and to determine if specific metabolites contribute to or reduce the development of female infertility.

The effects of maternal and children phthalate exposure on the neurocognitive function of 6-year-old children

The primary purpose of this study was to investigate the effects of phthalate exposure on the intelligence and attentional performance of 6-year old children when adjusting each other as covariates. We also investigated the differential effects of phthalate exposure on the intelligence and attention according to exposure period (maternal or children). Urine concentrations of mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-n-butyl phthalate (MBP) were analyzed. Multivariable linear regression models were used to investigate the relationship between exposure to various phthalates with IQ scores and continuous performance test (CPT) variables. There were robust associations between child MEHHP and MEOHP levels with full scale IQ (FSIQ) even after adjusting for demographic variables and CPT scores (MEHHP −9.27, 95% CI: −17.25, −1.29; MEOHP −9.83, 95% CI: −17.44, −2.21). Child MEHHP and MEHOP levels negatively affected omission errors (MEHHP −20.36, 95% CI: −34.17, −6.55; MEOHP −18.93, 95% CI: −32.58, −5.28) and the response time variability (MEHHP −21.07, 95% CI: −39.04, −3.10; MEOHP −20.41, 95% CI −38.14, −2.69) of the CPT after adjusting for demographic variables and IQ. Maternal phthalate exposure had no effects on IQ or CPT variables. These results suggest that children phthalate exposure, but not maternal exposure, has an adverse effect on IQ and attentional performance, and these associations were found to be independent of each other.

Biodegradation of phthalic acid esters (PAEs) and in silico structural characterization of mono-2-ethylhexyl phthalate (MEHP) hydrolase on the basis of close structural homolog

Three bacterial strains capable of degrading phthalates namely Pseudomonas sp. PKDM2, Pseudomonas sp. PKDE1 and Pseudomonas sp. PKDE2 were isolated and characterized for their degradative potential. These strains efficiently degraded 77.4%–84.4% of DMP, 75.0%–75.7% of DEP and 71.7%–74.7% of DEHP, initial amount of each phthalate is 500mgL−1 of each phthalate, after 44h of incubation. GC–MS results reveal the tentative DEHP degradation pathway, where hydrolases mediate the breakdown of DEHP to phthalic acid (PA) via an intermediate MEHP. MEHP hydrolase is a serine hydrolase which is involved in the reduction of the MEHP to PA. The predicted 3D model of MEHP hydrolase from Pseudomonas mosselii was docked with phthalate monoesters (PMEs) such as MEHP, mono-n-hexyl phthalate (MHP), mono-n-butyl phthalate (MBP) and mono-n-ethyl phthalate (MEP), respectively. Docking results show the distance between the carbonyl carbon of respective phthalate monoester and the hydroxyl group of catalytic serine lies in the range of 2.9 to 3.3Å, which is similar to the ES complex of other serine hydrolases. This structural study highlights the interaction and the role of catalytic residues of MEHP hydrolase involved in the biodegradation of PMEs to phthalate.

Exposure sources and their relative contributions to urinary phthalate metabolites among children in Taiwan.

Phthalate exposure is omnipresent and known to have developmental and reproductive effects in children. The aim of this study was to determine the phthalate exposure sources and their relative contributions among children in Taiwan. During the first wave of the Risk Assessment of Phthalate Incident in Taiwan (RAPIT), in 2012, we measured 8 urinary phthalate metabolites in 226 children aged 1-11 years old and in 181 children from the same cohort for the wave 2 study in 2014. A two-stage statistical analysis approach was adopted. First, a stepwise regression model was used to screen 80 questions that explored the exposure frequency and lifestyle for potential associations. Second, the remaining questions with positive regression coefficients were grouped into the following 6 exposure categories: plastic container/packaging, food, indoor environment, personal care products, toys, and eating out. A mixed model was then applied to assess the relative contributions of these categories for each metabolite. The use of plastic container or food packaging were dominant exposure sources for mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), and mono-n-butyl phthalate (MnBP). The indoor environment was a major exposure source of mono-methyl phthalate (MMP), mono-benzyl phthalate (MBzP), and mono-isobutyl phthalate (MiBP). The consumption of seafood showed a significant correlation with MEHP. The children's modified dietary behavior and improved living environment in the second study wave were associated with lower phthalate metabolite levels, showing that phthalate exposures can be effectively reduced.

Maternal urinary phthalates and sex-specific placental mRNA levels in an urban birth cohort

BackgroundPrenatal urinary concentrations of phthalates in women participants in an urban birth cohort were associated with outcomes in their children related to neurodevelopment, autoimmune disease risk, and fat mass at 3,5,7, and 8 years of life. Placental biomarkers and outcomes at birth may offer biologic insight into these associations. This is the first study to address these associations with candidate genes from the phthalate and placenta literature, accounting for sex differences, and using absolute quantitation methods for mRNA levels.MethodsWe measured candidate mRNAs in 180 placentas sampled at birth (HSD17B1, AHR, CGA, CYP19A1, SLC27A4, PTGS2, PPARG, CYP11A1) by quantitative PCR and an absolute standard curve. We estimated associations of loge mRNA with quartiles of urinary phthalate monoesters using linear mixed models. Phthalate metabolites (N = 358) and mRNAs (N = 180) were transformed to a z-score and modeled as independent, correlated vectors in relation to large for gestational age (LGA) and gestational diabetes mellitus (GDM).ResultsCGA was associated with 4 out of 6 urinary phthalates. CGA was 2.0 loge units lower at the 3rd vs. 1st quartile of mono-n-butyl phthalate (MnBP) (95% confidence interval (CI): −3.5, −0.5) in male placentas, but 0.6 loge units higher (95% CI: −0.8, 1.9) in female placentas (sex interaction p = 0.01). There was an inverse association of MnBP with PPARG in male placentas (−1.1 loge units at highest vs. lowest quartile, 95% CI: −2.0, −0.1). CY19A1, CYP11A1, CGA were associated with one or more of the following in a sex-specific manner: monobenzyl phthalate (MBzP), MnBP, mono-iso-butyl phthalate (MiBP). These 3 mRNAs were lower by 1.4-fold (95% CI: −2.4, -1.0) in male GDM placentas vs. female and non-GDM placentas (p-value for interaction = 0.04). The metabolites MnBP/MiBP were 16% higher (95% CI: 0, 22) in GDM pregnancies.ConclusionsPrenatal concentrations of certain phthalates and outcomes at birth were modestly associated with molecular changes in fetal placental tissue during pregnancy. Associations were stronger in male vs. female placentas, and associations with MnBP and MiBP were stronger than other metabolites. Placental mRNAs are being pursued further as potential mediators of exposure-induced risks to the health of the child.

A cohort study on association between the first trimester phthalates exposure and fasting blood glucose level in the third trimester

Objective: To examine the association between the phthalate exposure in the first trimester and fasting blood glucose level or gestational diabetes mellitus (GDM) in the third trimester in pregnant women. Methods: A total of 3 474 pregnant women, receiving their prenatal examination in Ma' anshan Maternal and Child Health-Care Hospital of Anhui province, were selected from May 2013 to September 2014. Questionnaires were used to collect the information about their socio-demographic characteristics, clinical characteristics and GDM diagnostic results in the first, second and third trimesters. Urine samples and fasting venous blood samples were collected. Concentrations of 7 kinds of phthalate metabolites in urine samples were detected by solid phase extraction-high performance liquid chromatography-tandem mass spectrometry (SPE-HPLC-MS/MS), and multiple linear regression model was used for statistical analyses. Logistic regression analysis on the risk of the first trimester phthalate exposure for GDM in the third trimester was conducted. Results: The prevalence of GDM in this study was 12.8%, monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEHHP) exposure levels were positively correlated with the fasting blood glucose level in the third trimester (P<0.05), but mono-(2-ethylhexyl) phthalate (MEHP) and mono-(2-ethyl-5-hydroxylhexyl) phthalate (MEOHP) exposure levels were negatively correlated with the fasting blood glucose level in the third trimester (P<0.05). Stratified analysis showed a positive correlation between MEHHP exposure and the third trimester fasting blood glucose level in both normal group and GDM group. However, MMP, MEP, MBP, MBzP, MEHP and MEOHP exposure levels had influences on the third trimester fasting blood glucose level in normal group but not in GDM group. MMP and MBP exposure might increase the risk of GDM, but MEOHP exposure might reduce the risk of GDM. Conclusion: The phthalate exposure in the first trimester might be associated with the fasting blood glucose level in the third trimester, MMP, MEP, MBP, MBzP and MEHHP concentrations were positively associated with the third trimester blood glucose level, MEHP and MEOHP concentrations were negatively associated with the third trimester blood glucose level. Moreover, the effects of different kinds of phthalates might be different.