Association between urinary phthalate metabolites and Anemia in US adults.

Initial research indicates a possible connection between exposure to phthalates and the development of anemia. To fill the gap in epidemiological data, our study utilized data from across the United States, representative on a national scale, to evaluate the association between the concentration of phthalate metabolites in urine and both anemia and iron levels. We gathered data on 11,406 individuals from the National Health and Nutrition Examination Survey (NHANES) database, spanning 2003-2018. We conducted logistic and linear regression analyses, adjusted for potential confounding factors, to evaluate the correlations between different phthalate metabolites and anemia, as well as serum iron levels, including gender-stratified analysis. Most urinary phthalate metabolites were positively correlated with an increased risk of anemia, and the majority were negatively correlated with serum iron levels. The study revealed that for every unit increase in ln-transformed metabolite concentrations, the odds ratios (ORs) for anemia increased to varying degrees, depending on the phthalate: Monobutyl phthalate (MBP) at 1.08 (95% CI 1.01-1.17, P = 0.0314), mono(3-carboxypropyl) phthalate (MCPP) at 1.17 (95% CI 1.10-1.24, P < 0.0001), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) at 1.08 (95% CI 1.02-1.15, P = 0.0153), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) at 1.14 (95% CI 1.07-1.21, P < 0.0001), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP) at 1.11 (95% CI 1.03-1.18, P = 0.0030), monocarboxynonyl phthalate (MCNP) at 1.11 (95% CI 1.03-1.19, p = 0.0050), and monocarboxyoctyl phthalate (MCOP) at 1.13 (95% CI 1.07-1.19, P < 0.0001). Increased levels of MBP, MEHP, MBzP, MCPP, MEHHP, MEOHP, MIBP, MECPP, MCNP, and MCOP were linked with changes in serum iron levels, ranging from - 0.99 µg/dL (95% CI - 1.69 to - 0.29) to - 3.72 µg/dL (95% CI - 4.32 to - 3.11). Mixed-exposure analysis shows consistency with single-exposure model. Further mediation analysis showed that the association between single urinary phthalates and the risk of anemia was mediated by serum iron with a mediation ratio of 24.34-95.48% (P < 0.05). The presence of phthalate metabolites in urine shows a positive correlation with the prevalence of anemia, which was possibly and partly mediated by iron metabolism. Nonetheless, to confirm a definitive causal link and comprehend the underlying mechanisms of how phthalate exposure influences anemia, additional longitudinal and experimental research is required.

Evaluation of Exposure to Bisphenol A, Bisphenol F, and Phthalates in Patients with Phenylketonuria and Its Differences According to Dietary Status.

BACKGROUND: Phenylketonuria (PKU) is the most common amino acid metabolism disorder. Patients with blood phenylalanine (Phe) levels of ≥6 mg/dL require treatment, and the most definitive treatment is the Phe-restricted diet. Bisphenols and phthalates are widely used endocrine-disrupting chemicals (EDCs) found in personal care products, baby bottles, and food packaging. METHODS: In this study, we evaluated the possible routes of exposure to these EDCs in patients diagnosed with PKU (n = 105, 2-6 years of age) and determined the relationship between the plasma levels of bisphenol A (BPA), bisphenol F (BPF), di-butyl phthalate (DBP), di-(2-ethylhexyl) phthalate (DEHP), mono-(2ethylhexyl) phthalate (MEHP), and dietary regimens. Participant characteristics and exposure routes were evaluated according to their dietary treatment status. RESULTS: Thirty-four of these patients were on a Phe-restricted diet, while the remaining 71 had no dietary restrictions. DBP and DEHP levels were higher in those using plastic tablecloths (p = 0.049 and p = 0.04, respectively). In addition, plasma DBP levels were higher in those who used bottled water (p = 0.01). Being under 4 years of age, using plastic food containers, and using plastic shower curtains were characteristics associated with higher MEHP levels (p = 0.027, p = 0.019, and p = 0.014, respectively). After adjustment for baseline characteristics (Model 1), the odds of having a plasma BPA level in the upper tertile were 3.34 times higher in the free-diet group (95% CI = 1.09-10.25). When we additionally adjusted for plastic exposure (Model 2), the odds ratio was found to be 18.64 (95% CI = 2.09-166.42) for BPA. In the free-diet group, the probability of having plasma DEHP levels in the upper tertile was increased by a relative risk of 3.01 (p = 0.039, 95% CI = 1.06-8.60). CONCLUSION: Our results indicate that exposure to bisphenols and phthalates varies with dietary treatment. The difference in sources of exposure to EDCs between the diet and non-diet groups indicates that diet plays an important role in EDC exposure.

Association between phthalates exposure and myocardial damage in the general population: A cross-sectional study.

BACKGROUND: Cardiovascular consequences of phthalates exposure have been given increasing attention, but the association of phthalates with subclinical cardiovascular disease (CVD) was unknown. Accordingly, this study aimed to investigate the association between phthalates exposure and high-sensitivity cardiac troponin I (hs-cTnI), a marker of myocardial injury, which was detectable in the subclinical stage of CVD. METHODS: Participants aged 6 years or older with available urinary phthalates metabolites and serum hs-cTnI concentrations were included in the National Health and Nutrition Examination Survey 2003-2004 cycle. Multivariable linear regression and weighted quantiles sum (WQS) regression were used to assess the association of hs-cTnI with individual phthalates and their co-exposure. Di-2-ethylhexylphthalate (ΣDEHP), high-molecular-weight phthalate (ΣHMWP), and low-molecular-weight phthalate (ΣLMWP) were defined as the molecular sum of phthalates metabolites in urine. RESULTS: 2241 participants were finally included. The percent change of serum hs-cTnI concentrations related to per 1-standard deviation increase of logarithmic urinary phthalates concentrations was 3.4% (0.1-6.7, P = 0.04) for ΣDEHP, 3.6% (0.3-6.9, P = 0.03) for ΣHMWP, and 3.5% (0.2-6.8, P = 0.04) for ΣLMWP. Co-exposure to phthalates metabolites expressed as the WQS index also demonstrated a positive association with hs-cTnI. A similar association pattern was found in the population with no prior CVD. CONCLUSIONS: This study indicated the potential of phthalates to myocardial injury which may occur even before clinically apparent CVD was identified, emphasizing the significance of reducing phthalates in the prevention of CVD.

Phthalate exposure during pregnancy and its association with thyroid hormones: A prospective cohort study.

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

The associations between pre-conception urinary phthalate concentrations, the serum metabolome, and live birth among women undergoing assisted reproduction.

BACKGROUND: Phthalates are ubiquitous endocrine disruptors. Past studies have shown an association between higher preconception urinary concentrations of phthalate metabolites and lower fertility in women; however, the biological mechanisms remain unclear. Our exploratory study aimed to understand the metabolites and pathways associated with maternal preconception phthalate exposure and examine if any may underline the association between phthalate exposure and live birth using untargeted metabolomics. METHODS: Participants (n = 183) were part of the Environment and Reproductive Health (EARTH) study, a prospective cohort that followed women undergoing in vitro fertilization (IVF) at the Massachusetts General Hospital Fertility Center (2005-2016). On the same day, women provided a serum sample during controlled ovarian stimulation, which was analyzed for metabolomics using liquid chromatography coupled with high-resolution mass spectrometry and two chromatography columns, and a urine sample, which was analyzed for 11 phthalate metabolites using targeted approaches. We used multivariable generalized linear models to identified metabolic features associated with urinary phthalate metabolite concentrations and live birth, followed by enriched pathway analysis. We then used a meet-in-the-middle approach to identify overlapping pathways and features. RESULTS: Metabolic pathway enrichment analysis revealed 43 pathways in the C18 negative and 32 pathways in the HILIC positive columns that were significantly associated (p < 0.05) with at least one of the 11 urinary phthalate metabolites or molar sum of di-2-ethylhexyl phthalate metabolites. Lipid, amino acid, and carbohydrate metabolism were the most common pathways associated with phthalate exposure. Five pathways, tryptophan metabolism, tyrosine metabolism, biopterin metabolism, carnitine shuttle, and vitamin B6 metabolism, were also identified as being associated with at least one phthalate metabolite and live birth following IVF. CONCLUSION: Our study provides further insight into the metabolites and metabolomics pathways, including amino acid, lipid, and vitamin metabolism that may underlie the observed associations between phthalate exposures and lower fertility in women.

Maternal exposure to bisphenols, phthalates, perfluoroalkyl acids, and trace elements and their associations with gestational diabetes mellitus in the APrON cohort.

The increasing global prevalence of gestational diabetes mellitus (GDM) has been hypothesized to be associated with maternal exposure to environmental chemicals. Here, among 420 women participating in the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort study, we examined associations between GDM and second trimester blood or urine concentrations of endocrine disrupting chemicals (EDCs): bisphenol-A (BPA), bisphenol-S (BPS), twelve phthalate metabolites, eight perfluoroalkyl acids (PFAAs), and eleven trace elements. Fifteen (3.57%) of the women were diagnosed with GDM, and associations between the environmental chemical exposures and GDM diagnosis were examined using multiple logistic and LASSO regression analyses in single- and multi-chemical exposure models, respectively. In single chemical exposure models, BPA and mercury were associated with increased odds of GDM, while a significant inverse association was observed for zinc. Double-LASSO regression analysis selected mercury (AOR: 1.51, CI: 1.12-2.02), zinc (AOR: 0.017, CI: 0.0005-0.56), and perfluoroundecanoic acid (PFUnA), a PFAAs, (AOR: 0.43, CI: 0.19-0.94) as the best predictors of GDM. The combined data for this Canadian cohort suggest that second trimester blood mercury was a robust predictor of GDM diagnosis, whereas blood zinc and PFUnA were protective factors. Research into mechanisms that underlie the associations between mercury, zinc, PFUnA, and the development of GDM is needed.

Prevalence and clinical implications of heightened plastic chemical exposure in pediatric patients undergoing cardiopulmonary bypass.

BACKGROUND: Phthalate chemicals are used to manufacture plastic medical products, including many components of cardiopulmonary bypass (CPB) circuits. We aimed to quantify iatrogenic phthalate exposure in pediatric patients undergoing cardiac surgery and examine the link between phthalate exposure and postoperative outcomes. STUDY DESIGN AND METHODS: The study included pediatric patients undergoing (n=122) unique cardiac surgeries at Children's National Hospital. For each patient, a single plasma sample was collected preoperatively and two additional samples were collected postoperatively upon return from the operating room and the morning after surgery. Concentrations of di(2-ethylhexyl) phthalate (DEHP) and its metabolites were quantified using ultra high-pressure liquid chromatography coupled to mass spectrometry. RESULTS: Patients were subdivided into three groups, according to surgical procedure: (1) cardiac surgery not requiring CPB support, (2) cardiac surgery requiring CPB with a crystalloid prime, and (3) cardiac surgery requiring CPB with red blood cells (RBCs) to prime the circuit. Phthalate metabolites were detected in all patients, and postoperative phthalate levels were highest in patients undergoing CPB with an RBC-based prime. Age-matched (<1 year) CPB patients with elevated phthalate exposure were more likely to experience postoperative complications. RBC washing was an effective strategy to reduce phthalate levels in CPB prime. DISCUSSION: Pediatric cardiac surgery patients are exposed to phthalate chemicals from plastic medical products, and the degree of exposure increases in the context of CPB with an RBC-based prime. Additional studies are warranted to measure the direct effect of phthalates on patient health outcomes and investigate mitigation strategies to reduce exposure.

Association of endocrine disrupting chemicals levels in serum, environmental risk factors, and hepatic function among 5- to 14-year-old children.

Endocrine-disrupting chemicals (EDCs) might increase the risk of childhood diseases by disrupting hormone-mediated processes that are critical for growth and development during childhood, however, the association among the exposure level of EDCs such as Nonylphenol (NP), Bisphenol A (BPA), Dimethyl phthalate (DMP) in children and environmental risk factors, as well as hepatic function has not been elaborated. This study aimed to discuss this interesting relationship among NP, BPA, DMP concentrations in serum, environmental risk factors, hepatic function of 5- to 14-year-old children in industrial zone, residential zone and suburb in northern district of Guizhou Province, China. In Zunyi city, 1006 children participated in cross-sectional health assessments from July to August 2018, and their parents completed identical questionnaires on the environmental risk factors of EDCs exposure to mothers and children. Serum NP, BPA and DMP concentrations were measured by high performance liquid chromatography (HPLC). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT, total bilirubin (TBIL), direct bilirubin (DBIL) and indirect bilirubin (IBIL) were detected with automatic biochemical analyzer. The median concentrations of serum NP, BPA, and DMP in the participants were 45.85 ng/mL, 26.31 ng/mL and 31.62 ng/mL, respectively, which were higher than the environmental concentration limits of the U.S. National Environmental Protection Agency (EPA). Hair gels used during pregnancy, types of domestic drinking water, nail polish and cosmetics used by children were significantly positive correlated with serum NP concentration (P < 0.05). Gender, feeding pattern, plastic water cup used during pregnancy, hair spray and perfume use for children, duration of children birth, materials for baby bottle or cup and ways to plastic products were significantly positively correlated with serum BPA concentration (P < 0.05). Gender, perms used during pregnancy, hair spray and perfume use for children, using plastic lunch box during pregnancy, duration of children birth, exposure to pesticides, parents' occupations were significantly positively correlated with serum DMP concentrations (P < 0.05). Serum NP (ß = 0.296, P = 0.036) and DMP (ß = 0.316, P = 0.026) concentrations and TBIL level were significantly positively correlated. Serum NP concentration and the levels of IBIL (ß = 0.382, P = 0.006) are significantly positively correlated. Cosmetics used during pregnancy significantly increased AST level (ß = 2.641, P = 0.021). There was a positive correlation between the frequency of hair spray and perfume use for children and the AST (ß = 4.241, P = 0.022). NP, BPA and DMP, which were commonly detected in the serum of children aged 5-14 years old in Zunyi City, Northern Guizhou Province, China, were closely related to the environmental risk factors of exposure environment during pregnancy, infancy and school age. Exposure to NP, BPA and DMP would have negative effects on hepatic function, and these effects showed differences in gender and geographical location. Notably,The relationships were more evident in girls than in boys.

Large-Scale Implementation and Flaw Investigation of Human Serum Suspect Screening Analysis for Industrial Chemicals.

Non-targeted analysis (NTA), including both suspect screening analysis (SSA) and unknown compound analysis, has gained increasing popularity in various fields for its capability in identifying new compounds of interests. Current major challenges for NTA SSA are that (1) tremendous effort and resources are needed for large-scale identification and confirmation of suspect chemicals and (2) suspect chemicals generally show low matching rates during identification and confirmation processes. To narrow the gap between these challenges and smooth implementation of NTA SSA methodology in the biomonitoring field, we present a thorough SSA workflow for the large-scale screen, identification, and confirmation of industrial chemicals that may pose adverse health effects in pregnant women and newborns. The workflow was established in a study of 30 paired maternal and umbilical cord serum samples collected at delivery in the San Francisco Bay area. By analyzing LC-HRMS and MS/MS data, together with the assistance of a combination of resources including online MS/MS spectra libraries, online in silico fragmentation tools, and the EPA CompTox Chemicals Dashboard, we confirmed the identities of 17 chemicals, among which monoethylhexyl phthalate, 4-nitrophenol, tridecanedioic acid, and octadecanedioic acid are especially interesting due to possible toxicities and their high-volume use in industrial manufacturing. Similar to other previous studies in the SSA field, the suspect compounds show relatively low MS/MS identification (16%) and standard confirmation (8%) rates. Therefore, we also investigated origins of false positive features and unidentifiable suspected features, as well as technical obstacles encountered during the confirmation process, which would promote a better understanding of the flaw of low confirmation rate and encourage gaining more effective tools for tackling this issue in NTA SSA.

Moderate Folic Acid Supplementation in Pregnant Mice Results in Altered Methyl Metabolism and in Sex-Specific Placental Transcription Changes.

SCOPE: Many pregnant women have higher folic acid (FA) intake due to food fortification and increased vitamin use. It is reported that diets containing five-fold higher FA than recommended for mice (5xFASD) during pregnancy resulted in methylenetetrahydrofolate reductase (MTHFR) deficiency and altered choline/methyl metabolism, with neurobehavioral abnormalities in newborns. The goal is to determine whether these changes have their origins in the placenta during embryonic development. METHODS AND RESULTS: Female mice are fed control diet or 5xFASD for a month before mating and maintained on these diets until embryonic day 17.5. 5xFASD led to pseudo-MTHFR deficiency in maternal liver and altered choline/methyl metabolites in maternal plasma (increased methyltetrahydrofolate and decreased betaine). Methylation potential (S-adenosylmethionine:S-adenosylhomocysteine ratio) and glycerophosphocholine are decreased in placenta and embryonic liver. Folic acid supplemented diet results in sex-specific transcriptome profiles in placenta, with validation of dietary expression changes of 29 genes involved in angiogenesis, receptor biology or neurodevelopment, and altered methylation of the serotonin receptor 2A gene. CONCLUSION: Moderate increases in folate intake during pregnancy result in placental metabolic and gene expression changes, particularly in angiogenesis, which may contribute to abnormal behavior in pups. These results are relevant for determining a safe upper limit for folate intake during pregnancy.

Integrating Intersectionality Into the Exposome Paradigm: A Novel Approach to Racial Inequities in Uterine Fibroids.

Intersectionality is a critical theoretical framework that emphasizes the influence of intersecting systems of oppression on the lived experiences of people marginalized by inequity. Although applications of intersectionality are increasing in public health, this framework is absent in environmental health, which has instead focused on the exposome, a paradigm that considers the totality of an individual's environmental exposures across the life course.Despite advancements in the biological complexity of exposome models, they continue to fall short in addressing health inequities. Therefore, we highlight the need for integrating intersectionality into the exposome. We introduce key concepts and tools for environmental health scientists interested in operationalizing intersectionality in exposome studies and discuss examples of this innovative approach from our work on racial inequities in uterine fibroids.Our case studies illustrate how interlocking systems of racism and sexism may affect Black women's exposure to environmental chemicals, their epigenetic regulation of uterine fibroids, and their clinical care. Because health relies on biological and social-structural determinants and varies across different intersectional positions, our proposed framework may be a promising approach for understanding environmental health inequities and furthering social justice.

Phthalate and Bisphenol Exposure during Pregnancy and Offspring Nonverbal IQ.

BACKGROUND: Prenatal exposures to phthalates and bisphenols are associated with impaired brain development in animals. However, epidemiological studies investigating the association between prenatal phthalate or bisphenol exposure and cognition have produced mixed findings and mostly had modest sample sizes and measured the exposure during the third trimester. OBJECTIVE: We examined the association between pregnancy maternal urinary biomarkers of phthalate or bisphenol exposure and nonverbal intelligence quotient (IQ) in children 6 years of age. METHOD: The study sample consisted of 1,282 mother-child pairs participating in the Generation R Study, a population-based birth cohort in Rotterdam, Netherlands (enrollment 2002-2006). We measured maternal urinary concentrations of 18 phthalate metabolites and 8 bisphenols at <18, 18-25, and >25 wks of gestation. Child nonverbal IQ was measured at 6 years of age using the Snijders-Oomen Nonverbal Intelligence Test-Revised. Linear regression models were fit for each of the three collection phases separately, the three collection phases jointly, and for the averaged prenatal exposure across pregnancy. RESULTS: Higher urinary concentrations of phthalate metabolites during early pregnancy were associated with lower child nonverbal IQ score [e.g., B per 10-fold increase in summed low-molecular weight phthalates=-1.7 (95% CI: -3.1, -0.3)]. This association remained unchanged when adjusted for mid and late pregnancy exposures. We also observed an inverse association between late pregnancy di-n-octyl phthalate (DNOP) exposure and nonverbal IQ. Maternal urinary concentrations of bisphenols were not associated with child nonverbal IQ. There was no effect estimate modification by sex. CONCLUSIONS: We did not observe that maternal biomarkers of bisphenol exposure are associated with nonverbal IQ. We found that phthalate exposure in early pregnancy and DNOP exposure in late pregnancy are associated with lower nonverbal IQ scores in children. Our results might suggest that particularly early pregnancy is a sensitive window of phthalate exposure, but future studies are needed to replicate our findings. https://doi.org/10.1289/EHP6047.

Oestrogenic Endocrine Disruptors in the Placenta and the Fetus.

Endocrine disrupting chemicals (EDCs) are exogenous substances that interfere with the stability and regulation of the endocrine system of the body or its offspring. These substances are generally stable in chemical properties, not easy to be biodegraded, and can be enriched in organisms. In the past half century, EDCs have gradually entered the food chain, and these substances have been frequently found in maternal blood. Perinatal maternal hormone levels are unstable and vulnerable to EDCs. Some EDCs can affect embryonic development through the blood-fetal barrier and cause damage to the neuroendocrine system, liver function, and genital development. Some also effect cross-generational inheritance through epigenetic mechanisms. This article mainly elaborates the mechanism and detection methods of estrogenic endocrine disruptors, such as bisphenol A (BPA), organochlorine pesticides (OCPs), diethylstilbestrol (DES) and phthalates (PAEs), and their effects on placenta and fetal health in order to raise concerns about the proper use of products containing EDCs during pregnancy and provide a reference for human health.

Use of stored serum in the study of time trends and geographical differences in exposure of pregnant women to phthalates.

BACKGROUND: Exposure to some phthalate diesters has been associated with adverse reproductive health outcomes in both rodents and humans indicative of anti-androgenic effects. Exposure during sensitive periods of development, such as prenatally, is of particular concern. OBJECTIVES: We wished to investigate whether phthalate metabolites measured in maternal serum samples from historical birth cohorts can be used to assess prenatal exposure. Further, we aimed to study temporal and geographical trends in phthalate exposure across three different birth cohorts. METHODS: We compared phthalate metabolite levels in maternal serum samples from an Australian (1989-91) and a Danish (1997-2001) birth cohort with levels in serum and urine samples from a recent Danish birth cohort (2012-14). Samples were analysed for 32 phthalate metabolites from 15 phthalate diesters by isotope-diluted liquid chromatography-tandem mass spectrometry (LC-MS/MS). Correlations between metabolites were tested by Spearman rank correlation test, and differences between the cohorts were tested by Mann-Whitney U test. RESULTS: Overall, we observed large variations in serum phthalate metabolite levels between individuals. Secondary metabolites of di-(2-ethyl-hexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP) in serum were weakly to moderately and positively correlated to the levels measured in urine, and secondary metabolites of DEHP were also moderately to strongly and significantly correlated in serum. Correlations with mono-(2-ethyl-hexyl) phthalate (MEHP) and mono-iso-nonyl phthalate (MiNP), the two primary metabolites of DEHP and DiNP, were inconsistent, and we found indications of sample contamination. We observed some significant differences in phthalate metabolite levels between the three cohorts with generally higher levels in the older birth cohorts. CONCLUSION: Based on comparison across two older birth cohorts and a recent cohort, our results support the concept that historical biobanked serum samples may be used for assessment of prenatal exposure to phthalates when using serum levels of the monoesters of the low-molecular weight (LMW) phthalates and the secondary metabolites of the high-molecular weight (HMW) phthalates. Serum phthalate measurements are, however, not suitable for human biomonitoring and should only be used to exploit historical samples from cohorts, where urine samples were not collected. Our findings suggest that phthalate exposure may have decreased over time from the early 1990s to the 2010s.

Inverse associations of bisphenol A and phthalate metabolites with serum bilirubin levels in Korean population.

Bisphenol A (BPA) and phthalates are endocrine disruptors that can induce oxidative stress. Serum bilirubin has antioxidant properties and may serve as a biomarker of oxidative stress. The objective of this study was to explore the relationship of BPA and phthalates with serum bilirubin levels in a Korean population. Urinary concentrations of BPA and six phthalate [mono-n-butyl phthalate (MnBP), mono-iso-butyl phthalate (MiBP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5- hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), and mono-benzyl phthalate (MBzP)] were measured in 709 participants. Serum concentrations of BPA and three phthalate metabolites [MnBP, MiBP, and mono-(2-ethylhexyl) phthalate (MEHP)] were measured in 752 participants. After excluding missing variables, associations between above chemicals and serum bilirubin levels were analyzed using multivariate linear regression with age, sex, BMI, GGT, GOT, GPT, and alcohol intake adjustment. Participants were further stratified by sex. Among the urinary chemicals, BPA and four phthalate metabolites (MnBP, MEOHP, MEHHP and MECPP) were inversely associated with serum bilirubin levels (BPA: ß = - 0.071, P < 0.0001; MnBP: ß = - 0.055, P = 0.025; MEOHP: ß = - 0.101, P < 0.0001; MEHHP: ß = - 0.106, P < 0.0001; MECPP: ß = - 0.052, P = 0.003). In a case of serum chemicals, only MiBP showed significantly positive association (ß = 0.036, P = 0.016). After stratification by sex, the associations of urinary BPA remained both in male and female, of which urinary phthalates disappeared in female. The association of serum MiBP was disappeared after stratification. Urinary BPA and phthalate metabolites were inversely associated with serum bilirubin levels, whereas serum MiBP showed positive association with bilirubin. These results could provide clues for understanding the mechanisms of endocrine disruptor from oxidative stress to excretion from our body.

Exposure to phthalates and bisphenol A is associated with higher risk of cardiometabolic impairment in normal weight children.

Some obese individuals have normal metabolic profile, and some normal-weight persons have impaired metabolic status. Our hypothesis was that one of the potential underlying factors for such differences in cardiometabolic profiles might be the exposure to some environmental chemicals. This study aimed to investigate the association of serum bisphenol A (BPA) and phthalate metabolites with cardiometabolic risk factors in children and adolescents independent of their weight status. This case-control study was conducted on a subsample of 320 participants of a national school-based surveillance program in Iran. We measured serum BPA and phthalate metabolites by gas chromatography mass spectrophotometry. We compared them in children and adolescents with and without excess weight and those with and without cardiometabolic risk factors (80 in each group). We categorized the concentrations of chemicals to tertiles and then we applied logistic regression models after adjustment for potential confounding factors. The concentrations of BPA and some metabolites of phthalates were significantly different in the four groups studied. MEHP concentration was associated with higher odds ratio of cardiometabolic risk factors in participants with normal weight (OR, 95% CI 2.82, 1.001-7.91) and those with excess weight (OR, 95% CI 3.15, 1.27-7.83). MBP concentration increased the odds ratio of cardiometabolic risk factors only in normal weight children and adolescents (OR, 95% CI 6.59, 2.33-18.59, P < 0.001). In participants without cardiometabolic risk factor, MMP and MEHHP were significantly associated with increased risk of excess weight (OR, 95% CI 5.90, 1.21-28.75 and 7.82, 1.5-41.8, respectively). This study showed that the association of BPA and phthalate with cardiometabolic risk factors is independent of the weight status. Our findings suggest that the metabolic impairment in some normal weight children and normal metabolic profile of some obese children can be, in part, related to exposure to these environmental chemicals. Graphical abstract.

Development and validation of a bioanalytical assay based on liquid chromatography-tandem mass spectrometry for measuring biomarkers of exposure of alternative plasticizers in human urine and serum.

Alternative plasticizers (APs) have been increasingly used in the last decade to replace conventional phthalate esters, in particular di(2-ethylhexyl) phthalate (DEHP), due to the toxicity of the latter. However, there is currently very little data about the toxicity of and exposure to APs. No method exists so far for the analysis of multiple exposure biomarkers. The objective of this work consisted in developing a simple bioanalytical procedure for the analysis of multiple exposure biomarkers of APs in human urine and serum. Focus was set on metabolites of di(2-propylheptyl) phthalate (DPrHpP), di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), di(2-ethylhexyl) terephthalate (DEHTP) and di-2-ethylhexyl adipate (DEHA). A sample preparation protocol was developed and optimized using Oasis HLB solid-phase extraction (SPE) cartridges. Subsequently, an instrumental method based on liquid-chromatography coupled to tandem mass spectrometry (LC-MS/MS) was optimized. Following established guidelines, the sample preparation and instrumental methods were validated in terms of recovery, matrix effects, carry-over, linearity, limits of quantification, within- and between-run precision and trueness. Obtained results were satisfactory for all compounds except for one of the metabolites of DEHA (i.e., mono(2-ethylhexyl) adipate (MEHA)). A pilot biomonitoring study was carried out to assess the method's ability to detect and quantify target analytes in human urine and serum. In urine, most analytes could be detected with frequencies ranging from 8% for mono(2-ethyl-5-hydroxyhexyl) adipate (OH-MEHA) and cyclohexane-1,2-dicarboxylic mono hydroxyisononyl ester (OH-MINCH) to 92% for mono(2-ethyl-5-oxohexyl) adipate (oxo-MEHA), whilst most compounds could not be detected in serum, except for mono(2-ethylhexyl) terephthalate (MEHTP) and mono-(2-propyl-6-hydroxyheptyl) phthalate (OH-MPrHpP) which were detected in all samples. The obtained results show that the developed method can be used to simultaneously analyse multiple exposure biomarkers to APs in human urine and serum.

Levels of phthalate acid esters and sex hormones and their possible sources in traffic-patrol policemen in Chongqing.

To investigate the correlation between the air phthalate acid ester (PAE) exposure and serum PAE concentration and the effects of PAE exposure on reproductive health among Chongqing traffic-patrol policemen. In 2013, 32 traffic-patrol policemen working in an area with poor air quality in Chongqing and 28 traffic-patrol policemen working in an area with good air quality were selected. Their blood levels of 14 PAEs and six reproductive hormones were determined. Air samples were collected from four traffic-patrol platforms. The concentrations of 14 PAEs in the air samples were evaluated. All 14 PAEs were detected in the blood samples. The concentrations of seven PAEs in the total suspended particulate, namely, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, bis (2-ethox-yethyl) phthalate, dihexyl phthalate, benzyl butyl phthalate, and bis (2-n-butoxyethyl) phthalate, were positively and significantly associated with the blood levels of these PAEs in the participants. All the sex hormone levels measured here were significantly different between the participants from the two areas. The PAE concentrations in the blood samples were correlated with the reproductive hormone levels in the participants. Air PAE pollution may be a major source of PAE exposure in the traffic-patrol policemen of Chongqing.

Human exposure to bisphenol AF and diethylhexylphthalate increases susceptibility to develop differentiated thyroid cancer in patients with thyroid nodules.

Pollutants represent potential threats to the human health, being ubiquitous in the environment and exerting toxicity even at low doses. This study aims at investigating the role of fifteen multiclass organic pollutants, assumed as markers of environmental pollution, most of which exerting endocrine-disrupting activity, in thyroid cancer development. The increasing incidence of differentiated thyroid cancer (DTC) may be related to the rising production and environmental dissemination of pollutants. Fifty-five patients, twenty-seven with diagnosis of benign thyroid nodules and twenty-eight suffering from differentiated thyroid cancer, were enrolled and the concentration levels of seven bisphenols, two phthalates (i.e. di(2-ethylhexyl) phthalate (DEHP) and its main metabolite, mono-(2-ethyl-hexyl) phthalate) (MEHP)), two chlorobenzenes, (1,4-dichlorobenzene and 1,2,4,5-tetrachlorobenzene), and 3 phenol derivatives (2-chlorophenol, 4- nonylphenol, and triclosan) were determined in their serum by using a validated analytical method based on high performance liquid chromatography with ultraviolet tandem fluorescence detection. A significant relationship was found between malignancy and the detection in the serum of both bisphenol AF and DEHP. Indeed, their presence confers a more than fourteen times higher risk of developing differentiated thyroid cancer. Relationship between these two pollutants and the risk of malignancy was dose-independent and not mediated by higher thyroid stimulating hormone levels. Even if a conclusive evidence cannot still be drawn and larger prospective studies are needed, the exposure to low doses of environmental endocrine-disrupting contaminants can be considered consistent with the development of thyroid cancer.