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1.
Artigo em Inglês | MEDLINE | ID: mdl-36368504

RESUMO

Di (2-ethylhexyl) phthalate (DEHP) is often used as a plasticizer for plastic products, and its excessive use can cause irreversible damage to aquatic animals and humans. Evodiamine (EVO) is an alkaloid component in the fruit of Evodia rutaecarpa, which has antioxidant and detoxification functions. To investigate the toxic mechanism of DEHP on grass carp (Ctenopharyngodon idellus) hepatocyte cell line (L8824) and the therapeutic effect of evodiamine, an experimental model of L8824 cells exposed to 800 µM DEHP and/or 10 µM EVO for 24 h was established. Flow cytometry, AO/EB fluorescence staining, real-time quantitative PCR, and western blot were used to detect the degree of cell injury, oxidative stress level, MAPK signaling pathway relative genes, and the expression of apoptosis-related molecules. The results showed that DEHP exposure could significantly increase the level of reactive oxygen species (ROS), inhibit the activities of antioxidant enzymes (CAT, SOD, GSH-Px), and cause the accumulation of MDA. DEHP also activated MAPK signaling pathway-related molecules (JNK, ERK, P38 MAPK), and then up-regulated the expression of pro-apoptotic factors Bcl-2-Associated X (Bax) and caspase 3, while inhibiting the anti-apoptotic factor B-cell lymphoma-2 (Bcl-2). In addition, EVO can also promote the dissociation of nuclear factor-E2-related factor 2 (Nrf2) into the nucleus, reduce the level of ROS and the occurrence of oxidative stress in grass carp hepatocytes, down-regulate the MAPK pathway, alleviate DEHP-induced apoptosis, and restore the expression of antioxidant genes. These results indicated that evodiamine could block Nrf2/MAPK pathway to inhibit DEHP-induced apoptosis of grass carp hepatocytes.


Assuntos
Carpas , Dietilexilftalato , Animais , Humanos , Fator 2 Relacionado a NF-E2/genética , Dietilexilftalato/toxicidade , Espécies Reativas de Oxigênio , Antioxidantes/farmacologia , Hepatócitos , Apoptose , Proteínas Proto-Oncogênicas c-bcl-2
2.
Sci Total Environ ; 855: 158924, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36152845

RESUMO

Mono(2-ethylhexyl) phthalate (MEHP) is a metabolite of DEHP which is one of phthalic acid esters (PAEs) widely used in daily necessities. Moreover, MEHP has been proven to have stronger biological toxicity comparing to DEHP. In particular, several recent population-based studies have reported that intrauterine exposure to MEHP results in adverse pregnancy outcomes. To explore the mechanisms and metabolic biomarkers of MEHP exposure, we examined the metabolic status of HTR-8/Svneo cell lines exposed to different doses of MEHP (0, 1.25, 5.0, 20 µM). Global and dose-response metabolomics tools were used to identify metabolic perturbations and sensitive markers associated with MEHP. Only 22 metabolic features (accounted for <1 %) were significantly changed when exposed to 1.25 µM. However, when the exposure dose was increased to 5 or 20 µM, the number of significantly changed metabolic features exceeded 300 (approximately 10 %). In particular, amino acid metabolism, pyrimidine metabolism and glutathione metabolism were widely affected according to the enrich analysis of those significant altered metabolites, which has and have previously been reported to be closely related to fetal development. Moreover, 5'-UMP and N-acetylputrescine with the lowest effective concentrations (EC-10 = 0.1 µM and EC+10 = 0.11 µM, respectively) were identified as sensitive endogenous biomarkers of MEHP exposure.


Assuntos
Dietilexilftalato , Ácidos Ftálicos , Gravidez , Feminino , Humanos , Dietilexilftalato/toxicidade , Dietilexilftalato/metabolismo , Trofoblastos/química , Trofoblastos/metabolismo , Ácidos Ftálicos/toxicidade , Ácidos Ftálicos/metabolismo , Biomarcadores/análise
3.
Chemosphere ; 310: 136811, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36220427

RESUMO

Di (2-ethylhexyl) phthalate (DEHP) is a widely used plastics additive that growing evidence indicates as endocrine disruptor able to negatively affect various reproductive processes both in female and male animals, including humans. However, the precise molecular mechanism of such actions is not completely understood. In the present study, scRNA-seq was performed on the ovaries of offspring from mothers exposed to DEHP from 16.5 days post coitum to 3 days post-partum, when the primordial follicle (PF) stockpile is established. While the histological observations of the offspring ovaries from DEHP exposed mothers confirmed previous data about a distinct reduction of oocytes enclosed in PFs. Focusing on oocytes, scRNA-seq analyses showed that the genes that mostly changed by DEHP were enriched GO terms related to histone H3-K4 methylation. Moreover, we observed H3K4me3 level, an epigenetics modification of H3 that is crucial for chromatin transcription, decreased by 40.28% (P < 0.01) in DEHP-treated group compared with control. When the newborn ovaries were cultured in vitro, the DEHP effects were abolished by tamoxifen (an estrogen receptor antagonist) or overexpression of Smyd3 (one specific methyltransferase of H3K4me3), in particular, the percentage of oocyte enclosed in PF was increased by 15.39% in DEHP plus Smyd3 overexpression group than of DEHP group (P < 0.01), which was accompanied by the upregulation of H3K4me3. Collectively, the present results discover Smyd3-H3K4me3 as a novel target of the deleterious ER-mediated effect of DEHP on PF formation during early folliculogenesis in the mouse and highlight epigenetics changes as prominent targets of endocrine disruptors like DEHP.


Assuntos
Dietilexilftalato , Disruptores Endócrinos , Animais , Feminino , Masculino , Camundongos , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Histona-Lisina N-Metiltransferase , Histonas , Folículo Ovariano
4.
Proc Natl Acad Sci U S A ; 119(47): e2208886119, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36375056

RESUMO

Uterine leiomyoma is the most common tumor in women and causes severe morbidity in 15 to 30% of reproductive-age women. Epidemiological studies consistently indicate a correlation between leiomyoma development and exposure to endocrine-disrupting chemical phthalates, especially di-(2-ethylhexyl) phthalate (DEHP); however, the underlying mechanisms are unknown. Here, among the most commonly encountered phthalate metabolites, we found the strongest association between the urine levels of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), the principal DEHP metabolite, and the risk of uterine leiomyoma diagnosis (n = 712 patients). The treatment of primary leiomyoma and smooth muscle cells (n = 29) with various mixtures of phthalate metabolites, at concentrations equivalent to those detected in urine samples, significantly increased cell viability and decreased apoptosis. MEHHP had the strongest effects on both cell viability and apoptosis. MEHHP increased cellular tryptophan and kynurenine levels strikingly and induced the expression of the tryptophan transporters SLC7A5 and SLC7A8, as well as, tryptophan 2,3-dioxygenase (TDO2), the key enzyme catalyzing the conversion of tryptophan to kynurenine that is the endogenous ligand of aryl hydrocarbon receptor (AHR). MEHHP stimulated nuclear localization of AHR and up-regulated the expression of CYP1A1 and CYP1B1, two prototype targets of AHR. siRNA knockdown or pharmacological inhibition of SLC7A5/SLC7A8, TDO2, or AHR abolished MEHHP-mediated effects on leiomyoma cell survival. These findings indicate that MEHHP promotes leiomyoma cell survival by activating the tryptophan-kynurenine-AHR pathway. This study pinpoints MEHHP exposure as a high-risk factor for leiomyoma growth, uncovers a mechanism by which exposure to environmental phthalate impacts leiomyoma pathogenesis, and may lead to the development of novel druggable targets.


Assuntos
Dietilexilftalato , Poluentes Ambientais , Leiomioma , Ácidos Ftálicos , Humanos , Feminino , Dietilexilftalato/toxicidade , Dietilexilftalato/urina , Cinurenina , Triptofano , Sobrevivência Celular , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes , Exposição Ambiental/efeitos adversos , Leiomioma/induzido quimicamente , Leiomioma/urina
5.
Hum Exp Toxicol ; 41: 9603271221139444, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36356568

RESUMO

Di(2-ethylhexyl) phthalate (DEHP) is one of the most common organic pollutants and is added to various plastic products as a plasticizer. DEHP oxidative metabolite content in the human body is associated with DNA damage in sperm and decreased testosterone levels in blood. In this study, a DEHP-induced sperm DNA damage mouse model was replicated and improved, and the transcriptomic and proteomic characteristics of the model were observed. Male mice in the two groups were exposed to DEHP 1 g/kg/d or the same amount of normal saline for 60 days, and the sperm DNA fragmentation index (DFI) was detected by a sperm chromatin structure assay (SCSA). The mRNA and protein expression profiles of the testis were detected by RNA-seq and data-independent acquisition (DIA). The sperm DFI of the DEHP group was significantly increased. Compared with the control group, 111 differentially expressed genes (DEGs) and 2147 differentially expressed proteins (DEPs), such as Lamb2, Ahnak, Tkt, Dnah8 and Tbl2, were found in the DEHP group. These genes were mainly enriched in metabolic pathways, pathways in cancer and the PI3K-Akt signaling pathway. Our results showed that DEHP 1 g/kg/d can induce sperm DNA damage in a male mouse model after 60 days of intragastric administration. The reproductive toxicity of DEHP may be related to metabolic pathways in cancer and the PI3K-Akt signaling pathway.


Assuntos
Dietilexilftalato , Masculino , Camundongos , Humanos , Animais , Dietilexilftalato/toxicidade , Transcriptoma , Proteômica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sêmen/metabolismo , Espermatozoides/metabolismo , Testículo/metabolismo , Dano ao DNA
6.
Environ Pollut ; 315: 120487, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36273695

RESUMO

Phthalates are organic pollutants frequently detected in the environment. The effects of these substances on male reproduction have been extensively studied but their potential impact on female reproductive behaviors in particular at environmental doses still remains to be documented. In the present study, we examined the effects of chronic exposure to di (2-ethylhexyl) phthalate (DEHP) alone at 5 or 50 µg/kg/d, or in an environmental phthalate mixture on maternal behavior of lactating female mice after a first (primiparous) and a second gestation (multiparous). Exposure of DEHP alone or in a phthalate mixture reduced pup-directed behaviors, increased self-care and forced nursing behaviors and altered nest quality for both primiparous and multiparous dams. In pup-retrieval test, primiparous and multiparous dams exposed to DEHP alone or in a phthalate mixture retrieved their pups more rapidly, probably due to a higher emission of ultrasonic vocalizations by the pups. At lactational day 2 following the third and last gestational period, the neural circuitry of maternal behavior was analyzed. A lower number of oxytocin-immunoreactive neurons in the paraventricular and anterior commissural nuclei was found in dams exposed to DEHP alone or in a phthalate mixture, while no changes were observed in the number of arginine-vasopressin immunoreactive cells. In the medial preoptic area, exposure to DEHP alone or in a phthalate mixture reduced ERα-immunoreactive cell number. Dendritic spine density assessed for DEHP at 5 µg/kg/d was also reduced. Thus, exposure to DEHP alone or in a phthalate mixture altered maternal behavior probably through a neuroendocrine mode of action involving oxytocin and estrogen through ERα, key pathways necessary for neuroplasticity and behavioral processing.


Assuntos
Dietilexilftalato , Disruptores Endócrinos , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Masculino , Camundongos , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Receptor alfa de Estrogênio , Lactação , Comportamento Materno , Exposição Materna , Ocitocina , Plastificantes
7.
Toxicol Appl Pharmacol ; 456: 116262, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36198370

RESUMO

Testicular dysgenesis syndrome in male neonates manifests as cryptorchidism and hypospadias, which can be mimicked by in utero phthalate exposure. However, the underlying phthalate mediated mechanism and therapeutic effects of taxifolin remain unclear. Di-(2-ethylhexyl) phthalate (DEHP) is the most abundantly used phthalate and can induce testicular dysgenesis syndrome in male rats. To explore the mechanism of DEHP mediated effects and develop a therapeutic drug, the natural phytomedicine taxifolin was used. Pregnant Sprague-Dawley female rats were daily gavaged with 750 mg/kg/d DEHP or 10 or 20 mg/kg/d taxifolin alone or in combination from gestational day 14 to 21, and male pup's fetal Leydig cell function, testicular MDA, and antioxidants were examined. DEHP significantly reduced serum testosterone levels of male pups, down-regulated the expression of SCARB1, CYP11A1, HSD3B1, HSD17B3, and INSL3, reduced the cell size of fetal Leydig cells, decreased the levels of antioxidant and related signals (SOD2 and CAT, SIRT1, and PGC1α), induced abnormal aggregation of fetal Leydig cells, and stimulated formation of multinucleated gonocytes and MDA levels. Taxifolin alone (10 and 20 mg/kg/d) did not affect these parameters. However, taxifolin significantly rescued DEHP-induced alterations. DEHP exposure in utero can induce testicular dysgenesis syndrome by altering the oxidative balance and SIRT1/PGC1α levels, and taxifolin is an ideal phytomedicine to prevent phthalate induced testicular dysgenesis syndrome.


Assuntos
Dietilexilftalato , Doenças Testiculares , Gravidez , Humanos , Ratos , Masculino , Feminino , Animais , Dietilexilftalato/toxicidade , Animais Recém-Nascidos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Testosterona/metabolismo , Sirtuína 1/metabolismo , Ratos Sprague-Dawley , Células Intersticiais do Testículo , Testículo , Doenças Testiculares/induzido quimicamente , Doenças Testiculares/prevenção & controle , Doenças Testiculares/metabolismo , Estresse Oxidativo , Antioxidantes/farmacologia , Antioxidantes/metabolismo
8.
Chemosphere ; 309(Pt 1): 136680, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36209858

RESUMO

Di(2-ethylhexyl) phthalate (DEHP) is a large-molecular-weight phthalate added to plastics to impart versatile properties. DEHP can be found in medical equipment and devices, food containers, building materials, and children's toys. Although DEHP exposure occurs most commonly by ingesting contaminated foods in the majority of the population, its effects on the gastrointestinal tract have not been well studied. Therefore, we analyzed the effects of subchronic exposure to DEHP on the ileum and colon morphology, gene expression, and immune microenvironment. Adult C57BL/6 female mice were orally dosed with corn oil (control, n = 7) or DEHP (0.02, 0.2, or 30 mg/kg, n = 7/treatment dose) for 30-34 days. Mice were euthanized during diestrus, and colon and ileum tissues were collected for RT-qPCR and immunohistochemistry. Subchronic DEHP exposure in the ileum altered the expression of several immune-mediating factors (Muc1, Lyz1, Cldn1) and cell viability factors (Bcl2 and Aifm1). Similarly, DEHP exposure in the colon impacted the gene expression of factors involved in mediating immune responses (Muc3a, Zo2, Ocln, Il6, and Il17a); and also altered the expression of cell viability factors (Ki67, Bcl2, Cdk4, and Aifm1) as well as a specialized epithelial cell marker (Vil1). Immunohistochemical analysis of the ileum showed DEHP increased expression of VIL1, CLDN1, and TNF and decreased number of T-cells in the villi. Histological analysis of the colon showed DEHP altered morphology and reduced cell proliferation. Moreover, in the colon, DEHP increased the expression of MUC2, MUC1, VIL1, CLDN1, and TNF. DEHP also increased the number of T-cells and Type 2 immune cells in the colon. These data suggest that subchronic DEHP exposure differentially affects the ileum and colon and alters colonic morphology and the intestinal immune microenvironment. These results have important implications for understanding the effects of DEHP on the gastrointestinal system.


Assuntos
Dietilexilftalato , Camundongos , Feminino , Animais , Dietilexilftalato/toxicidade , Antígeno Ki-67 , Óleo de Milho , Interleucina-6 , Camundongos Endogâmicos C57BL , Íleo , Colo , Plásticos , Proteínas Proto-Oncogênicas c-bcl-2
9.
Reprod Toxicol ; 114: 22-31, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36206922

RESUMO

Di-2-ethylhexyl phthalate (DEHP) has been proven to boost miR-155-5p level in trophoblasts, but how DEHP-induced miR-155-5p regulates trophoblastic functions is unclear. For in vivo experiments, DEHP was administered to pregnant Sprague-Dawley (SD) rats at various dosages. After birth, the development of rat fetuses was evaluated. The morphology of the placentae was evaluated using HE staining. miR-155-5p level in placentae was measured utilizing RT-qPCR. Placental cAMP/PKA pathway activation and lipid metabolism levels were assessed using WB, RT-qPCR, and ELISA. For in vitro experiments, DEHP, miR-155-5p inhibitor, or cAMP/PKA inhibitor were applied to treat HTR-8/Svneo cells. Cell viability and functions were investigated utilizing WB, RT-qPCR, CCK-8, transwell assay, plate colony formation assay, and flow cytometry. Besides, the cAMP/PKA pathway activation and lipid metabolism levels in HTR-8/Svneo cells were detected via ELISA, WB, and RT-qPCR. DEHP resulted in fetal malformations and abnormal placental histopathology. DEHP also promoted placental miR-155-5p expression, the cAMP/PKA inactivation, and lipid metabolism in placentae. miR-155-5p knockdown abrogated DEHP-induced proliferative, migrative, and invasive inhibition in HTR-8/Svneo cells. Moreover, miR-155-5p downregulation abolished DEHP-induced inactivation of the cAMP/PKA pathway and enhanced lipid metabolism. Additionally, DEHP-induced miR-155-5p facilitated lipid metabolism by inhibiting the cAMP/PKA signaling pathway in HTR-8/Svneo cells. The current study reveals that miR-155-5p plays an indispensable role in DEHP-induced trophoblastic toxicity by promoting lipid metabolism via inhibiting the cAMP/PKA signaling pathway, indicating miR-155-5p might be a promising therapeutic target for DEHP exposure during pregnancy.


Assuntos
Dietilexilftalato , MicroRNAs , Pré-Eclâmpsia , Humanos , Feminino , Gravidez , Ratos , Animais , Trofoblastos/metabolismo , Placenta/metabolismo , Metabolismo dos Lipídeos , Dietilexilftalato/toxicidade , MicroRNAs/genética , Ratos Sprague-Dawley , Transdução de Sinais , Movimento Celular , Pré-Eclâmpsia/metabolismo , Proliferação de Células
10.
Chemosphere ; 308(Pt 1): 136275, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36058374

RESUMO

As one of the most used phthalates, Di (2-ethylhexyl) phthalate (DEHP) is a widespread environmental contaminant. Extremely persistent plastic can enter the food chain of animals through the aquatic environment, affect metabolic pathways and cause damage to the digestive system. But the molecular mechanism of its toxic effects on the duodenum in birds has not been elucidated. To investigate the toxicity of phthalates in the duodenum, quails were gavaged with 250, 500, and 750 mg/kg doses of DEHP for 45 days, and water and oil control groups were retained. This study revealed that subchronic exposure to DEHP could lead to duodenal barrier defect in quail. The damage to duodenum was reflected in a reduction in V/C and tight junction proteins. Moreover, DEHP also led to a breakdown of antimicrobial defenses through the flora derangement, which acted as a biological barrier. The massive presence of Lipopolysaccharide (LPS) led to the activation of TLR4 receptors. In addition, DEHP activated oxidative stress, which synergized the inflammatory response induced by the TLR4-NFκB pathway, and further promoted duodenum damage. This study provides a base for the further effect of phthalates on the microbiota-barrier-immune interaction.


Assuntos
Dietilexilftalato , Microbiota , Animais , Dietilexilftalato/toxicidade , Duodeno , Lipopolissacarídeos , Ácidos Ftálicos , Plásticos , Codorniz , Proteínas de Junções Íntimas , Receptor 4 Toll-Like , Água
11.
Aquat Toxicol ; 252: 106312, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36174385

RESUMO

Pollution of water bodies with plasticizers is a serious environmental problem worldwide. In this study, we investigated the effects of plasticizers bis-(2-ethylhexyl) phthalate (DEHP) and bis-(2-ethylhexyl) adipate (DEHA) in Japanese medaka (Oryzias latipes). DEHP significantly increased the expression of all the genes tested: thyroid stimulating hormone beta subunit (tshß-like), tshß, deiodinase 1 (dio1), deiodinase 2 (dio2), and thyroid hormone receptor alpha (trα) and beta (trß). However, DEHA only significantly increased tshß at 7.4 µg/L but significantly decreased dio2 expression at 25.8, 111.1, and 412.6 4 µg/L, while other genes were not significantly affected. Both chemicals reduced eye size and total body length, but did not affect embryo development, hatching time and rate, and swimming performance. DEHA alone affected swim bladder inflation and not DEHP. This is the first report that not only DEHP but also DEHA disrupt thyroid hormone activity in fish. DEHP contamination (13.2 µg/L) was detected in tap water from Kobe, Japan; thus, tap water itself may disrupt thyroid hormone activity in Japanese medaka. Importantly, the effective concentration of DEHP for thyroid hormone-related gene expression and growth was close to or lower than DEHP concentrations reported in surface water elsewhere, indicating that DEHP contamination is a serious aquatic pollution.


Assuntos
Dietilexilftalato , Oryzias , Poluentes Químicos da Água , Animais , Plastificantes/toxicidade , Dietilexilftalato/toxicidade , Iodeto Peroxidase , Poluentes Químicos da Água/toxicidade , Adipatos , Hormônios Tireóideos , Tireotropina , Água , Receptores dos Hormônios Tireóideos
12.
Environ Sci Process Impacts ; 24(10): 1844-1854, 2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36107023

RESUMO

The study of phthalate migration in footwear is important from an environmental viewpoint and the consumer health perspective as it remains in direct contact with the user for a long time. In this research article, the migration of phthalate, specifically di-(2-ethylhexyl) phthalate (DEHP), from the poly(vinyl chloride) (PVC) shoe sole to the attached leather insole has been studied for six months under different environmental conditions. After one month, the DEHP concentration in the PVC sole decreased by 45-58%, and that in the leather insole increased from 0.35 mg g-1 to 38-58 mg g-1. After six months, about 90% of the DEHP has been lost from the PVC sole, and that in the leather insole reached close to its initial value (value before the experiment). The migration rate depends on the environmental conditions and the presence of phthalate soluble solvents in the sole-adhesive-insole system of the footwear. The influence of DEHP migration on the physicochemical characteristics of the PVC sole and leather insole has been studied by Fourier transform infrared spectroscopy-attenuated total reflectance (FTIR-ATR), thermo-gravimetric analysis (TGA), and differential scanning calorimetry (DSC). The migration and emission pathways of DEHP, the influence of environmental conditions, and the possibility of human exposure to phthalate through footwear are discussed.


Assuntos
Dietilexilftalato , Cloreto de Vinil , Humanos , Dietilexilftalato/toxicidade , Dietilexilftalato/análise , Plastificantes/análise , Plastificantes/química , Plastificantes/metabolismo , Cloreto de Polivinila/química , Cloreto de Vinil/análise , Solventes
13.
Life Sci ; 309: 121005, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36174712

RESUMO

AIMS: Di (2-ethylhexyl) phthalate (DEHP), as an environmental endocrine-disrupting chemical (EDC), can induce male reproductive injury. N6-methyladenosine (m6A) plays a vital role in environmental exposure-induced diseases by regulating gene expression. Therefore, we aim to investigate the role of m6A in DEHP-induced reproductive injury. MAIN METHODS: We established an in vivo model of mice exposed to DEHP to explore the effect of DEHP on reproductive injury and m6A. To further explore the molecular mechanism of DEHP toxicity, we built a model of GC-2 cells exposed to mono-(2-ethylhexyl) phthalate (MEHP) in vitro and further silenced Mettl3 in GC-2cells. Besides, we also conducted MeRIP-qPCR and RIP assays to identify the target genes for m6A modification. KEY FINDINGS: DEHP induced testicular injury and senescence. And telomeres shortening, reduced levels of telomere repeat-binding factor 1 (TRF1), TRF2, protection of telomeres 1 (POT1), and telomerase reverse transcriptase (TERT) can be observed in DEHP-treated testes. MEHP also induced GC-2 cellular senescence and telomere dysfunction. Besides, increased m6A mediated by METTL3 stabilized homeobox containing 1 (Hmbox1) in an m6A-dependent manner in MEHP-exposed GC-2 cells. Mettl3 knockdown led to lower m6A modification and reduced Hmbox1 stability, resulting in further shortening of telomere length. SIGNIFICANCE: our work uncovered that DEHP led to male reproductive injury by telomere dysfunction and m6A modified Hmbox1 contributed to maintaining telomere homeostasis in this process, suggesting that accurate regulation of m6A modification level by drugs has potential value in the treatment of DEHP-induced male reproductive injury.


Assuntos
Dietilexilftalato , Telomerase , Animais , Masculino , Camundongos , Dietilexilftalato/toxicidade , Telomerase/metabolismo , Telômero/genética , Adenosina , Proteínas de Homeodomínio/metabolismo
14.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(8): 1237-1243, 2022 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-36073224

RESUMO

OBJECTIVE: To investigate the effects of diethylhexyl phthalate (DEHP) exposure on anxiety-like behaviors and learning and memory ability in mice and explore the underlying mechanism. METHODS: Forty male ICR mice were randomized equally into control group (0 mg/kg) and 10, 50 and 100 mg/kg DEHP exposure groups, in which the mice were exposed to DEHP at the indicated doses by gavage for 4 weeks. After the treatments, the mice were assessed for behavioral changes using open filed test, elevated plus-maze and Morris water maze test. Brain tissues were collected from the mice for determination of malondialdehyde (MDA) content, pathologies and expressions of ZO-1 and occludin in the hippocampus. RESULTS: Compared with the control group, the mice with DEHP exposure for 4 weeks exhibited no significant body weight change (P>0.05) but presented with obvious behavioral changes, manifested by reduced movement distance (P < 0.05) and time spent in the center of the open field (P < 0.05), reduced movement distance (P < 0.05) and time spent in the open arm of the elevated maze (P < 0.05), significantly increased latency of searching for the platform (P < 0.05), and decreased frequency of crossing the platform (P < 0.05). HE staining showed obvious vertebral cell death in the hippocampal CA1 to CA3 regions of the mice with DEHP exposure. The exposed mice showed significantly increased MDA content and decreased expressions of ZO-1 and occludin at both the mRNA and protein levels in the hippocampus (P < 0.05 or 0.01). Multivariate linear regression analysis suggested a close correlation between anxiety-like behaviors and learning and memory abilities in DEHP-exposed mice. CONCLUSION: DEHP exposure may cause damages of the blood-brain barrier and the pyramidal cells in the hippocampus of mice, thereby inducing anxiety-like behaviors and learning and memory impairment.


Assuntos
Dietilexilftalato , Animais , Ansiedade/induzido quimicamente , Barreira Hematoencefálica/metabolismo , Dietilexilftalato/metabolismo , Dietilexilftalato/toxicidade , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos ICR , Ocludina/metabolismo , Ocludina/farmacologia
15.
Ecotoxicol Environ Saf ; 241: 113837, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36068761

RESUMO

Evidence of the influence of prenatal phthalate exposure on childhood longitudinal obesity markers is limited. Nested on the Ma'anshan birth cohort study, 990 mother-daughter pairs were included. Seven phthalate metabolites were determined in urine collected in each trimester. Each child underwent a physical examination from birth to 6 years of age twelve times. Latent class growth models were used to identify three trajectories of girls' body mass index (BMI). Logistic regression, quantile g-computation and Bayesian kernel machine regression models analyzed the relationships of prenatal exposure to individual and mixed phthalates with girls' body mass index (BMI) trajectory. Compared to the "lowest trajectory" class, prenatal average concentrations of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP, ORcrude = 2.095, 95 % CI = 1.014-4.328) and di(2-ethylhexyl) phthalate (DEHP, ORcrude = 2.336, 95 % CI = 1.022-5.338) during pregnancy were associated with an increased probability of being in the "highest trajectory" class. The average concentration of DEHP (ORcrude = 1.879, 95 % CI = 1.002-3.522) was associated with an increased probability of being in the "moderate trajectory" class. Stratified analyses by trimester of pregnancy mainly showed that third-trimester exposure to monoethyl phthalate (MEP, ORadjusted = 1.584, 95 % CI = 1.094-2.292), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP, ORadjusted = 2.885, 95 % CI = 1.367-6.088), MEHHP (ORadjusted = 2.425, 95 % CI = 1.335-4.407), DEHP (ORadjusted = 2.632, 95 % CI = 1.334-5.193) and high molecular weight phthalate (ORadjusted = 2.437, 95 % CI = 1.239-4.792) was associated with an increased probability of being in the "highest trajectory" class. However, the mixture of phthalates was not significantly related to the girl's BMI trajectory. In conclusion, in utero exposure to phthalates, including MEP and DEHP metabolites (MEHHP and MEOHP), was significantly associated with early childhood high BMI trajectories in girls. The third trimester of pregnancy seemed to be the window of vulnerability to phthalate exposure for girls' high BMI trajectory at periods of prenatal development. No evidence supported a significant relationship between combined exposure to phthalate metabolites and girls' high BMI trajectory.


Assuntos
Dietilexilftalato , Poluentes Ambientais , Ácidos Ftálicos , Teorema de Bayes , Índice de Massa Corporal , Criança , Pré-Escolar , Estudos de Coortes , Dietilexilftalato/toxicidade , Exposição Ambiental/análise , Poluentes Ambientais/análise , Feminino , Humanos , Lactente , Recém-Nascido , Ácidos Ftálicos/urina , Gravidez , Vitaminas
16.
J Hazard Mater ; 439: 129689, 2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-36104915

RESUMO

Male infertility is an attracting growing concern owing to decline in sperm quality of men worldwide. Phthalates, in particular to di (2-ethylhexyl) phthalate (DEHP) or its main metabolite mono-2-ethylhexyl phthalate (MEHP), affect male reproductive development and function, which mainly accounts for reduction in male fertility. Lycopene (LYC) is a natural antioxidant agent that has been recognized as a possible therapeutic option for treating male infertility. Testosterone (T)/androgen receptor (AR) signaling pathway is involved in maintaining spermatogenesis and male fertility. How DEHP causes spermatogenesis disturbance and whether LYC could prevent DEHP-induced male reproductive toxicity have remained unclear. Using in vivo and vitro approaches, we demonstrated that DEHP caused T biosynthesis reduction in Leydig cell and secretory function disorder in Sertoli cell, and thereby resulted in spermatogenic impairment. Results also showed that MEHP caused mitochondrial damage and oxidative damage, which imposes a serious threat to the progress of spermatogenesis. However, LYC supplement reversed these changes. Mechanistically, DEHP contributed to male infertility via perturbing T/AR signaling pathway during spermatogenesis. Overall, our study reveals critical role for T/AR signal transduction in male fertility and provides promising insights into the protective role of LYC in phthalate-induced male reproductive disorders.


Assuntos
Dietilexilftalato , Infertilidade Masculina , Androgênios , Dietilexilftalato/análogos & derivados , Dietilexilftalato/toxicidade , Humanos , Infertilidade Masculina/induzido quimicamente , Licopeno , Masculino , Ácidos Ftálicos , Receptores Androgênicos , Sêmen , Espermatogênese , Testosterona
17.
Environ Res ; 215(Pt 1): 114187, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36037918

RESUMO

Environmental exposures to mixtures of toxic chemicals have potential interaction effects that may lead to hazard index values exceeding one. However, current regulation levels, such as tolerable daily intake (TDI), are mostly based on experimental studies conducted with a single chemical compound. In this study, we assessed the relationships between melamine and di-(2-ethylhexyl) phthalate (DEHP) exposure and their coexposure with the early renal injury markers N-acetyl -D-glucosaminidase (NAG), albumin/creatinine ratio (ACR), and microalbuminuria in 1236 pregnant women. Various generalized linear models with interaction terms and Bayesian kernel machine regression models were used for the (co-)exposure response associations. We derived the benchmark dose (BMD) and the corresponding one-sided 95% confidence bound BMDL based on the estimated (covariate-adjusted) average daily intake of melamine and DEHP metabolites measured in spot urine of the women collected during the third trimester. Given a benchmark response of 0.1, the BMDL level of melamine (DEHP) exposure on NAG (ACR, microalbuminuria) was 2.67 (11.20, 4.45) µg/kg_bw/day, and it decreased to as low as 1.46 (3.83, 2.73) µg/kg_bw/day when considering coexposure to DEHP (melamine) up to the 90th percentile. Both the exposure threshold levels of melamine and DEHP for early renal injuries in pregnant women were several-fold to one order lower than the current recommended TDIs by the WHO and the US FDA and EPA and were even lower considering coexposure. Because of concurrent exposures in real-world environments, more stringent regulation levels are recommended in susceptible populations, such as pregnant women, due to potential synergistic mixture effects.


Assuntos
Dietilexilftalato , Poluentes Ambientais , Ácidos Ftálicos , Albuminas , Albuminúria/induzido quimicamente , Teorema de Bayes , Benchmarking , Biomarcadores/urina , Creatinina , Dietilexilftalato/toxicidade , Exposição Ambiental/análise , Poluentes Ambientais/urina , Feminino , Hexosaminidases , Humanos , Rim/metabolismo , Ácidos Ftálicos/urina , Gravidez , Gestantes , Triazinas
18.
Environ Toxicol ; 37(12): 2924-2936, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36005737

RESUMO

Di(2-ethylhexyl) phthalate (DEHP) could induce thyroid injury but the mechanism was unclear. This study combined in vivo and in vitro experiments to clarify the mechanism. In vivo, the offspring of Sprague Dawley rats were gavaged with different doses of DEHP (5, 50, and 250 mg/[kg⋅d]) from in utero to 12 weeks-old. Transcriptome sequencing was used to detect the mRNA expression profile of the offspring's thyroids. Differentially expressed genes were identified, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. In vitro, Nthy-ori 3-1 cells were exposed to DEHP's metabolite mono (2-ethylhexyl) phthalate (MEHP) to verify the pathway we found by KEGG analysis. The results indicated that DEHP could disorder the thyroid hormones. Compared with the offspring in control group, the mRNA levels of 656 genes were upregulated in the offspring exposed to 50 mg/(kg⋅d) DEHP. The upregulated genes were enriched in the pathway of "protein processing in the endoplasmic reticulum (ER)." It indicated that the ER stress might play significant role in the thyroid toxicity induced by DEHP. In vitro, the mitochondrial membrane potential (ΔΨm) level of cells was decreased while the reactive oxygen species level was increased after MEHP exposure. MEHP increased the intracellular Ca2+ level and induced ER stress. After ER stress was inhibited by the 4-phenylbutyric acid, the thyroid toxicity caused by MEHP was alleviated. Taken together, our results indicated that DEHP could induce thyroid toxicity by activating ER stress.


Assuntos
Dietilexilftalato , Animais , Ratos , Dietilexilftalato/toxicidade , Dietilexilftalato/metabolismo , Estresse do Retículo Endoplasmático , Glândula Tireoide/metabolismo , Ratos Sprague-Dawley , RNA Mensageiro
19.
Reprod Toxicol ; 113: 18-29, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35952901

RESUMO

Di-(2-ethylhexyl) phthalate (DEHP) is one of the most used plasticizers which have contaminated environment widely, and its extensive use causes female reproductive injury. Melatonin has a substantial protective effect against female reproductive toxicity. This study was undertaken to investigate the influence of melatonin on DEHP-induced damage of human granulosa cells (GCs) in vitro and explore the potential mechanisms. Here, we found that melatonin treatment alleviated DEHP-induced human GCs apoptosis and improved mitochondrial function via inhibiting dynamin-related protein 1 (Drp1) mediated mitochondrial fission. Melatonin inhibited the expression, activation and oligomerization of Drp1, which decreased translocation of Drp1 to mitochondria in DEHP-exposed human GCs. Inhibition of mitochondrial fission reduced intracellular reactive oxygen species (ROS) production, sustained mitochondrial membrane potential and decreased cytochrome c release. Further research showed that AMPK-PGC-1α signal pathway was involved in the inhibition of melatonin on Drp1 expression and activation. Melatonin treatment promoted AMPK activation suppressed by DEHP, and activated AMPK recovered the balance of Drp1 phosphorylation at Ser616 and Ser637 sites and enhanced PGC-1α expression. Moreover, PGC-1α could prevent mitochondrial fission by decreasing Drp1 expression directly via binding to its promoter. In contrast, blocking of AMPK or PGC-1α with specific inhibitor negated the protective effects of melatonin on mitochondrial homeostasis and GCs apoptosis. In summary, our results indicated the protective effects of melatonin on improving mitochondrial function and attenuating cells injury in DEHP-exposed human GCs. Melatonin treatment may be a promising therapeutic approach against DEHP-induced reproductive disorder.


Assuntos
Dietilexilftalato , Melatonina , Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose , Citocromos c/metabolismo , Citocromos c/farmacologia , Dietilexilftalato/toxicidade , Dinaminas/metabolismo , Dinaminas/farmacologia , Feminino , Células da Granulosa/metabolismo , Humanos , Melatonina/farmacologia , Dinâmica Mitocondrial , Ácidos Ftálicos , Plastificantes/toxicidade , Espécies Reativas de Oxigênio/metabolismo
20.
Food Chem Toxicol ; 168: 113324, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35917956

RESUMO

Di(2-ethylhexyl) phthalate (DEHP) is an omnipresent environmental pollutant. It has been determined that DEHP is involved in multiple health disorders. Lycopene (Lyc) is a natural carotenoid pigment, with anti-inflammatory and antioxidant properties. However, it is not clear whether Lyc can protect the spleen from DEHP-induced oxidative damage. A total of 140 mice were randomly divided into seven groups (n = 20) and continuously gavaged with corn oil, distilled water, DEHP (500 or 1000 mg/kg BW/day) and/or Lyc (5 mg/kg BW/day) for 28 days. Histopathological and ultrastructural results showed a DEHP-induced inflammatory response and mitochondrial injuries. Moreover, DEHP exposure induced redox imbalance, which resulted in the up-regulation of ROS activity and MDA content, and the down-regulation of T-AOC, T-SOD and CAT in the DEHP groups. Simultaneously, our results also demonstrated that DEHP-induced kelch-like ECH-associated protein 1 (Keap1) expression was downregulated, and the expression levels of P62, nuclear factor erythroid 2-related factor (NRF2) and their downstream target genes were up-regulated. However, the supplementary Lyc reverted these changes to normal levels. Together, Lyc prevented DEHP-induced splenic injuries by regulating the P62-Keap1-NRF2 signaling pathway. Hence, the protective effects of Lyc might be a therapeutic strategy to ameliorate DEHP-induced splenic damage.


Assuntos
Dietilexilftalato , Poluentes Ambientais , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Óleo de Milho/farmacologia , Dietilexilftalato/toxicidade , Poluentes Ambientais/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Licopeno/farmacologia , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ácidos Ftálicos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Baço/metabolismo , Superóxido Dismutase/metabolismo , Água
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