Phthalate Exposure Research Articles

Management of phthalates in Canada and beyond: can we do better to protect human health?

Ortho-phthalates (herein referred to as phthalates) are synthetic chemicals used in thousands of different everyday products and materials. Nearly ubiquitous environmental exposure is reflected by phthalate metabolites in the urine of almost all Canadians. However, phthalate exposure tends to be higher amongst people of low socioeconomic status and ethnic minorities. Substantial evidence shows that certain phthalates cause harm to human health, particularly developing fetuses and children. Governments vary in their approach to assessing and managing risks associated with phthalates. Canada continues to take a more permissive stance on phthalate regulations compared to the EU and some US states. We argue that the recent Canadian national risk assessment on phthalates does not appropriately reflect the growing evidence demonstrating harm to human health from phthalate exposure and does not adequately consider the evidence showing higher exposures faced by vulnerable populations. Canadians would benefit from adopting a more stringent regulatory approach to phthalates. Specifically, Canada should expand phthalate restrictions to apply to all consumer products, implement sunset dates toward eliminating the use of existing phthalates, and mandate publicly available evidence of no harm for phthalate alternatives. Canadian alignment on phthalate regulations with the EU and a growing number of US states could encourage other countries to follow suit.

Gestational phthalate exposure and behavioral problems in preschool-aged children with increased likelihood of autism spectrum disorder

BackgroundExperimental studies have shown associations between gestational phthalate exposure and behavioral problems among offspring; however, epidemiological evidence is still mixed. This study aims to investigate whether gestational phthalate exposure is associated with behavioral problems in preschool-aged children. MethodsParticipants include 178 mother-child pairs from MARBLES (Markers of Autism Risk in Babies – Learning Early Signs), a cohort with high familial likelihood of autism spectrum disorder (ASD). We quantified 14 phthalate metabolites in multiple maternal urine samples collected during the 2nd and 3rd trimesters. Preschool behavior problems were assessed using the Child Behavioral Checklist (CBCL), a standardized instrument for evaluating behavior problems of children aged 1.5–5 years. To examine associations of CBCL scores with both individual phthalate biomarker concentrations and their mixture, we used negative binomial regression and weighted quantile sum regression. ResultsOverall, maternal phthalate biomarker concentrations were not associated with child behavior problems. Monoisobutyl phthalate (MiBP) concentrations were inversely associated with child anxious/depressed symptoms and somatic complaints. Mono-hydroxy-isobutyl phthalate (MHiBP) and monobenzyl phthalate (MBzP) were also inversely associated with somatic complaints. When assessing trimester-specific associations, more behavior problems were associated with the 2nd trimester biomarker concentrations: mono(3-carboxypropyl) phthalate (MCPP) and monocarboxyisononyl phthalate (MCNP) were positively associated with somatic complaints. All associations became non-significant after false discovery rate correction. No association between a mixture of phthalates and CBCL scores was found. ConclusionsOur study observed no clear evidence of gestational phthalate exposure on child behavior problems. However, our findings based on the biomonitoring assessment of multiple samples per participant could improve our understanding of gestational phthalate exposure in association with behavior problems in preschool-aged children.

Phthalate exposure and reproductive effects in rodents: a model for approaches on the protective role of natural products.

This review article summarizes the experimental findings in rodents published between 2014 and 2024 concerning phthalates exposure and reproductive outcomes. Rodents were chosen for this review since most studies that have developmental aspects in different phases of exposure and that address more in-depth reproductive mechanisms have been carried out in mice and rats. The evidence of adverse effects of phthalates on fetal development and human and animal reproduction is extensive, with impacts ranging from gene expression to physiological alterations. Despite the large volume of scientific papers pointing out the harmful effects of exposure to phthalates, isolated or in mixtures, at different developmental periods, most of them are associated with the maternal exposure and long-term effects in the offspring. Regular vegetables, fruits, fish, dairy products, and whole grains intake rich in bioactive compounds can mitigate the adverse effects of EDCs in humans and animals at different developmental periods. Various food bioactive compounds (FBCs) such as genistein, resveratrol, lycopene, vitamin E, curcumin, selenium, and plant secondary metabolites (PSMs) present antioxidant, anti-inflammatory, anti-tumor, and other biological properties with the potential to reduce of deleterious effects of phthalates on the reproductive tract. In this review, we aimed to summarize the main studies produced in the last decade about phthalate exposure and reproductive disorders in males and females (at different developmental critical windows). Additionally, we proposed some FBCs and PSMs that could attenuate the main adverse effects caused by phthalate exposure on male reproduction since there is a lack of studies with females.

Associations of Phthalate Exposure with Adiposity and Metabolic Syndrome in US Adolescents and Adults, NHANES 2013-2018

Abstract Background/Objective Phthalates are ubiquitous endocrine-disrupting chemicals and suspected obesogens. However, the associations with fat distribution and associated cardiometabolic complications remain unclear. Therefore, we examined the associations between phthalate exposure, body fat (total and distribution patterns), and metabolic syndrome (MetS) among US adolescents and adults. Methods We analyzed cross-sectional data from 829 adolescents and 3905 adults in the 2013-2018 National Health and Nutrition Examination Survey. Total percent body fat (%BF), visceral adipose tissue (VAT) mass, and android to gynoid (A/G) ratio were determined using dual-energy x-ray absorptiometry. Associations between molar sums of low molecular weight (∑LMW), high molecular weight (∑HMW), and di(2-ethylhexyl) phthalate (∑DEHP) metabolites, and adiposity indicators and MetS were analyzed with multivariable linear and logistic regressions. Models included sex interaction terms, were stratified by age group, and adjusted for relevant covariates. Results ∑HMW and ∑DEHP exposures were positively associated with %BF in males, and all phthalate groups were associated with greater VAT mass and A/G ratio in adolescent males. Five-fold increases in ∑HMW and ∑DEHP metabolites were associated with 21.7% (95% CI: 10.5-33.9) and 18.0% (95% CI: 7.72-29.2) greater VAT mass among adolescent males, respectively. Sex modified the relationship between ∑HMW exposure and A/G ratio among adolescents (interaction p-value = 0.0185). Phthalates were not associated with odds of MetS. When assessing individual MetS components, phthalates were associated with hyperglycemia in adult males. Conclusion Greater exposure to phthalates was associated with greater %BF in all males, and with fat distribution in adolescent males; however, phthalates were not linked to MetS.

Prenatal exposure to phthalates and children’s mental health trajectories: Rhea Cohort, Greece

Abstract Background Accumulating evidence suggests that phthalate exposure affects neurodevelopment, including emotional and behavioral outcomes. Our aim was to investigate if prenatal phthalate exposure affects the developmental course of internalizing and externalizing symptoms from early childhood to adolescence. Methods Concentrations of seven phthalate metabolites were measured in first-trimester maternal spot urine samples, and DEHP, and high and low molecular weight phthalate concentrations were calculated (HMW and LMW, respectively). Mothers reported internalizing and externalizing symptoms via the Strengths and Difficulties Questionnaire at 4 years and the Child Behavior Checklist at 6, 11 and 15 years. Group-Based Trajectory Modeling was used to classify 546 participants of the Rhea Cohort (Crete, Greece) into 4 distinct groups (Stable low, Stable high, Low-Increasing, and High-Decreasing symptoms). We evaluated the association of prenatal phthalate exposure with the odds of an adverse (Stable high, Low-Increasing, and High-Decreasing) internalizing and externalizing symptom trajectory in 150 children using multivariable-adjusted logistic regression (reference group: stable low). Results Only for girls, exposure to DEHP and HMW phthalates was associated with higher odds of being grouped in an adverse internalizing symptoms trajectory (OR [95%CI]: 1.52 [1.03, 2.25] and 1.57 [1.03, 2.39], respectively). Regarding externalizing symptoms, interactions with gender emerged for DEHP (p = 0.024) and HMW (p = 0.028) phthalates, and increased odds of being grouped into an adverse trajectory were observed in girls, whereas boys showed the opposite trend, albeit none reached statistical significance. Conclusions The findings suggest programming effects of prenatal phthalate exposure on the developmental course of emotional symptoms in girls. Further research is needed to clarify the association between in utero phthalate exposure and behavioral symptoms. Key messages • Phthalate exposure is linked to adverse trajectories of emotional symptoms, emerging from preschool age and up to adolescence. • Phthalate effect on internalizing and externalizing symptoms varies by gender.

Associations between pre- and post-natal exposure to phthalate and DINCH metabolites and gut microbiota in one-year old children

The gut microbiota is a collection of symbiotic microorganisms in the gastrointestinal tract. Its sensitivity to chemicals with widespread exposure, such as phthalates, is little known. We aimed to investigate the impact of perinatal exposure to phthalates on the infant gut microbiota at 12 months of age. Within SEPAGES cohort (Suivi de l’Exposition à la Pollution Atmosphérique durant la Grossesse et Effet sur la Santé), we assessed 13 phthalate metabolites and 2 di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) metabolites in repeated urine samples collected in pregnant women and their offspring. We obtained stool samples from 356 children at 12 months of age and sequenced the V3-V4 region of the 16S rRNA gene, allowing gut bacterial profiling. We used single-chemical (linear regressions) and mixture (BKMR, Bayesian Kernel Machine Regression) models to examine associations of phthalates and DINCH metabolites, with gut microbiota indices of α-diversity (specific richness and Shannon diversity) and the relative abundances of the most abundant microbiota phyla and genera. After correction for multiple testing, di(2-ethylhexyl) phthalate (ΣDEHP), diethyl phthalate (DEP) and bis(2-propylheptyl) phthalate (DPHP) metabolites 12-month urinary concentrations were associated with higher Shannon α-diversity of the child gut microbiota in single-chemical models. The multiple-chemical model (BKMR) suggested higher α-diversity with exposure to the phthalate mixture at 12 months, driven by the same phthalates. There were no associations between phthalate and DINCH exposure biomarkers at other time points and α-diversity after correction for multiple testing. ΣDEHP metabolites concentration at 12 months was associated with higher Coprococcus genus. Finally, ΣDEHP exposure at 12 months tended to be associated with higher phylum Firmicutes, an association not maintained after correction for multiple testing. Infancy exposure to phthalate might disrupt children's gut microbiota. The observed associations were cross-sectional, so that reverse causality cannot be excluded.

Individual Inhalation Exposure to Phthalates and Their Associations with Anthropometric and Physiological Indices in Primary School Children in Jinan, China

Phthalates are commonly found in indoor environments. Consequently, children may be exposed to phthalates through the air, potentially causing health issues. We collected 72 air samples from 60 households and 12 classrooms in Jinan, surveyed and health-examined children, assessed their phthalate inhalation exposure, and analyzed the associations between inhalation exposure levels and children’s anthropometric and physiological indicators. Eight phthalates were detected in children’s households and classrooms, with detection frequencies ranging from 91.6% to 100%. Di-iso-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), and di (2-ethylhexyl) phthalate (DEHP) were the predominant phthalates. Children’s indoor inhalation exposure to phthalates ranged from 8.90 to 147 ng/(kg·day), with DEHP being the main inhaled phthalate. The non-carcinogenic risks of indoor environments where children live are within acceptable limits. DEHP has a low carcinogenic risk. Di-n-octyl phthalate (DnOP) exposure was associated with a decrease in body mass index z-score, waist circumference, and hip circumference. Additionally, DEHP exposure was negatively associated with the waist-to-hip ratio. DiBP exposure was negatively associated with the systolic blood pressure z-score, while DnOP exposure was negatively associated with the diastolic blood pressure z-score. Furthermore, DEHP exposure was positively associated with fractional exhaled nitric oxide z-score. The findings of this study suggest that phthalate inhalation exposure may substantially affect various health metrics in children, including body mass index, waist and hip circumference, and blood pressure, and increase the risk of respiratory tract inflammation.

Long-term inhalation exposure: A model for phthalate accumulation in the respiratory tract

BackgroundInhalation is a major pathway for phthalates (PAEs), an endocrine disruptor, to enter the human body. The actual internal exposure amount that participates in metabolism cannot be estimated by calculating total inhalation intake. ObjectiveTo estimate the accumulation in each region of the respiratory tract after long-term exposure to PAEs in different populations. MethodsA mass transfer model was developed to simulate the long-term accumulation of PAEs in respiratory tract through inhalation. The model considered (1) mass transfer of PAEs in three phases across seven regions, (2) the effect of temperature differences on the mass transfer process. Based on this model, we simulated adult exposure to PAEs in a laboratory, identified key model parameters, and further simulated various scenarios for children, adults, and elders. ResultsPAEs are not completely cleared from the respiratory tract after 16 hours, following 8 hours of daily exposure. Under regular laboratory environment, accumulation after 30 days is 3.8 times higher than that after the first day. The distribution of PAEs between the gas and mucus phases has a greater impact on the results than between the gas and particle phases. Children are at the highest risk to Diethyl phthalate (DEP) exposure compared with adults and elders. Nearly 80 % of DEP is exhaled, with 14 % accumulating in the alveolar region after an hour. ConclusionThis model links indoor air PAEs to human internal exposure, showing that most PAEs are exhaled, while the remainder accumulates in the respiratory tract and may participate in human metabolism.

Phthalate exposure induces cell death and ferroptosis in neonatal microglial cells.

Phthalates are the materials used for plasticizing polyvinyl chloride. Di-(2-Ethylhexyl) phthalate (DEHP) is one of the phthalates most frequently used in a wide range of applications, including medical equipment such as endotracheal and feeding tubes, intravenous catheters, central lines, extracorporeal membrane oxygenation sets, total parenteral nutrition bags, blood product sets, and intravenous pump lines, respiratory sets in neonatal intensive care units (NICUs). Studies have shown that phthalates, including DEHP, can cross the placenta and blood-brain barrier, possibly leading to neurodevelopmental impairment in vitro and in vivo. However, the molecular mechanisms affected by phthalate exposure have not been explored in depth. This study aimed to illuminate the effects of DEHP on neuroinflammation at the molecular level using neonatal microglial cells as the model. Mouse BV-2 neonatal microglia cells were exposed to DEHP under controlled conditions. Cellular toxicity was assessed via a cell viability assay and specific markers were used to evaluate the apoptosis/necrosis, cellular iron content, reactive oxygen species (ROS), and organelle integrity. Proinflammatory proteins were quantified using enzyme-linked immunosorbent assay, while ferroptosis was assessed using a ferroptosis blocker, and affected gene expressions were determined using quantitative reverse-transcriptase real-time polymerase chain reaction (RT-PCR). The results revealed that high concentrations of DEHP exposure increased toxicity via increased levels of ROS and inflammation. Elevated ROS levels were observed to increase the tendency for mitochondrial-lysosomal disruption, bringing about apoptosis or necrosis. Moreover, iron homeostasis was dysregulated by DEHP, which putatively triggered ferroptosis in a dose-dependent manner. This study indicates that neonatal exposure to DEHP may be linked to neurodevelopmental impairment via inflammation-related cell death and ferroptosis. The prevalence of DEHP in NICU medical devices raises concerns about potential neurodevelopmental deficits, including disorders like autism and mental retardation. These findings highlight the urgency of addressing DEHP exposure in neonatal care.

Association between phthalate exposure and sleep quality in pregnant women: results from the Korean Children’s Environmental Health Study with repeated assessment of exposure: Erratum

Association between phthalate exposure and sleep quality in pregnant women: results from the Korean Children’s Environmental Health Study with repeated assessment of exposure: Erratum

Non-dietary exposure to phthalates in primary school children: Risk and correlation with anthropometric indices, cardiovascular and respiratory diseases

Phthalates are endocrine disruptors of increasing concern for human health; however, previous studies have only assessed the association between internal exposure and human health. We aimed to assess the non-carcinogenic and carcinogenic risks of non-dietary exposure to phthalates in indoor environments among primary school children and their correlations with health indicators. A study involving 54 children was conducted in Jinan, Shandong Province, China. Questionnaires and health examinations were conducted, dust in hard-to-clean corners of students’ classrooms and homes was collected, and airborne phthalates in the middle of classrooms and family living rooms were sampled. The gas-phase phthalate concentrations, individual exposure, and non-carcinogenic and carcinogenic risks were calculated. Associations were estimated using linear mixed models. The findings revealed that phthalates posed a non-carcinogenic risk to 7.4 % of the children and a moderate carcinogenic risk to 27.8 % of the children, with higher non-carcinogenic and carcinogenic risks to girls than to boys. Five phthalates were negatively correlated with body mass index, dimethyl phthalate and diethyl phthalate (DEP) were significantly correlated with waist circumference, and di-iso-butyl phthalate (DiBP) was negatively correlated with hip circumference. DiBP, di-n-butyl phthalate, and DEP, were significantly correlated with cardiovascular disease, DEP and di (2-n-butoxyethyl) phthalate were correlated with decreased lung function, and di-n-octyl phthalate influenced airway inflammation. The findings indicated that phthalate exposure may negatively impact children's health, thereby warranting further comprehensive research on the health effects of these chemicals.

Associations of 1.5- and 3-year phthalate exposure levels with early adiposity rebound and overweight/obesity in Japanese children: An adjunct study of the Japan Environment and Children's Study

The relationship between early childhood phthalate exposure and early adiposity rebound (EAR) is unclear. This study aimed to investigate the association between 1.5- and 3-year phthalate exposure and EAR and overweight/obesity in 7.5-year-old Japanese children. A total of 452 mother–child pairs were enrolled from the Aichi Regional Cohort of the Japan Environment and Children's Study. The children were followed up at birth and at 1.5, 2, 3, 4, 5, 6, and 7.5 years of age for physical examination. Human biomonitoring of 16 urinary metabolites of eight phthalates was performed at 1.5 and 3 years of age. Latent class mixed models, binary logistic regression, and quantile g-computation were performed to identify body mass index (BMI) trajectories and investigate the relationships of single or mixed phthalate exposure with EAR and overweight/obesity. A one-unit increase in log10-transformed 3-year-old Σdi(2-ethylhexyl) phthalate (ΣDEHP) exposure levels was significantly associated with 6-year-old BMI in girls. The 1.5-year mono-iso-butyl phthalate and 3-year Σdi-isodecyl phthalate exposure levels were significantly associated with the repeated measures of longitudinal BMIs in girls. Single phthalate exposure showed null associations with EAR or overweight/obesity in the 7.5-year-old children. Σdi-isononyl phthalate, ΣDEHP, and mono-n-butyl phthalate exhibited the highest proportion of partial positive weights of being in the EAR trajectory after confounder adjustment. Phthalate mixture exposure in 1.5- and 3-year-old children was not significantly associated with EAR. Early childhood phthalate exposure was not related to EAR or overweight/obesity in 7.5-year-old Japanese children. However, few phthalates were positively associated with longitudinal BMIs in girls.

Exposure to Phthalates and Alternative Plasticizers in Patients with Impaired Kidney Function in Korea: Temporal Trend during 2011-2020 and Its Association with Chronic Kidney Disease.

Phthalates are chemical risk factors of chronic kidney disease (CKD); however, little is known about temporal trends of phthalate exposure and associated health risks among CKD patients. Such information is even scarce for alternative plasticizers. CKD patients were recruited from 2011 to 2020 in Korea (n = 200) and assessed for the temporal changes of both traditional and alternative plasticizer exposure. Their associations with kidney dysfunction were also investigated. In CKD patients, urinary levels of DEP, BBzP, and DEHP metabolites declined significantly during this period, while those of the DEHTP metabolite increased. The level of DEHP metabolites showed a negative association with the estimated glomerular filtration rate (eGFR) in multiple association models, but additional eGFR subgroup analysis failed to show consistent results. Associations between phthalate exposure and eGFR were influenced by the severity of kidney dysfunction: DEHP and BBzP exposure showed negative associations with eGFR only among the patients with moderate kidney dysfunction (eGFR 30-59 mL/min/1.73 m2). Changing associations by CKD severity may be explained by negative correlations between eGFR and both urinary creatinine concentration and specific gravity. Our observations show that DEHTP has rapidly replaced DEHP and exposure to several phthalates adversely influences kidney function even among CKD patients.

Placental Transcriptomic Signatures of Prenatal Phthalate Exposure and Identification of Placenta-Brain Genes Associated with the Effects of Phthalate Exposure on Neurodevelopment in Children.

Prenatal exposure to phthalates may affect placental function and fetal development, but the underlying mechanisms are unclear. The aim of our study was to explore the alterations in the placental transcriptome associated with prenatal phthalate exposure and to further analyze whether the placental-brain axis (PBA) genes play a mediating role in the association between prenatal phthalate exposure and children's neurodevelopment. We included 172 participants from the Ma'anshan Birth Cohort and collected data on seven phthalate metabolites in urine during pregnancy, placental tissue RNA-seq, and neurodevelopment of offspring. Bioinformatics analysis revealed that aberrant regulation of the placental transcriptome was associated with prenatal phthalate exposure. Exposure to phthalates during pregnancy was found to be associated with neurodevelopmental delay in children aged 6, 18, and 48 months using the multiple linear regression model. Meanwhile, employing mediation analysis, nine PBA genes were identified that mediate the association between exposure to phthalates during pregnancy and the neurodevelopment of children. Our study will provide a basis for potential mechanisms by which prenatal exposure to phthalates affects placental function and children's neurodevelopment.

Prenatal phthalate exposure and pubertal development in 16-year-old daughters: reproductive hormones and number of ovarian follicles.

Is there a possible association between prenatal phthalate exposure and late effects in teenage daughters with respect to reproductive hormone levels, uterine volume, and number of ovarian follicles? Our study showed subtle associations between phthalate metabolite concentrations in maternal serum from pregnancy or cord blood and LH and insulin-like growth factor 1 (IGF-1) levels as well as uterine volume in their daughters 16 years later. Endocrine-disrupting environmental chemicals may adversely affect human reproductive health, and many societies have experienced a trend toward earlier puberty and an increasing prevalence of infertility in young couples. The scientific evidence of adverse effects of foetal exposure to a large range of chemicals, including phthalates, on male reproductive health is growing, but very few studies have explored effects on female reproduction. This follow-up study included 317 teenage daughters who were part of the Copenhagen Mother-Child Cohort, a population-based longitudinal birth cohort of 1210 females born between 1997 and 2002. A total of 317 female participants (median age 16 years) were examined for weight, height, and menstrual pattern. A serum sample was analysed for concentrations of reproductive hormones, and trans-abdominal 3D ultrasonography was performed to obtain the number of ovarian follicles, ovarian and uterine size. Prenatal maternal serum samples were available for 115 females, and cord blood samples were available for 118 females. These were analysed for concentrations of 32 phthalate metabolites. Weighted quantile sum regression was used for modelling associations of combined prenatal phthalate exposure with the reproductive outcomes in post-menarcheal females. In bivariate correlation analyses, negative significant associations were found between several prenatal phthalate metabolite concentrations and serum hormone concentrations (testosterone, 17-OH-progesterone, and IGF-1) as well as number of ovarian follicles in puberty. Positive significant correlations were found between prenatal phthalate exposure and FSH and sex hormone-binding globulin concentrations. Combined analyses of phthalate exposure (weighted quantile sums) showed significant negative associations with IGF-1 concentration and uterine volume as well as a significant positive association with LH concentration. Phthalate metabolites were measured in serum from single prenatal maternal blood samples and cord blood samples. Potential concomitant exposure to other endocrine-disrupting environmental chemicals before or after birth was not controlled for. The study population size was limited. Our results support the need for further research into possible adverse effects of environmental chemicals during foetal development of the female reproductive system. The work was supported by The Center on Endocrine Disruptors (CeHoS) under The Danish Environmental Protection Agency and The Ministry of Environment and Food (grant number: MST-621-00 065). No conflicts of interest are declared. N/A.

Glycolysis mediates the association between phthalate exposure and the prevalence of childhood asthma: The National Health and Nutrition Examination Survey 2009–2018

Identified as a critical risk factor for childhood asthma, environmental pollution plays a pivotal role. However, research on the effects and mechanisms of phthalates mixture and their interactions in relation to childhood asthma is still lacking. In the National Health and Nutrition Examination Survey (NHANES) conducted from 2009 to 2018, our research explored the link between phthalates in urine and the prevalence of childhood asthma. In this study, which involved 810 participants, we used four different statistical analysis methods to investigate the association between urinary phthalate levels and childhood asthma. Additionally, we conducted a mediation analysis to explore whether the impact mechanism of phthalate exposure on childhood asthma operates through the glycolysis. Among the participants, 525 (64.81 %) individuals were diagnosed with asthma, with 330 (40.74 %) individuals undergoing testing for glycolytic markers. Through Spearman correlation analysis and weighted principal component analysis (W-PCA), it was found that mono-2-ethyl-5-carboxypentyl phthalate (MECPP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl)-hexyl phthalate (MEHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) are the four most highly correlated phthalates. In addition, comprehensive analysis by the weighted generalized linear models (W-GLM), weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models showed that phthalates mixture were positively associated with the prevalence of childhood asthma, especially MECPP, MEHHP and MEOHP. More importantly, glycolysis participated as a mediator in the relationship between MECPP, MEHHP and MEOHP exposure and the prevalence of childhood asthma, explaining 41.194 %, 38.322 % and 39.871 % of the effects respectively. Therefore, our study revealed that phthalate exposure is a risk factor for asthma in children, and glycolysis may be involved as a potential mediator in this process. This conclusion will be verified through more prospective studies in the future.

Metabolomic Alterations Associated with Phthalate Exposures among Pregnant Women in Puerto Rico.

Although phthalate exposure has been linked with multiple adverse pregnancy outcomes, their underlying biological mechanisms are not fully understood. We examined associations between biomarkers of phthalate exposures and metabolic alterations using untargeted metabolomics in 99 pregnant women and 86 newborns [mean (SD) gestational age = 39.5 (1.5) weeks] in the PROTECT cohort. Maternal urinary phthalate metabolites were quantified using isotope dilution high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS), while metabolic profiles in maternal and cord blood plasma were characterized via reversed-phase LC-MS. Multivariable linear regression was used in metabolome-wide association studies (MWAS) to identify individual metabolic features associated with elevated phthalate levels, while clustering and correlation network analyses were used to discern the interconnectedness of biologically relevant features. In the MWAS adjusted for maternal age and prepregnancy BMI, we observed significant associations between specific phthalates, namely, di(2-ethylhexyl) phthalate (DEHP) and mono(3-carboxypropyl) phthalate (MCPP), and 34 maternal plasma metabolic features. These associations predominantly included upregulation of fatty acids, amino acids, purines, or their derivatives and downregulation of ceramides and sphingomyelins. In contrast, fewer significant associations were observed with metabolic features in cord blood. Correlation network analysis highlighted the overlap of features associated with phthalates and those identified as differentiating markers for preterm birth in a previous study. Overall, our findings underscore the complex impact of phthalate exposures on maternal and fetal metabolism, highlighting metabolomics as a tool for understanding associated biological processes. Future research should focus on expanding the sample size, exploring the effects of phthalate mixtures, and validating identified metabolic features in larger, more diverse populations.

Oxidative stress as a potential mechanism linking gestational phthalates exposure to cognitive development in infancy

BackgroundGestational exposure to phthalates, endocrine disrupting chemicals widely used in consumer products, has been associated with poor recognition memory in infancy. Oxidative stress may represent one pathway linking this association. Hence, we examined whether exposure to phthalates was associated with elevated oxidative stress during pregnancy, and whether oxidative stress mediates the relationship between phthalate exposure and recognition memory. MethodsOur analysis included a subset of mother-child pairs enrolled in the Illinois Kids Development Study (IKIDS, N = 225, recruitment years 2013–2018). Concentrations of 12 phthalate metabolites were quantified in 2nd trimester urine samples. Four oxidative stress biomarkers (8-isoprostane-PGF2α, 2,3-dinor-5,6-dihydro-8-isoPGF2α, 2,3-dinor-8-isoPGF2α, and prostaglandin-F2α) were measured in 2nd and 3rd trimester urine. Recognition memory was evaluated at 7.5 months, with looking times to familiar and novel stimuli recorded via infrared eye-tracking. Novelty preference (proportion of time looking at a novel stimulus when paired with a familiar one) was considered a measure of recognition memory. Linear mixed effect models were used to estimate associations between monoethyl phthalate (MEP), sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP), sum of di(isononyl) phthalate metabolites (ΣDINP), and sum of anti-androgenic phthalate metabolites (ΣAA) and oxidative stress biomarkers. Mediation analysis was performed to assess whether oxidative stress biomarkers mediated the effect of gestational phthalate exposure on novelty preference. ResultsThe average maternal age at delivery was 31 years and approximately 50 % of participants had a graduate degree. A natural log unit increase in ΣAA, ΣDINP, and ΣDEHP was associated with a statistically significant increase in 8-isoPGF2α, 2,3-dinor-5,6-dihydro-8-isoPGF2α, and 2,3-dinor-8-isoPGF2α. The association was greatest in magnitude for ΣAA and 2,3-dinor-5,6-dihydro-8-isoPGF2α (β = 0.45, 95 % confidence interval = 0.14, 0.76). The relationship between ΣAA, ΣDINP, ΣDEHP, and novelty preference was partially mediated by 2,3-dinor-8-isoPGF2α. ConclusionsGestational exposure to some phthalates is positively associated with oxidative stress biomarkers, highlighting one mechanistic pathway through which these chemicals may impair early cognitive development.

Exploring the use of gull eggs as bioindicators of phthalate esters exposure

Plastic pollution and associated plasticizers are a global threat affecting aquatic environments. Phthalates are among the most used plasticizers that can impact on fauna due to their endocrine-disrupting properties. The aim of this study was to investigate the use of eggs of Audouin’s gull (Larus audouinii) and yellow-legged gull (Larus michahellis) as biomonitors of phthalate exposure. Sixteen phthalates were studied and the extraction and purification steps were optimized using various sorbents and clean-up processes to efficiently recover these contaminants in gull eggs. Analysis was performed using ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) using multiple reaction monitoring to obtain high selectivity and sensitivity. Quality control parameters and a comprehensive analysis of blank contribution are provided. The best performance was obtained with Oasis PRiME HLB cartridges with recoveries from 61 to 138% for most of the compounds. Pooled gull-egg samples from seven breeding colonies collected over the period 2016 – 2021 within the Iberian Peninsula revealed the presence of dibutoxyethyl phthalate (DBEP), hexyl 2-ethylhexyl phthalate (HEHP), dimethyl phthalate (DMP), diethyl phthalate (DEP), and dibutyl phthalate (DBP) at mean concentrations ranging from 2.27 to 1330 ng/g ww in Audouin's gull and from 2.74 to 487 ng/g ww in yellow-legged gull (DBP not detected). The absence of other phthalates is likely attributable to their metabolism and excretion by female adults. Overall, this study provides an accurate method to analyse phthalates in gull eggs and supports their use as bioindicators of phthalate contamination.

Urinary concentrations of phthalate and phthalate alternative metabolites and sperm DNA methylation: A multi-cohort and meta-analysis of men in preconception studies

Phthalates are ubiquitous pollutants in the environment; however, the mechanisms of phthalate-associated reproductive disorders in men are not fully understood. The aim of this study is to investigate associations between urinary phthalate metabolite concentrations and sperm DNA methylation. The study was conducted on 697 men from three prospective pregnancy cohorts: Longitudinal Investigation of Fertility and the Environment (LIFE) Study, Sperm Environmental Epigenetics and Development Study (SEEDS), and Environment and Reproductive Health (EARTH) Study. Eighteen phthalate and two phthalate alternative metabolites were quantified by mass spectrometry in preconception urinary samples and sperm DNA methylation was measured via Illumina EPIC Array (v1). Regional methylation analyses were conducted to identify cohort-specific loci associated with urinary phthalate metabolites. Models were adjusted for age, body mass index (BMI), race, smoking status, urinary creatinine/specific gravity, and analytical batch for phthalate measurements. The cohort-specific results were meta-analyzed using METAL. Participants had an average age of 30 years, most (79.6 %) of whom had BMI>25 kg/m2 and were non-smokers (90.1 %). A total of 7,979 differentially methylated regions (DMRs; 7,979 LIFE-specific DMRs, 72 SEEDS-specific DMRs, and 23 EARTH-specific DMRs) were associated with urinary MBzP, MiBP, MMP, MCNP, MCPP, MBP, and MCOCH. Meta-analysis identified fewer DMRs than cohort-specific models: 946 DMRs were associated with MBzP, 27 DMRs associated with MiBP, and 1 DMR associated with MEHP. The majority of cohort-specific and meta-analysis-derived DMRs displayed a positive association with phthalate metabolite concentrations and were enriched in genes associated with spermatogenesis, response to hormones and their metabolism, embryonic organ development and developmental growth. In conclusion, several preconception urinary phthalate metabolites were associated with increased DNA methylation patterns in sperm. These findings provide an epigenetic pathway by which environmental phthalate exposures can impact couples’ reproductive outcomes.