Di-(2-ethylhexyl) Phthalate Exposure Research Articles

Single-Cell Insights into Mouse Testicular Toxicity under Peripubertal Exposure to Di(2-ethylhexyl) phthalate.

Male fertility depends on normal pubertal development. Di(2-ethylhexyl) phthalate (DEHP) is a potent antiandrogen chemical, and exposure to DEHP during peripuberty can damage the developing male reproductive system, especially the testis. However, the specific cellular targets and differentiation processes affected by DEHP, which lead to testicular toxicity, remain poorly defined. Herein, we presented the first single-cell transcriptomic profile of the pubertal mouse testis following DEHP exposure. To carry out the experiment, two groups (n = 8 each) of three-week old male mice were orally administered 0.5% carboxymethylcellulose sodium salt or 100 mg/kg body weight DEHP daily from postnatal day 21 to 48, respectively. Using single-cell RNA sequencing, a total of 31 distinct cell populations were identified, notably, Sertoli and Leydig cells emerged as important targets of DEHP. DEHP exposure significantly decreased the proportions of Sertoli cell clusters expressing mature Sertoli markers (Sox9 and Ar), and selectively reduced the expression of testosterone synthesis genes in fetal Leydig cells. Through cell-cell interaction analyses, we observed changed numbers of interactions in Sertoli cells 1 (SCs1), Leydig cells 1 (LCs1) and interstitial macrophages (ITMs), and we also identified cell-specific ligand gene expressions in these clusters, such as Inha, Fyn, Vcam1, and Apoe. Complementary in vitro assays confirmed that DEHP directly reduced the expression of genes related to Sertoli cell adhesion and intercellular communication. In conclusion, peripubertal DEHP exposure reduced the number of mature Sertoli cells and may disrupt testicular steroidogenesis by affecting the testosterone synthesis genes in fetal Leydig cells rather than adult Leydig cells.

Prenatal diethylhexylphthalate exposure disturbs adult Leydig cell function via epigenetic downregulation of METTL4 expression in male rats

Prenatal exposure to diethylhexyl phthalate (DEHP) has been linked with a decline in testosterone levels in adult male rats, but the underlying mechanism remains unclear. We investigated the potential epigenetic regulation, particularly focusing on N6-methyladenosine (m6A) modification, as a possible mechanism. Dams were gavaged with DEHP (0, 10, 100, and 750 mg/kg/day) from gestational day 14 to day 21. The male offspring were examined at the age of 56 days. Prenatal DEHP administration at 750 mg/kg/day caused a decline in testosterone concentrations, an elevation in follicle-stimulating hormone, a downregulated expression of CYP11A1 HSD3B2, without affecting Leydig cell numbers. Interestingly, Methyltransferase Like 4 (METTL4), an m6A methyltransferase, was downregulated, while there were no changes in METTL3 and METTL14. Moreover, CYP11A1 showed m6A reduction in response to prenatal DEHP exposure. Additionally, METTL4 expression increased postnatally, peaking in adulthood. Knockdown of METTL4 resulted in the downregulation of CYP11A1 and HSD3B2 and an increase in SCARB1 expression. Furthermore, the increase in autophagy protection in adult Leydig cells induced by prenatal DEHP exposure was not affected by 3-methyladenosine (3MA) treatment, indicating a potential protective role of autophagy in response to DEHP exposure. In conclusion, prenatal DEHP exposure reduces testosterone by downregulating CYP11A1 and HSD3B2 via m6A epigenetic regulation and induction of autophagy protection in adult Leydig cells as a response to DEHP exposure.

Characterization and sources of childhood PAEs exposure from residential airborne dust in China cities

To explore the multicenter characteristics of endocrine-like phthalate esters (PAEs) in household dust and propose effective control strategies for global indoor public health. An on-site observational investigation was conducted in nine Chinese cities from 2018 to 2019. A total of 246 household dust samples were collected and analyzed for ten PAE congeners using Gas Chromatography-Mass Spectrometry (GC-MS). Questionnaires were used to gather information on building conditions, indoor behaviors, and ventilation habits. In residential dust from the nine cities, the total concentrations of the ten PAE congeners (∑PAEs) ranged from 0.921 to 29097.297 µg/g. Dicyclohexyl phthalate (DCHP) and di (2-ethylhexyl) phthalate (DEHP) were the dominant congeners in ∑PAEs. Childhood exposure to PAEs through dust ingestion was four orders of magnitude higher than through inhalation, with a carcinogenic risk of 5.47 × 10−6 for DEHP exposure in household dust. Higher ∑PAEs concentrations were associated with higher temperature, double glazing, wall paint usage, television and computer use, and indoor plant growth. This multicenter on-site investigation confirmed PAE pollution characteristics and uncovered the inacceptable risk of daily DEHP exposure in household dust under real living conditions. Effective mitigation measures based on household-related information, residential characteristics, decoration materials, and lifestyle should be taken to build a healthy household environment.

Modulating responses of indicator genes in cellular homeostasis, immune defense and apoptotic process in the Macrophthalmus japonicus exposed to di(2-ethylhexyl) phthalate as a plastic additive

Di(2-ethylhexyl) phthalate (DEHP), have been increasingly used as plasticizers to manufacture soft and flexible materials and ubiquitously found in water and sediments in the aquatic ecosystem. The aim of the present study was to evaluate the effect of DEHP exposure on cellular homeostasis (HSF1 and seven HSPs), immune responses (ILF), and apoptotic responses (p53, BAX, Bcl-2). DEHP exposure upregulated the expression of HSF1 and ILF. Moreover, it altered the expression levels of HSPs (upregulation of HSP70, HSP90, HSP40, HSP83, and HSP67B2 and downregulation of HSP60 and HSP21) in conjunction with HSF1 and ILF in the gills and hepatopancreas of M. japonicus exposed to DEHP. At the protein level, DEHP exposure changed apoptotic signals in both tissues of M. japonicus. These findings indicate that chronic exposures to several DEHP concentrations could disturb cellular balance, damage the inflammatory and immune systems, and induce apoptotic cell death, thereby affecting the survival of M. japonicus.

Di (2-ethylhexyl) phthalate effects on the growth, development, and reproduction of Moina macrocopa (Crustacea: Cladocera)

Di (2-ethylhexyl) phthalate (DEHP) is used as a plasticizer in plastics. The effects of DEHP on terrestrial vertebrates have been extensively reported but the effects of DEHP contamination on aquatic ecosystems have not been thoroughly studied. Since water bodies are one of the main mediums through which DEHP is released worldwide, the impacts of DEHP contamination should be manifested in water fleas. Therefore, maternal Moina macrocopa were exposed to 1, 10, 100, and 1000 μg/L concentrations of DEHP. Changes in growth and reproduction were evaluated. The findings demonstrated that DEHP exposure did not have a negative impact on growth or the ability to reproduce. An analysis of the ovary yolk body (YB) demonstrated that the average size and number of yolk bodies (YBs) produced by M. macrocopa exposed to 1000 μg/L DEHP were not significantly different to the average size and number of YBs produced in blank control and solvent control conditions. These outcomes support the cellular pathology data gathered by other researchers. Nevertheless, when M. macrocopa was exposed to 1000 μg/L DEHP for five days, a significant increase in YB numbers was observed with changes in YB morphology. The critical cellular pathology of YB showed morphological abnormalities, including rod-shaped YBs, and YB density was higher than in the blank and solvent controls. Even though these results suggest that antioxidative stress can be induced by DEHP exposure, growth, and reproduction were not significantly different among exposed water fleas compared to fleas in the blank and solvent controls. The result was attributed to the antioxidant response of the water flea. In conclusion, the present study enhances our understanding of previous findings from risk assessments of DEHP contamination in aquatic ecosystems.

Biotoxicity responses of zebrafish in environmentally relevant concentration of di (2-ethylhexyl) phthalate

As an emerging environmental contaminant, di (2-ethylhexyl) phthalate (DEHP) is widely present in the aquatic environment, however, the effects and underlying mechanisms of DEHP on the aquatic organisms are poorly understood. This study systematically investigated the ecotoxicity induced by chronic exposure to environmental relevant concentrations of DEHP (0.03 mg/L, 0.1 mg/L, and 0.3 mg/L) on zebrafish brain. Results indicated that DEHP exposure significantly increased the levels of ROS and disturbance of the antioxidant enzymes activities in the brain, which may further enhance lipid peroxidation and DNA damage. Furthermore, acetylcholinesterase activity was first stimulated and inhibited by exposure to DEHP, and the antioxidant and apoptosis related genes were mainly upregulated. Risk assessment indicated that the ecotoxicity of DEHP on the zebrafish showed an “enhancement-reduction” trend as the exposure time was prolonged. Overall, these results provided new insights and useful information to ecological risk assessment and environmental management of DEHP pollution.

Short-term exposure to di(2-ethylhexyl)phthalate may disrupt hepatic lipid metabolism through modulating the oxidative stress in male adolescent rats.

Di(2-ethylhexyl)phthalate (DEHP) is commonly used to increase the flexibility of plastics. In our previous study, DEHP may increase hepatic lipid accumulation through modulating of acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) expression. Nevertheless, it is hard to understand the association between DEHP and DGAT1 in the liver because only one dosage of DEHP was used. Thus, this study performed to investigate the role of DGAT1 on hepatic lipid metabolism after various dosages of DEHP exposure. Four-week-old male Sprague-Dawley rats (n = 5/group) were administered corn oil (vehicle) or DEHP (0.75, 7.5, 15, or 150 mg/kg/day) once daily for seven days. DEHP 150 mg/kg/day treated group increased body weight gain and relative liver weight compared to the control (P = 0.044 and P = 0.049, respectively). In histological observation, elevation of hepatic lipid accumulation was observed in all DEHP-treated groups, except DEHP 150 mg/kg/day, compared to that in the control (all P < 0.001). Portal inflammatory infiltration and acidophilic bodies were observed in the liver at DEHP 7.5 mg/kg/day and above treated groups. In addition, malondiadehyde levels, a marker of lipid peroxidation, in the liver were increased in DEHP 7.5, 15 and 150 mg/kg/day compared to the control (P = 0.017, P = 0.001, and P = 0.002, respectively). The expression of Dgat1 in the liver was significantly increased in DEHP 7.5, 15 and 150 mg/kg/day compared to the control group (P = 0.019, P = 0.002, and P < 0.001, respectively); however, there were no significant changes in the protein levels. Therefore, excessive oxidative stress caused by DEHP may induce liver damage such as inflammation rather than hepatic lipid accumulation by regulating DGAT1 transcription.

Exposure to di-2-ethylhexyl phthalate and breast neoplasm incidence: A cohort study

BackgroundPhthalates are ubiquitous environmental endocrine disruptors. As the predominant phthalate, di-2-ethylhexyl phthalate (DEHP) has been considered possibly carcinogenic to humans but large-scale longitudinal evidence is needed to further clarify its carcinogenicity. ObjectivesTo examine the association between DEHP exposure and incidence of breast malignant neoplasm, carcinoma in situ and benign neoplasm. MethodsA total of 273,295 women from UK Biobank cohort were followed up for a median of 13.5 years. Disease information was collected from National Health Service Cancer Registry and National Death Index. Baseline and yearly-average level of DEHP exposure were estimated for each individual by linking chemical monitoring record of European Environment Agency with home address of the participants by Kriging interpolation model. Cox proportional hazard model was employed to estimate the association between DEHP exposure and breast neoplasms. ResultsThe median (IQR) of baseline and yearly-average DEHP concentration were 8000.25 (interquartile range: 6657.85–11,948.83) and 8000.25 (interquartile range: 1819.93–11,359.55) μg/L. The highest quartile of baseline DEHP was associated with 1.11 fold risk of carcinoma in situ (95 % CI, 1.00, 1.23, p < 0.001) and 1.27 fold risk of benign neoplasm (95 % CI, 1.05, 1.54, p < 0.001). As for yearly-average exposure, each quartile of DEHP was positively associated with higher risk of malignant neoplasm (HR, 1.05; 95 % CI, 1.03, 1.07, p < 0.001), carcinoma in situ (HR, 1.08; 95 % CI, 1.04, 1.11, p < 0.001) and benign neoplasm (HR, 1.13; 95 % CI, 1.07, 1.20, p < 0.001). Stratification analysis showed no significant modification effects on the DEHP-neoplasm relationship by menopausal status or ethnicity but a suggestive higher risk in younger women and those who underwent oral contraceptive pill therapy. In sensitivity analysis, the associations remained when excluding the cases diagnosed within 2 years post baseline. ConclusionsReal-world level of DEHP exposure was associated with higher risk of breast neoplasms. Because of the health risks associated with DEHP, its release to the environment should be managed.

TFEB ameliorates DEHP-induced neurotoxicity by activating GAL3/TRIM16 axis dependent lysophagy and alleviating lysosomal dysfunction.

Di-(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer with known neurotoxic effects. However, the specific mechanism underlying this neurotoxicity remains unclear. This study aimed to investigate the role of lysosomal function and lysophagy in DEHP-induced neurotoxicity, with a particular focus on the regulatory role of Transcription factor EB (TFEB). To achieve this, we utilized in vitro models of DEHP-exposed SH-SY5Y cells and HT22 cells. Our findings revealed that DEHP exposure led to lysosomal damage and dysfunction. Moreover, we observed impaired autophagic degradation, characterized by elevated levels of LC3II and p62. DEHP treatment downregulated the expression of TFEB, GAL3, and TRIM16, while upregulating the expression of PARP. This led to the inhibition of GAL3/TRIM16 axis dependent lysophagy and ultimately excessive apoptosis in neuronal cells. Importantly, TFEB overexpression alleviated lysosomal dysfunction, activated lysophagy, and mitigated DEHP-induced apoptosis. Overall, our results suggest that DEHP induces not only lysosomal dysfunction, but also inhibits lysophagy through the suppression of GAL3/TRIM16 axis. Consequently, impaired clearance of damaged lysosomes occurs, culminating in neuronal apoptosis. Taken together, our findings highlight the critical role of TFEB in regulating lysophagy and lysosomal function. Furthermore, TFEB may serve as a potential therapeutic target for mitigating DEHP-induced neuronal toxicity.

Disruption of gonocyte development following neonatal exposure to di (2-ethylhexyl) phthalate

Pre- and/or post-natal administrations of di(2-ethylhexyl) phthalate (DEHP) in experimental animals cause alterations in the spermatogenesis. However, the mechanism by which DEHP affects fertility is unknown and could be through alterations in the survival and differentiation of the gonocytes. The aim of the present study was to evaluate the effect of a single administration of DEHP in newborn mice on gonocytic proliferation, differentiation and survival and its long-term effects on seminiferous epithelium and sperm quality. BALB/c mice distributed into Control and DEHP groups were used. Each animal in the DEHP group was given a single dose of 500 mg/Kg at birth. The animals were analyzed at 1, 2, 4, 6, 8, 10 and 70 days postpartum (dpp). Testicular tissues were processed for morphological analysis to determine the different types of gonocytes, differentiation index, seminiferous epithelial alterations, and immunoreactivity to Stra8, Pcna and Vimentin proteins. Long-term evaluation of the seminiferous epithelium and sperm quality were carried out at 70 dpp. The DEHP animal group presented gonocytic degeneration with delayed differentiation, causing a reduction in the population of spermatogonia (Stra8 +) in the cellular proliferation (Pcna+) and disorganization of Vimentin filaments. These events had long-term repercussions on the quality of the seminiferous epithelium and semen. Our study demonstrates that at birth, there is a period that the testes are extremely sensitive to DEHP exposure, which leads to gonocytic degeneration and delay in their differentiation. This situation can have long-term repercussions or permanent effects on the quality of the seminiferous epithelium and sperm parameters.

Mechanisms of imbalanced testicular homeostasis in infancy due to aberrant histone acetylation in undifferentiated spermatogonia under different concentrations of Di(2-ethylhexyl) phthalate (DEHP) exposure

Di (2-ethylhexyl) phthalate (DEHP), identified as an endocrine-disrupting chemical, is associated with reproductive toxicity. This association is particularly noteworthy in newborns with incompletely developed metabolic functions, as exposure to DEHP can induce enduring damage to the reproductive system, potentially influencing adult reproductive health. In this study, we continuously administered 40 μg/kg and 80 μg/kg DEHP to postnatal day 5 (PD5) mice for ten days to simulate low and high doses of DEHP exposure during infancy. Utilizing single-cell RNA sequencing (scRNA-seq), our analysis revealed that varying concentrations of DEHP exposure during infancy induced distinct DNA damage response characteristics in testicular Undifferentiated spermatogonia (Undiff SPG). Specifically, DNA damage triggered mitochondrial dysfunction, leading to acetyl-CoA content alterations. Subsequently, this disruption caused aberrations in histone acetylation patterns, ultimately resulting in apoptosis of Undiff SPG in the 40 μg/kg DEHP group and autophagy in the 80 μg/kg DEHP group. Furthermore, we found that DEHP exposure impacts the development and functionality of Sertoli and Leydig cells through the focal adhesion and PPAR signaling pathways, respectively. We also revealed that Leydig cells regulate the metabolic environment of Undiff SPG via Ptn-Sdc4 and Mdk-Sdc4 after DEHP exposure. Finally, our study provided pioneering evidence that disruptions in testicular homeostasis induced by DEHP exposure during infancy endure into adulthood. In summary, this study elucidates the molecular mechanisms through which DEHP exposure during infancy influences the development of testicular cell populations.

Prenatal DEHP exposure induces lifelong testicular toxicity by continuously interfering with steroidogenic gene expression.

Epidemiologic studies suggested the association between prenatal di-(2-ethylhexyl) phthalate (DEHP) exposure and disorders of sex development (DSD), adult male disorders, and reproductive aging. Inhibiting testosterone synthesis by interfering with steroidogenic gene expression induces testicular toxicity, however, whether prenatal DEHP exposure induces testicular toxicity through this mechanism remains uncertain. C57BL/6JGpt male mice underwent different doses (0, 100, 500, 1,000 mg/kg) of prenatal DEHP exposure during gestational day 10 to delivery day, the testicular toxicity (genital development, testosterone, semen quality, and morphology of testis tissue) in the neonatal, post-puberal and middle-aged stages was observed, and the steroidogenic gene (Lhcgr, Star, Cyp11a1, Cyp17a1, Hsd17b3, and Hsd3b2) expression was analyzed by quantitative polymerase chain reaction (qPCR) and Western blot (WB). The interference of steroidogenic gene expression in TM3 cells after mono-(2-ethylhexyl) phthalate (MEHP) exposure was also explored for verification. Prenatal DEHP exposure induced immediate testicular injury in the neonatal stage [reduced anogenital distance (AGD) and intratesticular testosterone], DSD in the post-puberal stage (poor genital development), and reproductive aging in the middle-aged stage (obesity, reduced testosterone and semen quality, and atrophic seminiferous tubules), especially in the high dose. Prenatal DEHP exposure continuously interfered with steroidogenic gene expression (Hsd3b2, Hsd17b3) in RNA and protein levels. MEHP inhibited testosterone synthesis of TM3 cells by interfering with steroidogenic gene expression (Hsd3b2, Hsd17b3) in RNA and protein levels. Prenatal DEHP exposure induces lifelong testicular toxicity by continuously interfering with steroidogenic gene expression, thus indicating the association between prenatal exposure and DSD, adult male disorders, and reproductive aging.

Endocrine-disrupting chemicals and hormonal profiles in PCOS women: A comparative study between urban and rural environment

Polycystic Ovary Syndrome (PCOS), a multifaceted endocrine disorder, affects a significant proportion of women globally, with its etiology rooted in both genetic and environmental factors. This study delves into the environmental aspect, particularly focusing on the role of endocrine-disrupting chemicals (EDCs) in the context of urbanization and industrialization. This research examines the impact of endocrine-disrupting chemicals (EDCs) — Bisphenol A (BPA), Mono-ethyl Hexyl Phthalate (MEHP), and Di-ethyl Hexyl Phthalate (DEHP) — on 40 women with Polycystic Ovary Syndrome (PCOS) across urban and rural Gujarat. Employing High-Performance Liquid Chromatography (HPLC) and chemiluminescence, we analyzed their blood samples for EDCs levels and hormonal parameters. Urban individuals displayed significantly higher BPA and DEHP concentrations, highlighting the environmental exposure differences. Notably, urban exposure to MEHP and DEHP correlated with a marked decrease in estradiol levels, while rural DEHP exposure was associated with an increase in estradiol but a decrease in prolactin and DHEAS levels. These findings illuminate the variable effects of EDC exposure on hormonal profiles in PCOS, influenced by geographical and environmental contexts. The study underscores the critical need for tailored environmental health policies to mitigate the diverse impacts of EDCs, advocating for a nuanced approach to PCOS management that considers environmental exposures. Our insights contribute to the understanding of PCOS’s hormonal dynamics, emphasizing the significance of addressing EDC exposure in different settings.

Phthalates Induce Neurotoxicity by Disrupting the Mfn2-PERK Axis-Mediated Endoplasmic Reticulum-Mitochondria Interaction.

Di-(2-ethylhexyl) phthalate (DEHP), as the most common phthalate, has been extensively used as a plasticizer to improve the plasticity of agricultural products, which pose severe harm to human health. Mitochondrial dynamics and endoplasmic reticulum (ER) homeostasis are indispensable for maintaining mitochondria-associated ER membrane (MAM) integrity. In this study, we aimed to explore the effect of DEHP on the nervous system and its association with the ER-mitochondria interaction. Here, we showed that DEHP caused morphological changes, motor deficits, cognitive impairments, and blood-brain barrier disruption in the brain. DEHP triggered ER stress, which is mainly mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) signaling. Moreover, DEHP-induced mitofusin-2 (Mfn2) downregulation results in imbalance of the mitochondrial dynamics. Interestingly, DEHP exposure impaired MAMs by inhibiting the Mfn2-PERK interaction. Above all, this study elucidates the disruption of the Mfn2-PERK axis-mediated ER-mitochondria interaction as a phthalate-induced neurotoxicity that could be potentially developed as a novel therapy for neurological diseases.

Prenatal exposure to Di(2-ethylhexyl) phthalate and high-fat diet synergistically disrupts gonadal function in male mice†.

Prenatal exposure to Di (2-ethylhexyl) phthalate (DEHP) impairs the reproductive system and causes fertility defects in male offspring. Additionally, high-fat (HF) diet is a risk factor for reproductive disorders in males. In this study, we tested the hypothesis that prenatal exposure to a physiologically relevant dose of DEHP in conjunction with HF diet synergistically impacts reproductive function and fertility in male offspring. Female mice were fed a control or HF diet 7days prior to mating and until their litters were weaned on postnatal day 21. Pregnant dams were exposed to DEHP or vehicle from gestational day 10.5 until birth. The male offspring's gross phenotype, sperm quality, serum hormonal levels, testicular histopathology, and testicular gene expression pattern were analyzed. Male mice born to dams exposed to DEHP + HF had smaller testes, epididymides, and shorter anogenital distance compared with those exposed to HF or DEHP alone. DEHP + HF mice had lower sperm concentration and motility compared with DEHP mice. Moreover, DEHP + HF mice had more apoptotic germ cells, fewer Leydig cells, and lower serum testosterone levels than DEHP mice. Furthermore, testicular mRNA expression of Dnmt1 and Dnmt3a was two to eight-fold higher than in DEHP mice by qPCR, suggesting that maternal HF diet and prenatal DEHP exposure additively impact gonadal function by altering the degree of DNA methylation in the testis. These results suggest that the combined exposure to DEHP and high-fat synergistically impairs reproductive function in male offspring, greater than exposure to DEHP or HF dietalone.

Exposure to di-2-ethylhexyl phthalate (DEHP) increases the risk of cancer

Cancer is a major socioeconomic burden that seriously affects the life and spirit of patients. However, little is known about the role of environmental toxicant exposure in diseases, especially ubiquitous di-(2-ethylhexyl) phthalate (DEHP) which is one of the most widely used plasticizers. Hence, the objective of this study was to assess the potential association between cancer and DEHP. The data were collected using the 2011–2018 National Health and Nutrition Examination Survey (NHANES) data (n = 6147), and multiple logistic regression was conducted to evaluate the association. The concentrations of DEHP were calculated by each metabolite and split into quartiles for analysis. After adjusting for confounding factors, DEHP was significantly associated with an increased risk of cancer prevalence, and the metabolites of DEHP showed similar results (OR > 1.0, p < 0.05). Simultaneously, the association remained when the analyses were stratified by age and sex, and the risk of cancer appeared to be higher in male patients. In addition, further analysis suggested that DEHP exposure obviously increased the risk of female reproductive system cancer, male reproductive system cancer, and other cancers (OR > 1.0, p < 0.05) but not skin and soft tissue cancer. DEHP exposure is associated with the risk of cancer, especially female reproductive system cancer, male reproductive system cancer and other cancers.

Sex-Specific Associations between Prenatal Exposure to Di(2-ethylhexyl) Phthalate, Epigenetic Age Acceleration, and Susceptibility to Early Childhood Upper Respiratory Infections.

Di(2-ethylhexyl) phthalate (DEHP) is a common plasticizer that can affect immune system development and susceptibility to infection. Aging processes (measured as epigenetic age acceleration (EAA)) may mediate the immune-related effects of prenatal exposure to DEHP. This study's objective was to examine associations between prenatal DEHP exposure, EAA at three months of age, and the number of upper respiratory infections (URIs) from 12 to 18 months of age using a sample of 69 maternal-child pairs from a Canadian pregnancy cohort. Blood DNA methylation data were generated using the Infinium HumanMethylation450 BeadChip; EAA was estimated using Horvath's pan-tissue clock. Robust regressions examined overall and sex-specific associations. Higher prenatal DEHP exposure (B = 6.52, 95% CI = 1.22, 11.81) and increased EAA (B = 2.98, 95% CI = 1.64, 4.32) independently predicted more URIs. In sex-specific analyses, some similar effects were noted for boys, and EAA mediated the association between prenatal DEHP exposure and URIs. In girls, higher prenatal DEHP exposure was associated with decreased EAA, and no mediation was noted. Higher prenatal DEHP exposure may be associated with increased susceptibility to early childhood URIs, particularly in boys, and aging biomarkers such as EAA may be a biological mechanism. Larger cohort studies examining the potential developmental immunotoxicity of phthalates are needed.

Role of sleep in asthenospermia induced by di (2-ethyl-hexyl) phthalate.

Di (2-ethyl-hexyl) phthalate (DEHP) mainly enters the human body through the digestive tract, respiratory tract, and skin. At the same time, it has reproductive and developmental toxicity, neurotoxicity, and so on, which can cause the decrease of sperm motility. Asthenospermia is also known as low sperm motility, and the semen quality of men in some areas of China is declining year by year. Interestingly, previous studies have shown that sleep disorders can also lead to asthenospermia. However, the relationship between sleep, DEHP, and asthenospermia is still unclear. Analysis of the National Health and Nutrition Examination Survey (NHANES) population database showed that DEHP was associated with sleep disorders, and subsequent experiments in mice and Drosophila indicated that DEHP exposure had certain effects on sleep and asthenospermia. Furthermore, we analyzed the Comparative Toxicogenomics Database (CTD) to find out the common signaling pathway among the three: hypoxia-inducible factor 1(HIF-1). Then Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) was used to screen out the proteins that DEHP affected the HIF-1 pathway: glyceraldehyde-3-phosphate dehydrogenase (GAPDH), serine/threonine-protein kinase (AKT1), epidermal growth factor receptor (EGFR), and finally Western blot analysis was used to detect the expression levels of the three proteins. Compared with the control group, DEHP decreased the protein expression levels of GAPDH and AKT1 in the HIF-1 pathway, and caused sleep disorders and decreased sperm motility. This study provides preliminary evidence for exploring the mechanism among DEHP, sleep disorders, and asthenospermia.

Regulation of BTB (POZ) Structural Domain 6b by MicroRNA-222b in Zebrafish Embryos after Exposure to Di(2-ethylhexyl)phthalate at Low Concentrations.

Di-(2-ethylhexyl) phthalate (DEHP) is a sort of endocrine disruptor that induces abnormal physiological and biochemical activities such as epigenetic alterations, apoptosis, and oxidative stress. MicroRNAs (miRNAs) are a class of short noncoding RNAs that may regulate the expression of many protein-coding genes when organisms are exposed to environmental chemicals. miR-222b is a differentially expressed miRNA after DEHP exposure. miRNA-mRNA prediction suggested that BTB (POZ) structural domain 6b (BTBD6B) might be a target mRNA of miR-222b, and DEHP exposure altered its expression. However, the correlation between miR-222b and BTBD6B has not been experimentally confirmed. The aim of this study was to investigate the regulation of BTBD6B by miR-222b in zebrafish embryos under the effect of low concentration of DEHP. Dual fluorescent protein assays and dual luciferase reporter gene assays confirmed the interaction between miR-222b and the 3'-untranslated region (3'-UTR) of BTBD6B. Ectopic expression assays showed that miR-222b could negatively regulate BTBD6B in ZF4 cells. However, the relative expression of miR-222b and BTBD6B was significantly higher at both transcriptional and post-transcriptional levels in zebrafish embryos exposed to low concentrations of DEHP. The results of this study improved our understanding of the molecular mechanism of DEHP exposure toxicity. It identified that the aberrant expression of miR-222b/BTBD6B may be one of the mechanisms of DEHP toxicity, which can provide a theoretical reference and scientific basis for environmental management and biological health risk assessment.

Uptake and accumulation of di(2-ethylhexyl) phthalate (DEHP) in a soil-ginseng system and toxicological mechanisms on ginseng (Panax ginseng C.A. Meyer)

Di(2-ethylhexyl) phthalate (DEHP) is regarded as a priority environmental pollutant. This study explored the adsorption and accumulation of DEHP within the ginseng-soil system and the mechanism of DEHP toxicity to ginseng (Panax ginseng C.A. Meyer). Under exposure to 22.10 mg/kg DEHP in soil, DEHP mainly accumulated in ginseng leaves (20.28 mg/kg), stems (4.84 mg/kg) and roots (2.00 mg/kg) after 42 days. The oxidative damage, metabolism, protein express of ginseng were comprehensively measured and analyzed. The results revealed that MDA presented an activation trend in ginseng stems and leaves after 42 days of DEHP exposure, while the opposite trend was observed for POD. Levels of ginsenoside metabolites Rg2, Rg3, Rg5, Rd, Rf and CK decreased in the ginseng rhizosphere exudates under DEHP stress. Further investigations revealed that DEHP disrupts ginsenoside synthesis by inducing glycosyltransferase (GS) and squalene synthase (SS) protein interactions. Molecular docking indicated that DEHP could stably bind to GS and SS by intermolecular forces. These findings provide new information on the ecotoxicological effect of DEHP on ginseng root.