Phthalate Exposure Research Articles

Investigating the modulation of the endocannabinoid system by probiotic Lactiplantibacillus plantarum IMC513 in a zebrafish model of di-n-hexyl phthalate exposure

Environmental pollutants used as plasticizers in food packaging and in thousands of everyday products have become harmful for their impact on human health. Among them, phthalates, recognized as emerging endocrine disruptors (EDs) can induce toxic effects leading to different health disorders. Only few studies evaluated the effects of di-n-hexyl phthalate (DnHP) in in vivo models and no studies have been conducted to investigate the effect of DnHP on the endocannabinoid system (ECS), one of the majors signaling pathways involved in the microbiota–gut–brain axis. Due to the current relevance of probiotic bacteria as beneficial dietary interventions, the present study was aimed at evaluating the potential neuroprotective impact of daily administration of Lactiplantibacillus (Lpb.) plantarum IMC513 on zebrafish adults exposed to DnHP, with a focus on ECS modulation. Gene expression analysis revealed a promising protective role of probiotic through the restoration of ECS genes expression to the control level, in the brain of zebrafish daily exposed to DnHP. In addition, the levels of main endocannabinoids were also modulated. These findings confirm the potential ability of probiotics to interact at central level by modulating the ECS, suggesting the use of probiotics as innovative dietary strategy to counteract alterations by EDs exposure.

Mixtures of phthalates disrupt expression of genes related to lipid metabolism and peroxisome proliferator-activated receptor signaling in mouse granulosa cells.

Phthalates are a class of known endocrine disrupting chemicals that are found in common everyday products. Several studies associate phthalate exposure with detrimental effects on ovarian function, including growth and development of the follicle and production of steroid hormones. We hypothesized that dysregulation of the ovary by phthalates may be mediated by phthalate toxicity towards granulosa cells, a major cell type in ovarian follicles responsible for key steps of hormone production and nourishing the developing oocyte. To test the hypothesis that phthalates target granulosa cells, we harvested granulosa cells from adult CD-1 mouse ovaries and cultured them for 96 hours in vehicle control, a phthalate mixture, or a phthalate metabolite mixture (0.1-100 μg/mL). After culture, we measured metabolism of the phthalate mixture into monoester metabolites by the granulosa cells, finding that granulosa cells do not significantly contribute to ovarian metabolism of phthalates. Immunohistochemistry of phthalate metabolizing enzymes in whole ovaries confirmed that these enzymes are not strongly expressed in granulosa cells of antral follicles and that ovarian metabolism of phthalates likely occurs primarily in the stroma. RNA sequencing of treated granulosa cells identified 407 differentially expressed genes, with overrepresentation of genes from lipid metabolic processes, cholesterol metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Expression of significantly differentially expressed genes related to these pathways was confirmed using qPCR. Our results agree with previous findings that phthalates and phthalate metabolites have different effects on the ovary, but both interfere with PPAR signaling in granulosa cells.

Associations between Phthalates Exposure and Oxidative Stress Biomarkers in the Risk of Recurrent Pregnancy Loss

Associations between Phthalates Exposure and Oxidative Stress Biomarkers in the Risk of Recurrent Pregnancy Loss

Persistent Associations of Prenatal Phenol and Phthalate Exposure with DNA Methylation in Childhood

Persistent Associations of Prenatal Phenol and Phthalate Exposure with DNA Methylation in Childhood

Associations of gestational phthalate and phenol exposure with infant cognition

Associations of gestational phthalate and phenol exposure with infant cognition

Prenatal phthalate exposure and anogenital distance in infants around 12 months

Prenatal phthalate exposure and anogenital distance in infants around 12 months

Phthalates exposure estimation from personal care products usage in participants of The Mexican Teachers' Cohort.

Phthalates exposure estimation from personal care products usage in participants of The Mexican Teachers' Cohort.

Evaluating the use of silicone wristbands and urine biomarkers for assessment of phthalate exposure

Evaluating the use of silicone wristbands and urine biomarkers for assessment of phthalate exposure

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

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

Portulaca Oleracea L. Phenolic Amide Methyl (3,4,5-Trimethoxybenzoyl) Valylprolinate Attenuates Diethylhexyl Phthalate-Induced Human Umbilical Vein Endothelial Cells' Inflammation Through NLRP3 and NF-κB Pathways.

Twelve polyphenol derivatives were obtained in a protective activity-guided isolation from the Portulaca oleracea L. extract on a cell model of human umbilical vein endothelial cells (HUVECs) under diethylhexyl phthalate (DEHP) exposure. Among them, methyl (3,4,5-trimethoxybenzoyl) valylprolinate (PP-10) performed the most protective activity and inhibited DEHP exposure-induced HUVECs' apoptosis. PP-10 also inhibited the DEHP-induced inflammatory cytokines (TNF-α, IL-6, IL-1β, and IL-8) and adhesion molecule (ICAM-1 andVCAM-1) overexpression. Furthermore, DEHP-induced NLRP3 inflammasomes' and NF-κB signaling pathway activation was significantly inhibited after the PP-10 treatments. Of note, the current results suggest the potential application of Portulaca oleracea L. and PP-10 in the prevention of DEHP-induced inflammatory damages in HUVECs.

Maternal symptoms of depression and anxiety as modifiers of the relationship between prenatal phthalate exposure and infant neurodevelopment in the Atlanta African American maternal-child cohort

BackgroundPrenatal exposure to phthalates, a group of synthetic chemicals widely used in consumer products, has previously been associated with adverse infant and child development. Studies also suggest that maternal depression and anxiety, may amplify the harmful effects of phthalates on infant and child neurodevelopment. Study designOur analysis included a subset of dyads enrolled in the Atlanta African American Maternal-Child Cohort (N = 81). We measured eight phthalate metabolites in first and second trimester (8–14 weeks and 24–32 weeks gestation) maternal urine samples to estimate prenatal exposures. Phthalate metabolite concentrations were averaged across visits and natural log-transformed for analysis. Maternal symptoms of depression and anxiety were assessed using validated questionnaires (Edinberg Postnatal Depression Scale and State Trait Anxiety Inventory, respectively) and the total score on each scale was averaged across study visits. The NICU Network Neurobehavioral Scale (NNNS) was administered at two weeks of age. Our primary outcomes included two composite NNNS scores reflecting newborn attention and arousal. Linear regression was used to estimate associations between individual phthalate exposures and newborn attention and arousal. We assessed effect modification by maternal depression and anxiety. ResultsHigher levels of urinary phthalate metabolites were not associated with higher levels of infant attention and arousal, but true associations may still exist given the limited power of this analysis. In models examining effect modification by maternal depression, we observed that an interquartile range increase in mono (2-ethlyhexyl) phthalate (MEHP), mono (2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) was associated with a significant increase in newborn arousal only among those with high depressive symptoms (MEHP: β = 0.71, 95% confidence interval [CI] = 0.10, 1.32 for high, β = −0.30, 95% CI = −0.73, 0.12 for low; MEOHP: β = 0.60, 95% CI = −0.03, 1.23 for high, β = −0.12, 95% CI = −0.58, 0.33 for low; MEHHP: β = 0.54, 95% CI = −0.04, 1.11 for high, β = −0.11, 95% CI = −0.54, 0.32 for low). Similar patterns were observed in models stratified by maternal anxiety, although CIs were wide. ConclusionOur results suggest maternal anxiety and depression symptoms may exacerbate the effect of phthalates on infant neurodevelopment. Future studies are needed to determine the optimal levels of attention and arousal in early infancy.

Metabolic Stress Responses in Labeo rohita Subjected to Di (2-ethylhexyl) Phthalate (DEHP), Dibutyl Phthalate (DBP), and Diethyl Phthalate (DEP)

This study investigates the stress response of glucose and cholesterol levels in Labeo rohita (Rohu) upon exposure to three widely used phthalates: Di(2-ethylhexyl) phthalate (DEHP), Dibutyl phthalate (DBP), and Diethyl phthalate (DEP). Phthalates, recognized for their endocrine-disrupting properties, are prevalent environmental contaminants. Specimens of Labeo rohita were subjected to environmentally relevant concentrations of DEHP, DBP, and DEP over a controlled period. Blood samples were collected periodically to measure fluctuations in glucose and cholesterol levels, serving as biomarkers of metabolic stress. The results indicate significant alterations in both glucose and cholesterol concentrations, with each phthalate demonstrating a distinct impact on these metabolic parameters. DEHP and DBP elicited more pronounced disruptions compared to DEP, underscoring their higher toxicity. These findings highlight the differential metabolic responses of Labeo rohita to various phthalates and underscore the ecological risks associated with phthalate contamination. The study advocates for stricter regulatory measures to mitigate phthalate pollution and protect aquatic ecosystems. This research enhances our understanding of the biochemical pathways affected by phthalate exposure and lays the groundwork for future investigations into the mechanisms underlying phthalate-induced stress in fish.

Temporal trends in phthalate metabolite exposure of girls in the United States across sociodemographic factors and intersectional social identities: National Health and Nutrition Examination Survey (NHANES) 2001–2018

BackgroundExposure to phthalates during the pubertal window is linked to an increased risk of chronic diseases. Understanding temporal trends in exposure can inform public health initiatives. ObjectiveCharacterize temporal trends in phthalate metabolite levels in adolescent girls overall and by sociodemographic characteristics. MethodsWe used the cross-sectional data from each cycle of NHANES from years 2001–2018. We included participants aged 8–14 years who had at least one urinary measurement of the selected 12 phthalate metabolites within the study period (n = 2063). We used multivariable linear regression to assess temporal trends for selected individual phthalate metabolite concentrations (ng/ml) and source groupings of parent metabolites (sum low and high molecular weight phthalates; ∑LMW and ∑HMW), overall and by sociodemographic characteristics (race/ethnicity), nativity, socioeconomic status (SES), intersection of race/ethnicity-SES) to assess for modification. ResultsOverall, levels of ∑HMW and ∑LMW declined between 2001 and 2018; however, only ∑LMW consistently differed by all sociodemographic characteristics. Trends in ∑LMW concentration were significantly higher across all racial/ethnic groups, ranging from an average of 35% (Other Hispanic) to 65% (Mexican American and non-Hispanic Black) higher than non-Hispanic White (all p-values <0.0001). Compared to non-Hispanic White, a significant decrease in MiBP concentrations was observed for non-Hispanic Black (15% decrease βSpline = −0.16, p < 0.0001) and Other Hispanic (28% decrease, βSpline = −0.33, p = 0.01) in 2011–2018 versus 2001–2010. Summary and individual LMW metabolite phthalate concentrations were 11%–49% higher among girls with low vs. high SES. LMW metabolites MBP and MiBP were on average 22% and 35% higher, respectively, among foreign-born vs. U.S.-born girls. Compared to non-Hispanic Whites, all racial/ethnic groups had statistically significant higher trends in ∑LMW concentrations irrespective of SES. SignificanceGirls identifying with a historically disadvantaged racial/ethnic groups exhibited elevated ∑LMW concentrations irrespective of SES; suggesting the need for targeted interventions to mitigate exposure among the most historically disadvantaged strata.

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

BackgroundCardiovascular 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. MethodsParticipants 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. Results2241 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. ConclusionsThis 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.

Assessment of maternal phthalate exposure in urine across three trimesters and at delivery (umbilical cord blood and placenta) and its influence on birth anthropometric measures

Phthalates, commonly used in plastic manufacturing, have been linked to adverse reproductive effects. Our research from the Saudi Early Autism and Environment Study (2019–2022), involving 672 participants, focused on the impacts of maternal phthalate exposure on birth anthropometric measures. We measured urinary phthalate metabolites in 390 maternal samples collected during each of the three trimesters of pregnancy and in cord serum and placental samples obtained at delivery. We employed various statistical methods to analyze our data. Intraclass correlation coefficients were used to assess the consistency of phthalate measurements, generalized estimating equations were used to explore temporal variations across the trimesters, and linear regression models, adjusted for significant confounders and Bonferroni correction, were used for each birth outcome. Exposure to six phthalates was consistently high across trimesters, with 82 %–100 % of samples containing significant levels of all metabolites, except for mono-benzyl phthalate. We found a 3.15 %–3.73 % reduction in birth weight (BWT), 1.39 %–1.69 % reduction in head circumference (HC), and 3.63 %–5.45 % reduction in placental weight (PWT) associated with a one-unit increase in certain urinary di(2-ethylhexyl) phthalate (DEHP) metabolites during the first trimester. In the second trimester, exposure to MEP, ∑7PAE, and ∑LMW correlated with a 3.15 %–4.5 % increase in the APGAR 5-min score and increases in PWT by 8.98 % for ∑7PAE and 9.09 % for ∑LMW. Our study also highlighted the maternal-to-fetal transfer of DEHP metabolites, indicating diverse impacts on birth outcomes and potential effects on developmental processes. Our study further confirmed the transfer of DEHP metabolites from mothers to fetuses, evidenced by variable rates in the placenta and cord serum, with an inverse relationship suggesting a passive transfer mechanism. Additionally, we observed distinct phthalate profiles across these matrices, adversely impacting birth outcomes. In serum, we noticed increases associated with DEHP metabolites, with birth gestational age rising by 1.01 % to 1.11 %, HC by 2.84 % to 3.67 %, and APGAR 5-min scores by 3.77 % to 3.87 %. Conversely, placental analysis revealed a different impact: BWT decreased by 3.54 % to 4.69 %, HC reductions ranged from 2.57 % to 4.69 %, and chest circumference decreased by 7.13 %. However, the cephalization index increased by 3.67 %–5.87 %. These results highlight the complex effects of phthalates on fetal development, indicating their potential influence on crucial developmental processes like sexual maturation and brain development.

Effects of Endocrine-Disrupting Chemicals on Bone Health.

This comprehensive review critically examines the detrimental impacts of endocrine-disrupting chemicals (EDCs) on bone health, with a specific focus on substances such as bisphenol A (BPA), per- and polyfluoroalkyl substances (PFASs), phthalates, and dioxins. These EDCs, by interfering with the endocrine system's normal functioning, pose a significant risk to bone metabolism, potentially leading to a heightened susceptibility to bone-related disorders and diseases. Notably, BPA has been shown to inhibit the differentiation of osteoblasts and promote the apoptosis of osteoblasts, which results in altered bone turnover status. PFASs, known for their environmental persistence and ability to bioaccumulate in the human body, have been linked to an increased osteoporosis risk. Similarly, phthalates, which are widely used in the production of plastics, have been associated with adverse bone health outcomes, showing an inverse relationship between phthalate exposure and bone mineral density. Dioxins present a more complex picture, with research findings suggesting both potential benefits and adverse effects on bone structure and density, depending on factors such as the timing and level of exposure. This review underscores the urgent need for further research to better understand the specific pathways through which EDCs affect bone health and to develop targeted strategies for mitigating their potentially harmful impacts.

Associations of bisphenol and phthalate exposure and anti-Müllerian hormone levels in women of reproductive age

In women, exposure to endocrine disrupting chemicals might accelerate the depletion of the ovarian reserve and might be associated with accelerative reproductive aging and fertility. We examined the longitudinal associations of exposure to bisphenols and phthalates with anti-Müllerian hormone concentrations. Pregnant women of 18 years or older that resided in Rotterdam between 2002 and 2006 were eligible for participation in this longitudinal prospective cohort study. We measured urinary bisphenol and phthalate concentration at three time-points in pregnancy among 1405 women, of whom 1322 women had serum Anti-Müllerian Hormone (AMH) measurements 6 and/or 9 years postpartum. We performed linear regression models to assess the association of urinary bisphenol and phthalate metabolites with AMH after 6 and 9 years, and linear mixed-effect model to assess the association with AMH over time. Models were adjusted for sociodemographic and lifestyle factors. In our multivariable linear regression models we observed associations of higher urinary pregnancy-averaged mono-isobutyl phthalate (mIBP), mono-(2-ethyl-5-oxohexyl) phthalate (mEOHP), and monobenzyl phthalate (mBzBP) with lower serum AMH after both 6 and 9 years. However, these associations did not remain after adjustment for multiple testing. No significant associations of bisphenol A with AMH were present in our study sample. In our linear mixed-effects models, higher mIBP, mono-(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), mEOHP, and mBzBP were associated with lower overall AMH levels (differences-0.07 (95% CI -0.13,-0.02),-0.09 (-0.15,-0.02),-0.08 (95% CI -0.14,-0.02), and-0.08 (-0.13,-0.03) μg/L per doubling in mIBP, mEHHP, mEOHP, and mBzBP respectively) (all False Discovery Rate adjusted p-values < 0.05). We identify decreases in indices of ovarian reserve in relationship to prenatal phthalate exposures. Studies are needed replicating our results among large multi-ethnic non-pregnant populations and assessing transgenerational effects of exposure on ovarian reserve. This study was supported by the Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organisation for Health Research and Development, the European Research Council, the Dutch Heart Foundation, the Dutch Diabetes Foundation, the European Union's Horizon 2020 Research and Innovation Program, the National Institutes of Health, Ansh Labs Webster, and the Royal Netherlands Academy of Arts and Sciences.

Exploring associations between the Phthalate Environmental Reproductive Health Literacy (PERHL) scale & biomarkers of phthalate exposure: A pilot study.

Perinatal exposure to phthalates is associated with adverse health impacts for parents and children. The field of environmental health literacy seeks to measure how environmental health information is conceptualized and used to inform behaviors. We assessed whether scores on the validated Phthalate Environmental Reproductive Health Literacy (PERHL) scale were associated with biomarkers of phthalate exposure. 42 members of the Environmental Reproductive and Glucose Outcomes (ERGO) cohort completed the PERHL scale and provided spot urine samples. Phthalate summary measures for model outcomes were created by calculating molar sums of specific gravity-corrected metabolite concentrations representing exposure to parent phthalate, Di(2-ethylhexyl)phthalate (DEHP), personal care product (PCP)-associated phthalates, and parent butyl-phthalates. Linear regression models were used to estimate the associations of the PERHL scale scores with phthalate summary measures, controlling for educational attainment (college degree or higher vs. no college degree), age (years), and race and ethnicity (non-Hispanic White vs. non-White). Higher scores on the PERHL Scale and subscales were generally associated with lower ΣDEHP, Σbutyl, and ΣPCP metabolite concentrations. A one-point increase in the 'Protective Behavior/Risk Control' subscale score was significantly associated with a -30.3% (95% CI: -50.1, -2.6) decrease in ΣDEHP, and a -30.6% (95% CI: -51.5, -0.63) decrease in Σbutyl metabolite concentrations.

Socio-Demographic Patterning of Urinary Mono-ethyl Phthalate Levels among Children and Adults in the U.S. (1999-2018)

Abstract Background: Phthalates are chemicals used to make plastics flexible and durable. They are found in clothes, varnishes, toys, pharmaceuticals, containers, and personal care products. Phthalates make their way into human bodies through ingestion, inhalation, and dermal absorption, and the breakdown of them within bodies can be measured as phthalate metabolites in urine. They pervade all aspects of the environment and our bodies, contributing to negative health outcomes. Education, SES, and gender influence where people live (their built environment), time-use patterns, occupation, treatment at healthcare facilities, and purchasing patterns; all affect phthalate exposures, and therefore phthalate metabolites in urine are also likely to vary by socio-demographic characteristics. Objectives: To study how levels of mono-ethyl phthalate (MEP) in urine samples of children and adults in the U.S. vary among key socio-demographic groups. We expect that disadvantaged groups will have the highest levels of phthalates. Methods: Using quantitative methods, we analyze levels of urinary MEP as a biomarker indicating exposure to phthalates. Within the National Health and Nutrition Examination Survey (NHANES) (1999-2018) participants, we compare MEP levels across the following socio-demographic groups: age, gender, education, race/ethnicity, family income to poverty level, citizenship status. We use multivariate regression models to adjust results for differences in other factors that potentially influence MEP levels. Results: Historically disadvantaged groups – women, Non-Hispanic Blacks, Mexican Americans, Other Hispanics, and those with lower educational attainment – have higher predicted phthalate levels, even when holding all covariates that could be related to differences in phthalate levels by socio-demographic factors constant. Discussion: Our results suggest differences in socio-demographic factors could be leading to unequal exposures to phthalates and MEP excretions in their urine. This research contributes to understanding health experiences outside of clinical definitions, drawing attention to structural vulnerabilities and the way that environmental toxicants are embodied in individuals and populations.

Associations between urinary level of bisphenol A, phthalates, 8-iso-prostaglandin-F2α, and emotional and behavioral problems among Chinese adolescents

BackgroundEmotional and behavioral problems (EBPs) of adolescents is a worldwide public health problem. Bisphenol A (BPA) and phthalate (PAEs) are prevalent and potentially toxic to human health. Therefore, this study aimed to investigate the associations between urinary level of BPA, PAEs, 8-iso-prostaglandin-F2α (8-iso-PGF2α), and EBPs. MethodsA total of 865 Chinese adolescents were included in this study and EBPs was assessed using the Strengths and Difficulties Questionnaire (SDQ). Urinary concentrations of BPA and seven PAEs metabolites in adolescents were determined by high performance liquid chromatography-tandem mass spectrometry. Urinary 8-iso-PGF2α concentration was detected by enzyme-linked immunosorbent assay (ELISA). Spearman rank correlation analysis, multivariate logistic regression analysis, restricted cubic spline functions were used to explore the relationship between the levels of BPA, PAEs, 8-iso-PGF2α and EBPs. ResultsBPA and PAEs metabolites were positively associated with EBPs in Chinese adolescents. And the 8-iso-PGF2α was significantly non-linearly correlated with emotional symptoms, conduct problems, peer problems and total difficulties. Furthermore, 8-iso-PGF2α may partially mediate the association between BPA and PAEs exposure and EBPs. LimitationsThis study was a cross-sectional study, the cause-effect relationship between BPA, PAEs exposure and EBPs could not be determined. A single spot urine sample for BPA and PAEs exposure characterization maybe could not represent their long-term exposure level. ConclusionsHigh exposure of BPA and PAEs are associated with EBPs, which may be partly mediated by oxidative stress among adolescents. The results of this study could provide certain ideas for subsequent related research.