Di-(2-ethylhexyl) Phthalate Exposure Research Articles

The associations between prenatal plastic phthalate exposure and lipid acylcarnitine levels in humans and mice.

Phthalates are ubiquitous environmental pollutants known for their endocrine-disrupting properties, particularly during critical periods such as pregnancy and early childhood. Phthalates alter lipid metabolism, but the role of prenatal exposure on the offspring lipidome is less understood. In particular, we focused on long chain acylcarnitines - intermediates of fatty acid oxidation that serve as potential biomarkers of mitochondrial function and energy metabolism. This study aimed (i) to investigate the association between prenatal phthalate exposure and the child's blood acylcarnitine concentrations and, (ii) to evaluate the impact of prenatal administration of di-(2-ethylhexyl) phthalate (DEHP) on acylcarnitine levels in mouse offspring blood, brain and liver. We conducted analyses of both a prospective birth cohort study and an experimental study in mice. From the Barwon Infant Study cohort (1074 mother-child pairs), prenatal phthalate exposure was assessed at 36 weeks' gestation and its association with acylcarnitine levels was examined in cord blood, and child's blood at 6 months, 12 months and 4 years. In mice, pregnant C57BL/6J mouse dams were exposed to 20μg/kg DEHP for 5 days mid-gestation, and offspring tissues were analyzed at 1 month of age postnatally for acylcarnitine profiles. Our findings demonstrate that prenatal phthalate levels (specifically butyl benzyl phthalate (BBzP) and diisobutyl phthalate (DiBP)) are inversely associated with total long chain acylcarnitine levels in human cord blood at birth. In contrast, BBzP was positively associated with the long chain acylcarnitines at 12 months of age. In mice, prenatal DEHP exposure for only 5 days led to decreased palmitoylcarnitine (AC16:0) levels in the brain and liver, but not in blood. Taken together, our findings highlight that prenatal phthalate exposure can alter acylcarnitine profiles, indicating disruptions in fatty acid metabolism that may have long-term effects on metabolic health.

Pets and related allergens modify the association between early life DEHP exposure and respiratory outcomes in children.

Throughout the perinatal period children are exposed to complex mixtures, including indoor chemicals such as phthalates, and biological agents. However, few studies focus on interactions between early-life co-exposures to shed light on how co-exposures modify their individual effects. Therefore, our study aims to assess whether early-life exposure to pets and related biological agents, namely pet allergens and endotoxin, modifies the association between di-(2-ethylhexyl) phthalate (DEHP) and asthma and wheeze in preschoolers to gain insight into interactions. Using data from a Canadian birth cohort study (CHILD), we conducted two complementary analyses on respiratory outcomes. First, we combined pet ownership with DEHP measurements from house dust (N=726). Second, we focused on a subgroup of children with exposure measurements of both DEHP and biological agents in dust (N=261). We used multivariable logistic regression models to assess whether pets and quantified biological agent levels modify associations between DEHP and asthma at 5 years and recurrent wheeze between 2 and 5 years. Interaction terms were included in the models and stratified analyses were further conducted. Associations between DEHP and asthma and wheeze were modified by pet ownership and related biological agents. For persistent/recurrent wheeze, the association with DEHP became larger among children with dogs at home and with higher dog allergens (p-interaction <0.1) and became smaller and insignificant when exposed to cats. Similarly, for asthma, the association with DEHP tended to be larger among children with dogs (also higher dog allergens) and among children without cats (also lower cat allergens) at home, respectively. Endotoxin levels modified the association between DEHP and persistent wheeze (p-interaction < 0.1). Early-life exposure to pets and related biological agents may modify the associations between phthalates and asthma and wheeze in children. Heterogeneity in single exposure studies could be a result of differences in co-exposures among studies.

The benefits of removing toxic chemicals from plastics

More than 16,000 chemicals are incorporated into plastics to impart properties such as color, flexibility, and durability. These chemicals may leach from plastics, resulting in widespread human exposure during everyday use. Two plastic-associated chemicals-bisphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP)-and a class of chemicals-brominated flame retardants [polybrominated diphenyl ethers (PBDEs)]-are credibly linked to adverse health and cognitive impacts. BPA exposures are associated with ischemic heart disease (IHD) and stroke, DEHP exposure with increased all-cause mortality among persons 55 to 64 y old, and prenatal PBDE exposures in mothers with IQ losses in their children. We estimate BPA, DEHP, and PBDE exposures in 38 countries containing one-third of the world's population. We find that in 2015, 5.4 million cases of IHD and 346,000 cases of stroke were associated with BPA exposure; that DEHP exposures were linked to approximately 164,000 deaths among 55-to-64 y olds; and that 11.7 million IQ points were lost due to maternal PBDE exposure. We estimate the costs of these health impacts to be $1.5 trillion 2015 purchasing power parity dollars. If exposures to BPA and DEHP in the United States had been at 2015 levels since 2003, 515,000 fewer deaths would have been attributed to BPA and DEHP between 2003 and 2015. If PBDE levels in mothers had been at 2015 levels since 2005, over 42 million IQ points would have been saved between 2005 and 2015.

DEHP impairs the oxidative stress response and disrupts trace element and mineral metabolism within the mitochondria of detoxification organs.

Di(2-ethylhexyl) phthalate (DEHP), a widely utilized plasticizer in various consumer products, is classified as an endocrine disruptor and has been implicated in numerous adverse health effects, including oxidative stress, inflammation, and metabolic disturbances. Despite the growing body of literature addressing the systemic effects of DEHP, the specific influence of DEHP-induced oxidative stress on mitochondrial function within detoxification organs, particularly the liver and kidneys, remains largely unexplored. This study evaluated the effects of DEHP exposure (0, 100, 200, and 400mg/kg/day) on mitochondrial oxidative stress, trace elements, and mineral metabolism associated with signaling pathways in the liver and kidneys of rats. Altered mitochondrial oxidative stress status was indicated by impaired glucose 6-phosphate dehydrogenase (G6PD), 6-phosphoglucerate dehydrogenase (6-PGD), glutathione reductase (GR), glutathione s-transferase (GST), and glutathione peroxidase (GPx) activities, along with significant disruptions in essential minerals and trace elements, including Na, Mg, Cu, Zn, and Fe. Key oxidative stress signaling pathways, such as NF-κB, Akt, STAT3, and CREB, glucose, and tissue homeostasis, displayed dose-dependent responses to DEHP, indicating complex regulatory mechanisms. This study represents the first comprehensive investigation into DEHP-induced mitochondrial dysfunction, highlighting its effects on oxidative stress metabolism, trace element homeostasis, and cellular signaling pathways in detoxification organs. These findings provide novel insights into the mitochondrial mechanisms underlying DEHP toxicity and underscores the need for further research into the implications of plasticizer exposure on human health.

Exposure to environmentally relevant concentrations of di-(2-ethylhexyl) phthalate (DEHP) induced reproductive toxicity in female koi carp (Cyprinus carpio).

A frequently utilized plasticizer is di-(2-ethylhexyl) phthalate (DEHP), considered a ubiquitous contaminant in the environment and reported to have severe impacts on animals. Although it disrupts the female reproductive system in mammals, little is known about how it effects on fish reproduction. The reproductive parameters of female adult koi carp (Cyprinus carpio) were investigated in this study subjected to environmentally relevant exposure of DEHP (1, 10 and 100 μg/L). After 60 days experiment, significantly lower GSI was recorded in females of 10 and 100 μg/L DEHP-exposed groups. The examination of ovarian histology showed defective histoarchitecture, which included the existence of atretic oocytes, the emergence of intra-oocyte vacuoles as well as necrosis. The groups exposed to DEHP (10 and 100 μg/L) showed significant decreases in fecundity and ova-diameter values. Significant changes in the biochemical (total protein, glucose and cholesterol) and ionic (sodium, potassium, calcium and magnesium) composition were noticed in the ovarian fluid of exposed groups. The groups treated with DEHP showed higher levels of 11-ketotestosterone along with reduced levels of 17β-estradiol. Using real-time PCR, the mRNA expression of several genes linked to reproduction, such as Fshr, Lhr, Ar, Erα and Erβ were assessed and observed that there was a concentration-dependent alternation. The pairing of exposed females with untreated males significantly lowered the rates of fertilization, hatching and larval survival. In summary, the results of this investigation validated that exposure to DEHP in a nominal concentration could potentially reduce the reproductive health of female fish.

Multi-omics revealed activation of TNF-α induced apoptosis signaling pathway in testis of DEHP treated prepubertal male rat

Di-(2-ethylhexyl) phthalate (DEHP) exposure has been associated with male reproductive damage, but the mechanisms involved remain incompletely defined. This study aims to investigate the effects of DEHP exposure on the testes of prepubertal rats through an integrative analysis of metabolomics and transcriptomics, combined with molecular experiments. DEHP exposure resulted in decreased testis weight and increased oxidative stress level in the testis tissues of prepubertal male rats. Moreover, our findings showed a disordered testis structure, reduced spermatogenic and Sertoli cells as well as destruction of mitochondria structure in the testis tissues of DEHP-treated prepubertal male rats. Transcriptome function analysis together with metabolome function analysis indicated that spermatogenesis, apoptosis, inflammatory, lipid metabolism as well as DNA repair signaling pathway were enriched in the testis of DEHP-treated prepubertal male rats. The integrative omics analysis further suggested that TNF-α induced apoptosis played a crucial role in mediating the detrimental effects of DEHP exposure on the testis of prepubertal rats, which was validated by ELISA, Western blotting and Tunel assays. Validation experiments conducted in vitro using GC-2 cells corroborated these findings, demonstrating that mono-(2-ethylhexyl) phthalate (MEHP), the main active metabolite of DEHP, significantly inhibits cell proliferation and increases apoptosis via activating the TNF-α apoptosis pathway. Overall, these findings provided a novel mechanism of dysregulated spermatogenesis of DEHP exposure on the testes of prepubertal rats.

Putative signaling pathways for contraction and its recovery from DEHP arrest in Hymeniacidon heliophila

With sessile habits, sponges (phylum Porifera) are susceptible to marine pollution impacts and recently microplastics were identified as one source of contamination. Microplastics have a physical impact on filtration rates and plastics additives such as di(2-ethylhexyl)phthalate (DEHP), a ubiquitous marine contaminant, were already identified in their tissues indicating bioaccumulation. However, few studies assessed the impacts of such compounds in its physiology. One verified effect of phthalate exposure is the arrest of the contraction cycles observed in the sponge Hymeniacidon heliophila. In this work, proteomics of DEHP exposed organisms of this species was performed to identify modifications in signaling pathways that could lead to this arrest and recovery. The results indicate that exposed organisms had different expressed 5HT receptors, associated to intracellular calcium signaling, the principal pathway to contraction animals. The Myosin Light-Chain Kinase (MLCK) pathway is detected only in exposed organisms as well as components linked to binding of organic cyclic compounds. Results show that for healing from DEHP exposure, H. heliophila may activate an alternative contraction signaling pathway, the MLCK pathway. These coordinate mechanisms could restore contractions in H. heliophila after acute exposure to DEHP. SynopsisResearch into the impact of microplastics on organisms uses animal models known to science such as mussels. In our work, we tested the effects of a plastic additive, DEHP, on the physiology of a much less studied marine organism: sponges.

ROS-mediated M1 polarization-necroptosis crosstalk involved in Di-(2-ethylhexyl) phthalate-induced chicken liver injury

The widespread use of plasticizers poses a serious threat to the environment and poultry health. Di-(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer that can cause liver damage with prolonged exposure. Oxidative stress is closely associated with DEHP toxicity. Macrophage polarization plays an important role in many physiological and pathological processes and regulates disease development. This study aims to elucidate the mechanism of chronic DEHP exposure leading to chicken liver injury through oxidative stress-induced M1 polarization-necroptosis. In this study, the DEHP exposure model of chicken liver and the single and co-culture model of LMH and HD11 cells were established. With increasing dose and time, DEHP decreased body weight, increased liver coefficient, raised activities of liver function indicators and caused pathological liver damage in chickens. Further studies revealed the increase of reactive oxygen species (ROS) level and malonaldehyde (MDA) content, and the decrease of total antioxidant capacity (T-AOC) level, total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px) activities, which led to excessive oxidative stress in the liver. In addition, there was increased infiltration of liver macrophages (CD68), upregulation of M1 polarization indicators (CD86, iNOS, IL-1β, TNF-α) and downregulation of M2 polarization indicators (CD163, Arg-1, IL-10, TGF-β) and appearance of necroptosis (RIPK1, RIPK3, MLKL). The vitro experiments confirmed the addition of N-acetylcysteine (NAC) inhibited M1 polarization and necroptosis. Besides, M1 polarization of HD11 cells promoted necroptosis of LMH cells in the HD11-LMH co-culture system. In brief, ROS-mediated M1 polarization-necroptosis is involved in DEHP-induced liver injury. This study provides a reference for environmental toxicant exposure in livestock and poultry farming.

Association of Di(2-ethylhexyl) Phthalate Exposure with Reproductive Hormones in the General Population and the Susceptible Population: A Systematic Review and Meta-Analysis.

Di(2-ethylhexyl) phthalate (DEHP), an environmental endocrine disruptor, has hormone-like activity and endocrine-disrupting effects. However, the types of reproductive hormones associated with DEHP vary across the studies. Thus, we conducted a systematic review and meta-analysis to pool existing epidemiological evidence. We searched three databases up to January 31, 2024, for eligible original studies to ultimately include 37 studies from eight countries with a total of 28 911 participants. DEHP exposure was evaluated with urinary metabolites. Since the main types, production sites, blood concentrations, and functions of reproductive hormones differ between men and women, we reported the combined effect values by gender. Subgroup analyses were conducted by age, subfertility status, and the national sociodemographic index (SDI) level. Furthermore, the effect of maternal exposure during pregnancy on children's reproductive hormone levels was analyzed separately. Overall, in general, in men, DEHP was positively correlated with sex hormone binding-globulin (SHBG) and adversely correlated with total testosterone (TT), free androgen index (FAI), and follicle-stimulating hormone (FSH). Results indicated that among men of reproductive age, DEHP exposure was associated with more significant hormonal suppression in infertile men compared with fertile men. Notably, age subgroup analysis among women revealed that postmenopausal women were more vulnerable to DEHP, which was related to lower TT and estradiol (E2). However, this study did not observe a significant association between prenatal DEHP metabolites and reproductive hormone levels in children. Our research identifies the most susceptible hormones (androgen suppression) after DEHP exposure and suggests that infertile men and postmenopausal women are in great need of more attention as sensitive populations.

Dietary exposure to di(2-ethylhexyl) phthalate for 6months alters markers of female reproductive aging in mice†.

The female reproductive system ages before any other physiological system, making it a sensitive indicator of aging. Early reproductive aging is associated with the early onset of infertility and an increased risk of several diseases. During aging, systemic and reproductive oxidative stress and inflammation levels increase through inflammasome activation, leading to ovarian follicle loss. Other markers of reproductive aging include increased fibrosis and shortening of telomeres in ovarian cells. The factors that accelerate reproductive aging are unclear, but likely involve exposure to endocrine-disrupting chemicals such as phthalates. Di(2-ethylhexyl) phthalate (DEHP) is a widely used phthalate and humans areexposed to it daily. Several studies show that DEHP induces reproductive toxicity by affecting estrous cyclicity, follicle numbers, and hormone levels. However, little is known about the mechanisms underlying DEHP-induced early onset of reproductive aging. Thus, this study tested the hypothesis that dietary exposure to DEHP induces early reproductive aging by affecting inflammation, fibrosis, and the expression of telomere regulators and antioxidant enzymes. Adult CD-1 female mice were exposed to vehicle (corn oil) or DEHP (0.5, 1.5, or 1500ppm) via the chow for 6months. Exposure to DEHP increased the expression of antioxidant enzymes and Caspase 3, increased expression of telomere-associated genes, and increased fibrosis levels in the ovary. In addition, DEHP exposure for 6months altered ovarian and systemic inflammatory status. Collectively, our novel data suggest that 6-month dietary exposure to DEHP may accelerate reproductive aging by affecting several reproductive aging markers in female mice.

Network toxicology and cell experiments reveal the mechanism of DEHP-induced diabetic nephropathy via Wnt signaling pathway

Di(2-ethylhexyl) phthalate (DEHP), a widely recognized endocrine disruptor, has been linked to the pathogenesis of diabetic nephropathy (DN) through its interference with hormonal and metabolic homeostasis. This study integrates network toxicology with cell-based assays to elucidate the molecular mechanisms of DEHP-induced DN, seeking to identify novel targets for toxicity assessment and therapeutic intervention. Through comprehensive screening across multiple toxicology and disease-related databases, six core genes (CTNNB1, EGFR, TNF, CCND1, BCL2, CASP3) were identified as shared mediators of DEHP exposure and DN. These genes are predominantly associated with the Wnt signaling pathway, a pivotal regulator of podocyte function, including cellular adhesion, differentiation, apoptosis, and inflammatory response. Mouse glomerular podocytes (MPC-5) exposed to graded concentrations of DEHP, with or without the Wnt pathway inhibitor XAV-939, displayed significant DEHP-induced disruptions: reduced cell adhesion, proliferation, and differentiation; increased autophagy, apoptosis, and migratory activity; elevated inflammatory mediator release; and pronounced activation of the Wnt signaling pathway, evidenced by upregulation of β-catenin, EGFR, TNF, CCND1, BCL2 and downregulation of CASP3. DEHP exposure further altered transcriptional activity and chromatin structure at key loci (CTNNB1, EGFR, and TNF). XAV-939 effectively mitigated these effects, underscoring the Wnt pathway's central role in DN progression under DEHP influence. These findings highlight the complex multi-target, multi-pathway interactions of DEHP in DN pathophysiology, offering deeper mechanistic insights and potential targets for therapeutic intervention against DEHP-induced nephrotoxicity.

Environmental endocrine disrupting chemical-DEHP exposure-provoked biotoxicity about microbiota-gut-mammary axis in lactating mice via multi-omics technologies

Plastics, pervasive in humans and nature, often contain Di (2-ethylhexyl) phthalate (DEHP) that enhance plastic’s elasticity. However, DEHP is an environmental endocrine disruptor, affecting organisms upon exposure. Understanding mammary gland development in lactating females is crucial for offspring nourishment and dairy production. Employing multi-omics technology, this study aimed to uncover DEHP’s impact on the microbial–gut–mammary axis. Forty mice were exposed to varying DEHP doses for 18 d. We performed 16S sequencing, metabolomics, mammary tissue observation, and gene expression profiling. Results revealed DEHP’s influence on microbial diversity, with increased Lactobacillus abundance and reduced Proteobacteria, alongside colonic inflammation. Elevated GMP and adenosine 5′-monophosphate levels in the bloodstream were noted, while ascorbic acid, glycitein, and others decreased. MEHP, a DEHP metabolite, damaged mammary tissues, inhibiting ERK1/2 phosphorylation, triggering apoptosis and ferroptosis. These findings unveil potential therapeutic targets for DEHP-induced chronic toxicity in humans and animals, aiding dairy livestock health and human well-being. This study underscores the importance of understanding the adverse effects of DEHP exposure on mammalian systems.

PiRNA array analysis provide insight into the mechanism of DEHP-induced testicular toxicology in pubertal male rats

Di-(2-ethylhexyl) phthalate (DEHP), a widely used plasticizer, could cause male reproductive toxicity by disrupting spermatogenesis. Piwi-interacting RNAs (piRNAs) are a small non-coding RNAs specifically highly expressed in the germline and interact with PIWI proteins to regulate spermatogenesis. Accumulating studies have confirmed that environmental poisons could induce male reproductive injury via altering piRNA expression. However, it remains unclear whether DEHP causes male reproductive dysfunction by perturbing piRNA expression levels. In this study, we conducted piRNA microarray expression analyses on testes of DEHP-exposed and control male rats and performed some in vitro and in vivo studies to explore the role of piRNA on DEHP-induced male reproductive toxicity. Our results showed that DEHP exposure leaded to changed expression profiles of piRNAs in pubertal male rat testes. And bioinformatics analyses revealed that down-regulated piR-rno-26751 probably targeted Insr mRNA expression regulation. Results from gene and protein expression tests demonstrated that DEHP caused decreased expression level of INSR mainly in spermatogonia. Moreover, MEHP, the main metabolite of DEHP resulted in cell apoptosis and down-regulation of INSR and its downstream p-IRS1, p-PI3K, p-AKT and p-FOXO1 in GC-1spg cells. Conversely, overexpression of INSR restored cell apoptosis and the down-regulation of the above proteins in GC-1spg cells. In conclusion, these findings suggest that DEHP-induced down-regulation of piR-rno-26751 targets the suppression of INSR, leading to apoptosis of spermatogonia in pubertal male rats.

Arrhythmogenic effects of DEHP exposure: insights into cardiac electrophysiology and myocardial cells

Abstract Introduction Hemodialysis patients, who are exposed to plasticizers through the hemodialysis circuit, face a high risk of cardiovascular disease (CVD). Plasticizers, such as the endocrine-disrupting compound Di(2-ethylhexyl) phthalate (DEHP), have emerged as potential contributors to CVD. This study explores the impact of DEHP on cardiac electrophysiology and myocardial cells, providing insights into its cardiotoxic effects. Methods We employed optical mapping techniques to assess cardiac electrophysiology in Langendorff-perfused rat hearts exposed to DEHP, comparing them to a control group. Additionally, we evaluated the effect of DEHP on cardiac muscle cells using H9C2 rat cardiomyoblasts. Results Prolonged DEHP exposure resulted in elevated heart rate, increased electrocardiographic variability, and higher low-frequency values, indicative of sympathetic nervous system overactivity. Action potential duration at APD80 increased, leading to greater action potential triangulation. Electrical alternans observed in the DEHP-treated group heightened the risk of arrhythmias. Single-cell analysis revealed severe mitochondrial damage, myocardial cell apoptosis, and disrupted calcium ion balance. Conclusion This study highlights DEHP's cardiotoxicity, suggesting its potential role in arrhythmogenesis and cardiac dysfunction. Environmental pollutants like DEHP warrant consideration as contributors to cardiovascular diseases, emphasizing the need for further research on preventive strategies.

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.

Di-(2-ethylhexyl) Phthalate Exposure Induces Developmental Toxicity in the Mouse Fetal Heart via Mitochondrial Dysfunction.

Congenital heart disease (CHD) is a major cause of infant mortality and morbidity, with growing interest in the role of environmental factors in its etiology. Di-(2-ethylhexyl) phthalate (DEHP), an environmental endocrine disruptor, has been implicated in the development of CHD. This study aimed to investigate the effects of DEHP exposure on fetal heart development in mice. Pregnant mice exposed to DEHP exhibited increased fetal malformations, decreased fetal weight, and reduced crown-rump length.f Transcriptomic analysis revealed the downregulation of genes involved in aerobic respiration and mitochondrial ATP synthesis. Functional assays demonstrated reduced mitochondrial respiration, decreased ATP production, elevated reactive oxygen species levels, and lowered mitochondrial membrane potential in DEHP-exposed fetal cardiomyocytes. These findings underscore the detrimental effects of DEHP on fetal cardiac health and provide insights into the molecular mechanisms underlying DEHP-induced CHD. Understanding these mechanisms is crucial for developing preventive strategies against environmental toxicants that affect fetal cardiac development.

Diethylhexyl phthalate induces immune dysregulation and is an environmental immune disruptor

Diethylhexyl phthalate (DEHP) is the most abundant phthalate compound in the environment, and has been linked with multiple human diseases. The immune system is closely associated with the occurrence and progression of various diseases. However, minimal research has addressed the impact of DEHP on the immune system. In this study, single-cell RNA sequencing was performed using spleen tissue of mice to comprehensively determine alterations of the immune system in response to DEHP. The results showed that DEHP exposure reduced the absolute number of peripheral white blood cells (WBCs), including lymphocytes, monocytes, eosinophils, basophils, and neutrophils in mice. In addition, scRNA-seq analyses showed that inflammatory signaling and the expression of heat shock proteins (HSPs) were reduced in all peripheral immune cell populations. Furthermore, we established a mice cecal ligation and puncture (CLP) model, and showed that DEHP exacerbated sepsis-induced immunosuppression and organ damage. These results suggest that DEHP is an environmental immune disruptor that undermines the immune system, exacerbating acute infections and organ damage. Our findings offer a novel perspective on the hazards of DEHP to human health.

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.

Mitigation of di-(2-ethylhexyl) phthalate contamination exposure over supramolecular organic heterojunction

Di-(2-ethylhexyl) phthalate (DEHP) with endocrine disrupting toxicity has been widely concerned owing to its widespread presence in environment and food. As an essential part of the daily diet, edible oil has become an emerging and nonnegligible source of DEHP intake exposure. Herein, we demonstrated a two-step method to mitigate DEHP exposure from edible oil including firstly selective adsorption and then photocatalytic degradation by supramolecular organic nanomaterial composites. Perylene diimide (PDI) heterojunction with Bi2WO6 was synthesized by a facile ultrasonic-water bath heating method. It was found that PDI/Bi2WO6 showed selective adsorption of DEHP in edible oil via π-π stacking, hydrophobic interactions, and monolayer chemisorption compared with other phthalates. Adsorption kinetics and isotherm simulation results showed that the adsorption process conformed to the second-order kinetics and Langmuir model. Then, under visible light irradiation, PDI/Bi2WO6 with 35 % m(PDI)/m(Bi2WO6) had the highest degradation rate of DEHP, which was 2.16 and 1.76 times higher than that of PDI and Bi2WO6, respectively. The reactive species generated under visible light irradiation, superoxide radicals (•O2−), hydroxyl radicals (•OH), and holes (h+) were synergistically involved in the photodegradation of DEHP to the intermediates of mono(2-ethylhexyl) phthalate (MEHP), mono-dibutyl phthalate (MBP), phthalic acid (PA), and 4-oxohexanoic acid. These findings may provide a technology for minimizing and treating contaminants exposure in the environment and foodstuffs through supramolecular organic nanomaterial heterojunction.

Di(2-ethylhexyl) phthalate disrupts circadian rhythm associated with changes in metabolites and cytochrome P450 gene expression in Caenorhabditis elegans

The plasticizer di(2-ethylhexyl) phthalate (DEHP) is a widespread environmental pollutant due to its extensive use. While circadian rhythms are inherent in most living organisms, the detrimental effects of DEHP on circadian rhythm and the underlying mechanisms remain largely unknown. This study investigated the influence of early developmental exposure to DEHP on circadian rhythm and explored the possible relationship between circadian disruption and DEHP metabolism in the model organism Caenorhabditis elegans. We observed that DEHP disrupted circadian rhythm in a dose-dependent fashion. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed that DEHP-induced circadian disruption accompanies with altered proportions of DEHP metabolites in C. elegans. RNA sequencing data demonstrated that DEHP-induced circadian rhythm disruption caused differential gene expression. Moreover, DEHP-induced circadian disruption coincided with attenuated inductions of DEHP-induced cytochrome P450 genes, cyp-35A2, cyp-35A3, and cyp-35A4. Notably, cyp-35A2 mRNA exhibited circadian rhythm with entrainment, but DEHP exposure disrupted this rhythm. Our findings suggest that DEHP exposure disrupts circadian rhythm, which is associated with changes in DEHP metabolites and cytochrome P450 gene expression in C. elegans. Given the ubiquitous nature of DEHP pollution and the prevalence of circadian rhythms in living organisms, this study implies a potential negative impact of DEHP on circadian rhythm and DEHP metabolism in organisms.