Di(2-ethylhexyl) Phthalate Treatment Research Articles

The combination of polystyrene microplastics and di (2-ethylhexyl) phthalate promotes the conjugative transfer of antibiotic resistance genes between bacteria.

Plastic pollution has become a common phenomenon. The process of plastic degradation is accompanied by the release of microplastics and plasticizers. However, the coexistence of microplastics and plasticizers on the transfer of antibiotic resistance genes (ARGs) has not been reported until now. Here, polystyrene (PS) microplastics and plasticizer di (2-ethylhexyl) phthalate (DEHP) were used for combined treatment experiment and their effects and mechanisms on the transfer of ARGs between bacteria were explored. By increasing cell membrane permeability and the expression of correlated genes, the combined treatment group showed promoting effects on the transfer of ARGs than that of control, with the highest promoting effects observed at 1 mg/L PS and 0.1 mg/L DEHP, which was 3.0 times higher in ARGs transfer rate than that of control. It was found that PS and DEHP treatment alone also led to a higher conjugative transfer frequency, and the frequency of the combined treatment was lower than that of the corresponding single treatment group. This indicated that the effects of DEHP and microplastics on ARGs transfer might be antagonistic. Transcriptome analysis indicated that the transfer of ARGs affects bacterial ion binding, oxidative stress, and energy metabolism processes, while the expression of genes related to cell membrane permeability, DNA repair, bacterial drug resistance, and quorum sensing also increase. This study may provide new insights for explaining the combined effects of various pollutants in the environment on the spread of ARGs.

Se-Methylselenocysteine Ameliorates DEHP-Induced Ferroptosis in Testicular Sertoli Cells via the Nrf2/GPX4 Axis.

Di (2-ethylhexyl) phthalate (DEHP) is an important plasticizer in industrial production, and its toxic effects on testes are widely recognized. Se-methylselenocysteine (SMC) is a major selenium compound found in selenium-rich plants, which possesses unique biological properties such as antioxidants. However, the effect of SMC on DEHP-induced testicular injury and the specific mechanism remains unknown. In this study, 50 mice were randomly divided into 5 groups and were given corn oil (Control), DEHP, low-dose SMC (L-SMC), moderate-dose SMC (M-SMC), or high-dose SMC (H-SMC). The sperm quality of the mice in each group was determined, and HE staining and transmission electron microscopy (TEM) were applied to observe testicular morphology, and testicular tissues were collected for the subsequent molecular biological analyses. The TM4 cell line was applied in vitro for mechanism validation. Our results showed that DEHP could lead to decreased sperm quality and blood-testis barrier damage in mice, which could be alleviated by SMC. Mitochondrial damage accompanied by accumulation of total iron content, MDA, and 4-HNE, as well as downregulation of antioxidants SOD, GSH, and GSH-Px were observed after DEHP treatment, which exhibited a typical ferroptosis feature. In vitro experiments confirmed that SMC promoted upregulation of GPX4 in TM4 cells and was able to alleviate DEHP metabolite MEHP-induced ferroptosis and promote the expression of cell junction key proteins ZO-1, Occludin, and Connexin 43, which could be inhibited by the GPX4 inhibitor RSL3 or the Nrf2 inhibitor ML385. Overall, the above results suggest that SMC ameliorates the DEHP-induced ferroptosis in testicular Sertoli cells, protects the blood-testis barrier, and prevents sperm aberrations via the Nrf2/GPX4 axis.

Quercetin antagonizes apoptosis, autophagy and immune dysfunction induced by di(2-ethylhexyl) phthalate via ROS/ASK1/JNK pathway

Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer that can damage various organizations and physiques through oxidative stress. Quercetin (Que) is a rich polyphenol flavonoid with good anti-inflammatory and antioxidant effects. However, the protection mechanism of Que against DEHP exposure-induced IPEC-J2 cell injury and the implication of autophagy, apoptosis and immunity are still unclear. In this experiment, we looked into the toxicity regime of DEHP exposure on IPEC-J2 cells and the antagonistic function of Que on DEHP. In the experiment, 135 μM DEHP and/or 80 μM Que were used to treat the IPEC-J2 cells for 24h. Experiments indicated that DEHP exposure can cause increased reactive oxygen species (ROS) levels leading to oxidative stress, decreased CAT, T-AOC and GSH-Px activities, increased MDA and H2O2 accumulation, activated the ASK1/JNK signalling pathway, and further increases in the levels of apoptosis markers Bax, Caspase3, Caspase9, and Cyt-c, while reduced the Bcl-2 expression. DEHP also increased the expression of genes linked to autophagy (ATG5, Beclin1, LC3), while decreasing the expression of P62. Additionally, DEHP exposure led to elevated levels of IL1-β, IL-6, MCP-1, and TNF expression. When exposed to Que alone, there were no significant changes in cellular oxidative stress level, ASK1/JNK signalling pathway expression level, apoptosis, autophagy and cellular immune function. The combination of DEHP and Que treatment remarkably decreased the proportion of autophagy and apoptosis, and recovered cellular immunity. In summary, Que can attenuate DEHP-induced apoptosis and autophagy in IPEC-J2 cells by regulating the ROS/ASK1/JNK signalling pathway and improving the immune dysfunction of IPEC-J2 cells.

An insight into carcinogenic activity and molecular mechanisms of Bis(2-ethylhexyl) phthalate.

Di(ethylhexyl) phthalate (DEHP) is a ubiquitous environmental contaminant to which humans are exposed via multiple routes. Human health risk assessments for this substance have recently been updated, focusing on reproductive toxicity, including DEHP, in the list of chemicals classified as carcinogenic, mutagenic, or toxic to reproduction (CMR). Moreover, DEHP has also been defined as probably and possibly carcinogenic to humans based on its carcinogenicity in rodents. However, the mechanism of action of DEHP and its relevance in humans remain unclear. Rodent data suggests that DEHP induces cancer through non-genotoxic mechanisms related to multiple molecular signals, including PPARα activation, perturbation of fatty acid metabolism, induction of cell proliferation, decreased apoptosis, production of reactive oxygen species, and oxidative stress. According to the DEHP toxicological dataset, several in vitro cell transformation assays have been performed using different protocols and cellular models to produce different results. This study aimed to evaluate the carcinogenic potential of DEHP by using the A31-1-1 BALB/c-3T3 cell line in a standard cell transformation assay. Additionally, transcriptomic analysis was performed to explore the molecular responses and identify the affected toxicological pathways. Although DEHP treatment did not induce transformation in BALB/c-3T3 cells, the transcriptomic results revealed significant modulation of several pathways associated with DEHP metabolism, tissue-specific functions related to systemic metabolism, and basal cellular signaling with pleiotropic outcomes. Among these signaling pathways, modulation of cell-regulating signaling pathways, such as Notch, Wnt, and TGF-β, can be highlighted. More specific modulation of such genes and pathways with double functions in metabolism and neurophysiology underlies the well-known crosstalk that may be crucial for the mechanism of action of DEHP. Our findings offer evidence to support the notion that these models are effective in minimizing the use of animal testing for toxicity assessment.

Morin hydrate ameliorates Di-2-ethylhexyl phthalate (DEHP) induced hepatotoxicity in a mouse model via TNF-α and NF-κβ signaling.

Di-(2-ethylhexyl) phthalic acid (DEHP) pollutes the environment, and posing a significant risk to human and animal health. Consequently, a successful preventative strategy against DEHP-induced liver toxicity needs to be investigated. Morin hydrate (MH), a flavanol compound, possesses toxic preventive attributes against various environmental pollutants. However, the effects of MH have not been investigated against DEHP-induced liver toxicity. Female Swiss albino mice were divided into four groups: control, DEHP (orally administered with 500mg/kg, DEHP plus MH 10mg/kg, and DEHP plus MH 100mg/kg for 14days. The results showed that the MH treatment ameliorated the DEHP-induced liver dysfunctions by decreasing the alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin, liver histoarchitecture, fibrosis, and markers of oxidative stress. Furthermore, DEHP increased apoptosis, increased active caspase 3 and decreased B cell lymphoma-2 (Bcl-2) expression. However, the MH treatment showed a differential effect on these proteins; a lower dose increased, and a higher dose decreased the expression. Thus, a lower dose of MH could be involved in the disposal of damaged hepatocytes. Expression of Estrogen receptors alpha (ERα) also showed a similar trend with active caspase 3. Furthermore, the expression of Tumor necrosis factor alpha (TNF-α) and Nuclear factor-κβ (NF-κβ) were up-regulated by DEHP treatment, and MH treatment down-regulated the expression of these two inflammatory markers. Since this down-regulation of TNF-α and NF-κβ coincides with improved liver functions against DEHP-induced toxicity, it can be concluded that MH-mediated liver function involves the singling of TNF-α and NF-κβ.

Risk assessment of di-(2-ethylhexyl) phthalate plus a high-fat diet in the rat kidney

Di-(2-ethylhexyl) phthalate (DEHP) is used in food packaging and medical products, resulting in unintentional human ingestion. Concurrently, a high fat (HF)-oriented diet is very popular for many people worldwide. Here we investigated the regulatory role of renin-angiotensin system in kidney dysfunction. The HF diet-fed rats were fed a HF diet plus different doses of 10, 100 and 300 mg/kg bw DEHP for 35 days by gavage. Serum lipid contents and protein activities of renin-angiotensin system (RAS) components were measured using biochemical methods and ELISA; key metabolic genes and proteins of the kidney were determined by RT-PCR and western blotting techniques. Kidney morphology was examined through hematoxylin-eosin (HE) staining. Kidney weight to body weight ratio and mRNA expression of kidney damage markers were significantly increased following DEHP plus HF administration, which corresponded histologically with glomerular basement membrane thickening and glomerular swelling. Furthermore, DEHP treatment plus a HF diet induced dyslipidemia, accompanied by increased levels of renin-angiotensin system components, such as ACE protein, MAS-1 protein, serum renin and aldosterone. In addition, mRNA expression levels of pro-inflammatory cytokines were significantly upregulated in the kidneys. Pearson correlation analysis revealed that higher kidney ACE expression and ACE/ACE-2 ratio were positively associated with TG, TC and LDL-C levels. These data suggest that combined exposure to DEHP exposure plus a HF diet feeding may induce renal damage through overactivation of RAS.

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.

Chronic di(2-ethylhexyl) phthalate exposure at environmental-relevant doses induces osteoporosis by disturbing the differentiation of bone marrow mesenchymal stem cells

Di(2-ethylhexyl) phthalate (DEHP) is a widely used plastic additive with persistent characteristics in the environment. This study was designed to investigate the detrimental effects of chronic DEHP exposure at environmental-relevant doses on bone metabolism and the underlying mechanisms. It was found that exposure to 25 μg/kg bw and 50 μg/kg bw DEHP for 29 weeks led to a reduction of whole-body bone mineral density (BMD), femur microstructure damage, decreased femur new bone formation, and increased femur bone marrow adipogenesis in C57BL/6 female mice, which was not observed in mice exposed to 5000 μg/kg bw DEHP. Further in vitro study showed that DEHP treatment robustly promoted adipogenic differentiation and suppressed osteogenic differentiation of the bone marrow mesenchymal stem cells (BMSCs). Mechanistically, DEHP exposure resulted in elevated expressions of DYRK1B, CDK5, PPARγ, and p-PPARγSer273 in both bone tissue and BMSCs. Interestingly, co-IP analysis showed potential interactions among DYRK1B, PPARγ, and CDK5. Lastly, antagonists of DYRK1B and CDK5 effectively alleviated the BMSCs differentiation disturbance induced by DEHP. These results suggest that DEHP may disturb the BMSCs differentiation by upregulating the PPARγ signaling which may be associated with the activation of DYRK1B and CDK5.

DEHP and DINP accelerate aging effects in male and female of Drosophila melanogaster depend on AKT/FOXO pathway

Phthalates are commonly used as plasticizers. Numerous studies have focused on endocrine, reproductive, and developmental toxicity of phthalates exposure to male organisms. In recent years, some studies looking into the aging effects of phthalates exposure in D. melanogaster showed discrepant results. In this study, we compared the different concentrations of Di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DINP) for acute and chronic treatment for different gender D. melanogaster and explored the potential mechanism of DEHP and DINP exposure. The results showed that acute exposure to DEHP or DINP at a high dose significantly decreased the lifespan of female and male D. melanogaster under HFD stress. Chronic exposure significantly decreased the lifespan of flies in all exposure groups except for the low-dose DINP exposure female group. Among them, in the normal feeding group, we found that female flies seemed to be more resistant to DEHP or DINP exposure. Meanwhile, the locomotion ability and fertility of flies exhibited a dose-dependent decline. Furthermore, phthalates did not significantly reduce the lifespan or health status of akt and foxo mutant flies in the mutant fly assays, and real-time quantitative-PCR (q-PCR) data revealed akt and foxo significant change with 10 μM DEHP or DINP treatment. This suggests that akt and foxo played a role in the process by which DEHP and DINP caused age-related declines in D. melanogaster.

Di-(2-ethylhexyl) phthalate aggravates psoriasis-like skin lesions: In vitro and in vivo evaluation

Di-(2-ethylhexyl) phthalate (DEHP), which is a widely used phthalate (PAE), has recently received public attention owing to it causing health problems. The aim of this study was to elucidate the aggravating effects of DEHP on psoriasis and skin toxicity. Human keratinocyte (HaCaT) cells were treated with gradient concentrations of DEHP, and mice with imiquimod (IMQ)-induced psoriasiform dermatitis were hypodermically injected with 40 μg/kg/day of DEHP for seven consecutive days. The skin condition was assessed based on the psoriasis area and severity index score, which indicated the deterioration of IMQ-induced psoriasis-like skin lesions after DEHP exposure. To further analyze the effect of DEHP on psoriasis, the proliferation, inflammation, and tight junction (TJ) damage were examined, which correlated with the development and severity of psoriasis. The results showed that DEHP promoted proliferation both in vivo and in vitro, which manifested as epidermal thickening; an increase in cell viability; upregulation of Ki67, CDK2, cyclinD1, and proliferating cell nuclear antigen; and downregulation of p21. An excessive inflammatory response is an important factor that exacerbates psoriasis, and our results showed that DEHP can trigger the release of inflammatory cytokines as well as the infiltration of T cells. TJ disorders were found in mice and cells after DEHP treatment. Additionally, p38 mitogen-activated protein kinase (MAPK) was strongly activated during this process, which may have contributed to skin toxicity caused by DEHP. In conclusion, DEHP treatment promotes proliferation, inflammation, TJ disruption, and p38 MAPK activation in HaCaT cells and psoriasis-like skin lesions.

Ecotoxicological Evaluation of Earthworm (Eisenia fetida) Induced by Enrofloxacin and Di-(2-Ethylhexyl) Phthalate

We found that the typical fluoroquinolone antibiotic enrofloxacin (ENR) and plasticizer di-(2-ethylhexyl) phthalate (DEHP) are often detected simultaneously and at high frequencies in the environment, but their combined exposure effects on soil animals are poorly understood. Here, oxidative stress, DNA damage and changes in digestibility of the earthworm were investigated to reflect the toxicological effects of single and combined exposure of DEHP and ENR on earthworms (Eisenia fetida). We found that the DEHP treatment group and the combined pollution treatment group showed significantly increased reactive oxygen species content of earthworms at 14 d and 28 d. ENR exposure alone had little effect on the antioxidant enzyme system, while DEHP and combined treatment showed a trend of inhibition and then activation. Addition of both pollutants caused a rise in the lipid peroxidation levels of earthworms. Malonaldehyde (MDA) was mainly scavenged by glutathione sulfur transferase (GST). ENR and DEHP caused more DNA damage to earthworm tissue than their combined pollution under the regulation of GST. Both single and combined pollution inhibited the digestive enzyme activity of earthworms, but the combined pollution had a stronger inhibitory effect. Cellulase, MDA and GST were the three most sensitive indicators on PCA. The toxicity was ENR + DEHP > DEHP > ENR according to the IBR index, and the combined toxicity showed a synergistic effect. The results showed that the combined pollution of phthalate esters and antibiotics in the actual environment was a significant ecological risk that deserves special attention.

Single-cell transcriptomic dissection of the toxic impact of di(2-ethylhexyl) phthalate on immature testicular development at the neonatal stage.

Di(2-ethylhexyl) phthalate (DEHP) early exposure leads to immature testicular injury, and we aimed to utilize single-cell RNA (scRNA) sequencing to comprehensively assess the toxic effect of DEHP on testicular development. Therefore, we gavaged pregnant C57BL/6 mice with 750mg/kg body weight DEHP from gestational day 13.5 to delivery and performed scRNA sequencing of neonatal testes at postnatal day 5.5. The results revealed the gene expression dynamics in testicular cells. DEHP disrupted the developmental trajectory of germ cells and the balance between the self-renewal and differentiation of spermatogonial stem cells. Additionally, DEHP caused an abnormal developmental trajectory, cytoskeletal damage and cell cycle arrest in Sertoli cells; disrupted the metabolism of testosterone in Leydig cells; and disturbed the developmental trajectory in peritubular myoid cells. Elevated oxidative stress and excessive apoptosis mediated by p53 were observed in almost all testicular cells. The intercellular interactions among four cell types were altered, and biological processes related to glial cell line-derived neurotrophic factor (GDNF), transforming growth factor-β (TGF-β), NOTCH, platelet-derived growth factor (PDGF) and WNT signaling pathways were enriched after DEHP treatment. These findings systematically describe the damaging effects of DEHP on the immature testes and provide substantial novel insights into the reproductive toxicity of DEHP.

Di-(2-ethylhexyl) phthalate impairs angiogenesis and hematopoiesis via suppressing VEGF signaling in zebrafish

Di-(2-ethylhexyl) phthalate (DEHP) is among the most widely used plasticizers in plastic production, which has been detected in various environments. However, DEHP safety remains poorly known. Using zebrafish models, the effects of DEHP on the angiogenesis and hematopoiesis, and the underlying mechanism, were studied. Transgenic zebrafish embryos with specific fluorescence of vascular endothelial cells, myeloid cells, or hematopoietic stem cells were exposed to 0, 100, 150, 200, or 250 nM of DEHP for 22, 46 or 70 h, followed by fluorescence observation, endogenous alkaline phosphatase activity measurement, erythrocyte staining, and gene expression analysis by quantitative PCR and whole mount in situ hybridization. High DEHP concentrations decreased the sprouting rate, average diameter, and length, and the expansion area of the vessels lowered the EAP activity and suppressed the vascular endothelial growth factor (vegf) and hematopoietic marker genes, including c-myb, hbae1, hbbe1, and lyz expressions. DEHP treatment also decreased the number of hematopoietic stem cells, erythrocytes, and myeloid cells at 24 and 72 hpf. These DEHP-induced angiogenetic and hematopoietic defects might be alleviated by vegf overexpression. Our results reveal a plausible mechanistic link between DEHP exposure-induced embryonic angiogenetic defect and hematopoietic impairment.

Exposure to Di-(2-Ethylhexyl) phthalate drives ovarian dysfunction by inducing granulosa cell pyroptosis via the SLC39A5/NF-κB/NLRP3 axis

Endocrine-disrupting chemicals (EDCs) have been reported to affect populations by disrupting the human endocrine system. Di-(2-ethylhexyl) phthalate (DEHP) is an EDC that is present in various consumer products. Exposure to DEHP could contribute to reproductive system dysfunction, with subsequent adverse female reproductive outcomes. Granulosa cells (GCs) play essential roles in ovarian function and fertility. To further reveal the underlying mechanism by which DEHP impairs female fertility and affects the normal function of GCs, in vivo and in vitro experiments were performed. Transcript sequencing was used to identify genes that were differentially expressed in GCs after DEHP treatment. SLC39A5 was shown to be overexpressed in the DEHP group compared to the normal control group. DEHP treatment and overexpression of SLC39A5 activated NF-κB-related factors, followed by an increase in the transcript expression level of NLRP3. NLRP3 inflammasomes play crucial roles in pyroptosis by acting as sensors. Pyroptosis is a type of inflammation-related cell death associated with various diseases, including ovarian cancer and polycystic ovary syndrome. Activation of NF-κB contributed to the upregulation of pyroptosis in GCs, while pyroptosis factors were downregulated after the inhibition of NF-κB with JSH-23. The same phenomenon was also observed in a mouse model in which DEHP-treated mice had higher expression levels of NF-κB and pyroptosis markers in GCs. Moreover, this phenomenon could be partially reversed by the NF-κB inhibitor JSH-23. DEHP treatment also disrupted the normal expression of ovarian function-related genes and inhibited the proliferation of GCs. Reproductive system impairment was observed in mice exposed to DEHP. DEHP-treated mice had a lower body weight, smaller reproductive organs, fewer healthy follicles, and diminished ovarian reserve. Thus, DEHP contributes to ovarian dysfunction by inducing pyroptosis via the SLC39A5/NF-κB/NLRP3 axis in GCs.

Reproductive and Developmental Alterations on Zebrafish (Danio rerio) Upon Long-Term Exposure of Di-ethyl phthalate (DEP), Di-isononyl phthalate (DINP) and Di (2-ethylhexyl) phthalate (DEHP)

Di (2-ethylhexyl) phthalate (DEHP), di-ethyl phthalate (DEP) and di-isononyl phthalate (DINP) are all endocrine disrupting chemicals (EDCs) for organisms. However, little research has been done on the effects of long-term EDC exposure. The present study found that the zebrafish barely grew during the 7months of DINP exposure. The fecundity rate (%) of female spawning was lower in the DEHP treatment by 4months compared to other exposure groups. Zebrafish treated with 12.5-25.0ppm of DEP for 4months presented no spawning. Gonadal-somatic index (GSI) levels significantly decreased, and there were more oocytes in the atresia and peri-nucleus stage compared to the control group. In addition, the hatching rate of embryos were 71.02%, 56.92%, and 21.70% for females treated with DINP, DEHP and DEP, respectively. There were also abnormal craniofacial chondrogenesis development on 72hpf embryos upon females treated with the three EDCs. In conclusion, long term exposure of DEHP, DINP, and DEP did not only affect the reproductive capacity of female zebrafish, but the 3 plasticizers also influence craniofacial cartilage development of its offspring.

Impact of Plasticizer on the Intestinal Epithelial Integrity and Tissue-Repairing Ability within Cells in the Proximity of the Human Gut Microbiome.

Toxicological research into the impact of plasticizer on different organs has been reported in the past few decades, while their effects on shifting the gut microbiota and immune cells homeostasis in zebrafish were only studied recently. However, studies on the impact of plasticizer on human gut microbiota are scarce. In this study, we co-incubated healthy human fecal microbiota with different concentrations of Di(2-ethylhexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DINP), analyzed microbial composition by 16S rDNA sequencing, and compared the influence of their derived microbiomes on the human enterocyte (HT-29) and murine macrophage (RAW264.7) cell lines. Microbial diversity is reduced by DEHP treatment in a dose-dependent manner. DEHP treatment reduced the phyla Firmicutes/Bacteroidetes ratio, while DINP treatment promoted Proteobacteria. Expressions of tight/adherens junction genes in HT-29 and anti-inflammatory genes in RAW264.7 were down-regulated by plasticizer-co-incubated microbiota derived metabolites. Overall, it is observed that selected plasticizers at high dosages can induce compositional changes in human microbiota. Metabolites from such altered microbiota could affect the tight junction integrity of the intestinal epithelium and upset macrophage differentiation homeostasis in proximity. Chronic exposure to these plasticizers may promote risks of dysbiosis, leaky gut or the exacerbation of intestinal inflammation.

Phthalate induces mitochondrial injury in cerebellum through Sirt1-PGC-1α and PINK1/Parkin-mediated signal pathways

Di-(2-ethylhexyl) phthalate (DEHP) is an environmental toxicant that is widely used in the whole world as a plasticizer that can enhance plastic properties. A number of reserarches have demonstrated that DEHP could cause varying degrees of damage to the normal function of nerve. The research aimed to investigate the mechanism of DEHP-induced cerebellar toxicity. In present study, we set DEHP-caused cerebellar injury models of quail and implied that DEHP induced cerebellar dysplasia by abnormity of Purkinje cell and reduction of cerebellar granule cell. Furthermore, the mitochondrial damage was confirmed by the swelling, cristae reduction, membrane rupture of mitochondria or even the occurrence of autophagic vacuole. To clarified DEHP-induced mitochondrial damage in cerebellum, we examined the relevant genes of mitochondrial biogenesis, mitochondrial dynamics, oxidative damage, the pathways related to Nrf2 and PINK1/Parkin in cerebellum. Based on data, it appeared that DEHP treatment had a damaging effect on the cerebellum and led to mitophagy as well as oxidative stress. In conclusion, the research indicated that DEHP-actuated mitochondrial injury has a directly relationship with mitophagy. DEHP-actuated reduced mitochondrial biogenesis and dysregulation of mitochondrial dynamics. The increase of oxidative stress damaged mitochondria, and the redundant ROS in damaged mitochondria that gave rise to cerebellar harm.

Vitamin C mitigates hematological and biochemical alterations caused by di(2-ethylhexyl) phthalate toxicity in female albino mice, Mus musculus.

Di(2-ethylhexyl) phthalate (DEHP) is ubiquitous environmental contaminant and identified as endocrine-disrupting chemical (EDC), present in plastics as plasticizer. Due to its versatile use, human exposure level reaches to danger limit. The main focus of our study is to see the effect of vitamin C on hematological and biochemical alterations caused by Di(2-ethylhexyl) Phthalate toxicity in female albino mice, Mus musculus. It is found to cause defects of the liver, kidney, and lungs. Its anti-androgenic nature brings the main focus on its toxicity associated with reproductive and endocrine system. In this experimental study, 18 young female Swiss albino mice, Mus musculus, were used and divided into 3 groups of 6 animals each as control (corn oil vehicle), DEHP group (100 mg/kg body weight dissolved in corn oil), and DEHP + vitamin-C group (100 mg/kg body weight each, dissolved in corn oil and double distilled water, respectively) for 90 days. In this research, serum metabolites were evaluated to study the effect of DEHP on glucose, total protein, and lipid profile along with some hematological, enzymological, and oxidative stress parameters. Simultaneously, we compared the effectiveness of vitamin-C against DEHP toxicity to mitigate the serum homeostasis disturbance. In present study, we observed, in DEHP-treated animals, glucose, triglycerides, very-low-density lipoprotein (VLDL), total protein, alkaline phosphatase (ALP), acid phosphatase (ACP), and alanine aminotransferase (ALT) levels increased remarkably, whereas total cholesterol, high-density lipoproteins (HDL), aspartate aminotransferase (AST), total RBC count, total WBC count, and hemoglobin (Hb) level significantly decreased as compared to control group. In addition, we noticed there was a decrease in superoxide dismutase (SOD) and increase in levels of lipid peroxidation (MDA) and interleukin-6 (IL-6) in DEHP treatment group as compared to control group. The results indicated vitamin C had a better improving effect against DEHP toxicity on balancing metabolic abnormalities and inflammation-related comorbidities.

Polystyrene nanoparticles enhance the adverse effects of di-(2-ethylhexyl) phthalate on male reproductive system in mice

Coexposure of nanoplastics (NPs) with other pollutants adsorbed from the surroundings has received extensive attention. Currently, the combined effects of NPs and plasticizers remain unclear. Di-(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer that has raised much concern owing to its ubiquitous pollution and endocrine-disrupting potential. This study aimed to investigate the toxic effects on the male reproductive system upon coexposure to NPs and DEHP. The C57BL/6J mice were orally administrated with polystyrene nanoparticles (PSNPs), DEHP or both for 35 days to evaluate their effects on sperm quality, histology of testes and epididymides, testicular transcriptomic characteristics as well as expression of some important genes in the epididymides. The low-dose PSNPs used here did not induce significant changes in sperm quality, while DEHP alone or cotreatment with DEHP and PSNPs caused notable impairment, mainly manifesting as decreased sperm quality and aberrant structure of the testis and epididymis. Moreover, enhanced toxic effects were found in the cotreatment group when compared with the individual DEHP treatment group, as manifested by more obvious alterations in the sperm parameters as well as histological changes in the testis and epididymis. Testicular transcriptomic analysis revealed differential regulation of genes involved in immune response, cytoplasmic pattern recognition receptor signaling pathways, protein ubiquitination, oxidative stress, necrotic cell death, ATP synthesis and the cellular respiratory chain. RT-qPCR verified that the expression patterns of Cenpb, Crisp1 and Mars were changed in testes, and genes relevant to epididymal function including Aqp9 and Octn2 were downregulated in epididymides, particularly in the cotreatment group. Collectively, our results emphasize that DEHP at an environmentally relevant dose can induce male reproductive toxicity, and PSNPs may aggravate the toxic effects.

Curative Potentials of Garlic (Allium sativum) Extract against Di-(2-Ethylhexyl) Phthalate Induced Reproductive Toxicity in Female Mice

The present study was intended to find out the curative potentials of Garlic (Allium sativum) against di-(2-Ethylhexyl) phthalate (DEHP) induced toxicity in the reproductive system of female mice. Forty female mice were divided into four groups (n=10) as the (a) control group was given normal feed and drinking water, (b) aqueous garlic extract treated group (500 mg/kg), (c) DEHP group received 500 mg/kg in corn oil, and (d) DEHP + aqueous garlic extract each at a dosage of 500 mg/kg body weight. All treatments were given daily through oral gavage for 28 days. After completion of the experiment, all the animals were dissected through cervical dislocation to get reproductive organs. Collected organs were weighed and processed through the conventional histology technique of staining with eosin and hematoxylin. This study indicated that DEHP exposure caused a significant decrease (P<0.001) in body weight and weight of the complete female reproductive tract as compared to the control group, while the garlic co-administered group showed prominent improvement in body and organ weight when compared to only DEHP treatment. The adverse effect of DEHP on the histology of the ovary such as a decreased mean number of developing follicles, thin and irregular corona radiata, disruption of cumulus oophorus, and reduction in the size of the antral cavity of the tertiary follicle was observed. However, a significant recovery in the development of follicles was seen in DEHP plus garlic-treated group. DEHP plus garlic extract treatment showed protective effects on the uterus, such as a significant increase in the diameter of the uterus (P<0.001), muscularis, mean number of endometrial glands (P<0.001), and endometrial epithelial heights as compared to only DEHP exposed group. Hence, garlic extract showed significant ameliorative potential against DEHP-induced reproductive anomalies in female mice.