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1.
Sci Total Environ ; 783: 147035, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-33872906

RESUMO

Prenatal exposure to phthalates negatively affects the offspring's health. In particular, epigenetic alterations, such as DNA methylation, may connect phthalate exposure with health outcomes. Here, we evaluated the association of di-2-ethylhexyl phthalate (DEHP) exposure in utero with cord blood epigenome-wide DNA methylation in 203 mother-child pairs enrolled in the Hokkaido Study on Environment and Children's Health, using the Illumina HumanMethylation450 BeadChip. Epigenome-wide association analysis demonstrated the predominant positive associations between the levels of the primary metabolite of DEHP, mono(2-ethylhexyl) phthalate (MEHP), in maternal blood and DNA methylation levels in cord blood. The genes annotated to the CpGs positively associated with MEHP levels were enriched for pathways related to metabolism, the endocrine system, and signal transduction. Among them, methylation levels of CpGs involved in metabolism were inversely associated with the offspring's ponderal index (PI). Further, clustering and mediation analyses suggested that multiple increased methylation changes may jointly mediate the association of DEHP exposure in utero with the offspring's PI at birth. Although further studies are required to assess the impact of these changes, this study suggests that differential DNA methylation may link phthalate exposure in utero to fetal growth and further imply that DNA methylation has predictive value for the offspring's obesity.


Assuntos
Dietilexilftalato , Ácidos Ftálicos , Efeitos Tardios da Exposição Pré-Natal , Criança , Saúde da Criança , Metilação de DNA , Dietilexilftalato/toxicidade , Epigenoma , Feminino , Sangue Fetal , Desenvolvimento Fetal , Humanos , Recém-Nascido , Ácidos Ftálicos/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética
2.
Int J Mol Sci ; 22(8)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923623

RESUMO

Di(2-ethylhexyl) phthalate (DEHP) is widely used as a plasticizer in the manufacture of polyvinylchloride plastics and has been associated with concerns regarding male reproductive toxicity. In this study, we hypothesized that maternal exposure to DEHP induces transgenerational inheritance of adult-onset adverse reproductive outcomes through the male germline in the F1, F2, and F3 generations of male offspring. Pregnant rats were treated with 5 or 500 mg of DEHP/kg/day through gavage from gestation day 0 to birth. The offspring body weight, anogenital distance (AGD), anogenital index (AGI), sperm count, motility, and DNA fragmentation index (DFI) were measured for all generations. Methyl-CpG binding domain sequencing was performed to analyze sperm DNA methylation status in the F3. DEHP exposure at 500 mg/kg affected AGD, AGI, sperm count, mean DFI, and %DFI in the F1; AGD, sperm count, and mean DFI in the F2; and AGD, AGI, mean DFI, and %DFI in the F3. DEHP exposure at 5 mg/kg affected AGD, AGI, sperm count, and %DFI in the F1; sperm count in the F2; and AGD and AGI in F3. Compared with the control group, 15 and 45 differentially hypermethylated genes were identified in the groups administered 5 mg/kg and 500 mg/kg DEHP, respectively. Moreover, 130 and 6 differentially hypomethylated genes were observed in the groups administered 5 mg/kg and 500 mg/kg DEHP. Overall, these results demonstrated that prenatal exposure to DEHP caused transgenerational epigenetic effects, which may explain the observed phenotypic changes in the male reproductive system.


Assuntos
Metilação de DNA , Dietilexilftalato/toxicidade , Epigênese Genética , Plastificantes/toxicidade , Efeitos Tardios da Exposição Pré-Natal/genética , Espermatozoides/efeitos dos fármacos , Animais , Peso Corporal , Feminino , Genitália Masculina/anatomia & histologia , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley
3.
Artigo em Inglês | MEDLINE | ID: mdl-33925988

RESUMO

BACKGROUND: The general population (including children) is exposed to chemical mixtures. Plasticizers such as Bisphenol A (BPA) and Phthalates (mainly Bis(2-ethylhexyl) phthalate-DEHP) are widespread contaminants classified as endocrine disrupters which share some toxicological profiles and coexist in food and environment. METHODS: To identify hazards of DEHP and BPA mixtures, the juvenile toxicity test-where rodents are in peripubertal phase of development, resembling childhood-was selected using exposure data from biomonitoring study in children. Biological activity and potential enhanced and/or reduced toxicological effects of mixtures due to common mechanisms were studied, considering endpoints of metabolic, endocrine and reproductive systems. The degree of synergy or antagonism was evaluated by synergy score calculation, using present data and results from the single compound individually administered. RESULTS: In metabolic system, synergic interaction predominates in female and additive in male rats; in the reproductive and endocrine systems, the co-exposure of BPA and DEHP showed interactions mainly of antagonism type. CONCLUSIONS: The present approach allows to evaluate, for all the endpoints considered, the type of interaction between contaminants relevant for human health. Although the mode of action and biological activities of the mixtures are not completely addressed, it can be of paramount usefulness to support a more reliable risk assessment.


Assuntos
Dietilexilftalato , Disruptores Endócrinos , Animais , Compostos Benzidrílicos/toxicidade , Criança , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Feminino , Humanos , Masculino , Fenóis/toxicidade , Ácidos Ftálicos , Plastificantes/toxicidade , Ratos
4.
Chemosphere ; 271: 129740, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33736212

RESUMO

Di(2-ethylhexyl) phthalate (DEHP) has been well acknowledged for its endocrine disruption and associated metabolic diseases, leading to the search for safer industrial alternatives including di-isononyl phthalate (DINP). However, safety data for the latter chemical has been relatively scarce particularly regarding potential damage to the kidney at low doses. Five-week-old ICR male mice were exposed to vehicle, DEHP or DINP (0.05 and 4.8 mg/kg bw) daily via gavage for 5 weeks. We observed increased levels of reactive oxygen species and malondialdehyde, decreased levels of reduced glutathione, in the kidney at higher dose for both chemicals suggestive of oxidative damage. Elevated levels of inflammatory cytokines tumor necrosis factor-α and interleukin-6 of the kidney further suggested inflammatory status as a result of phthalate exposure in both high dose groups. Targeted lipidomics demonstrated greatest changes in the kidney induced by high dose of DEHP, although DINP also induced significant changes in phospholipids diacylglycerides that are associated with lipid accumulation in glomerular podocytes and inflammatory responses. Our data suggest that oxidative stress may be involved in both DEHP- and DINP-induced renal lipidomic disruption and continue to question the suitability of DINP as proper DEHP substitute.


Assuntos
Dietilexilftalato , Ácidos Ftálicos , Animais , Dietilexilftalato/toxicidade , Rim , Lipidômica , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estresse Oxidativo , Ácidos Ftálicos/toxicidade
5.
Environ Pollut ; 278: 116799, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33743268

RESUMO

The mediating influence of thyroid function on the association of phthalate exposure with glucose metabolism, including insulin resistance, remains unclear. We explored the mediating influence of thyroid hormone levels on the phthalate exposure-insulin resistance association. This cross-sectional study of 217 Taiwanese adults assessed insulin resistance (Homeostatic Model Assessment for Insulin Resistance, HOMA-IR scores) and the levels of 11 urinary phthalate metabolites and 5 thyroid hormones. Multiple regression models were used to analyze the associations among serum thyroid hormone levels, urinary phthalate metabolite levels, and HOMA-IR scores. The mediation analysis assessed the influence of thyroid function on the phthalate exposure-HOMA-IR association. Our data indicated urinary mono-ethylhexyl phthalate (MEHP) levels was negatively associated with free thyroxine (T4) (ß = -0.018; 95% confidence interval [CI]: -0.031, -0.005) and positively associated with HOMA-IR scores (ß = 0.051, 95% CI: 0.012, 0.090). The study also revealed urinary mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) levels was negatively associated with free T4 (ß = -0.036, 95% CI: -0.056, -0.017) and HOMA-IR (ß = 0.070, 95% CI: 0.013, 0.126). Free T4 and HOMA-IR had a negative association (ß = -0.757, 95% CI: -1.122, -0.392). In the mediation analysis, free T4 mediated 24% and 35% of the associations of urinary MEHP and MEOHP with HOMA-IR, respectively. Our findings revealed the mediating role of thyroid function in the phthalate exposure-glucose metabolism association in adults.


Assuntos
Dietilexilftalato , Ácidos Ftálicos , Estudos Transversais , Dietilexilftalato/toxicidade , Exposição Ambiental , Glucose , Ácidos Ftálicos/toxicidade , Glândula Tireoide
6.
Environ Toxicol ; 36(6): 1226-1242, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33665894

RESUMO

Di-(2-ethylhexyl) phthalate (DEHP) is one of the most commonly used plasticizers, and it is widely applied in various plastic products. DEHP is an endocrine-disrupting chemical (EDC) that has been shown to disrupt the function of reproductive system in females. Although many studies have shown that DEHP potentially causes female reproductive toxicity, including depletion of the primordial follicle and decreased sex hormone production, the specific mechanisms by which DEHP affects female reproduction remain unknown. In recent years, research focused on the intestinal flora has provided an idea to eliminate our confusion, and gut bacterial dysbiosis may contribute to female reproductive toxicity. In the present study, the feces of DEHP-exposed mice were collected and analyzed using 16S rRNA amplicon sequencing and untargeted global metabolite profiling of metabolomics. DEHP obviously causes reproductive toxicity, including the ovarian organ coefficient, estradiol level, histological features of the ovary and estrus. Furthermore, DEHP exposure alters the structure of the intestinal microbiota community and fecal metabolite profile in mice, suggesting that the reproductive toxicity may be caused by gut bacterial dysbiosis and altered metabolites, such as changes in the levels of short-chain fatty acid (SCFA). Additionally, it is well known that changes in gut microbiota and fecal metabolites cause inflammation and tissue oxidative stress, expectedly, we found oxidative stress in the ovary and systemic inflammation in DEHP exposed mice. Thus, based on our findings, DEHP exposure may cause gut bacterial dysbiosis and altered metabolite profiles, particularly SCFA profiles, leading to oxidative stress in the ovary and systemic inflammation to ultimately induce female reproductive toxicity.


Assuntos
Dietilexilftalato , Microbioma Gastrointestinal , Animais , Dietilexilftalato/toxicidade , Fezes , Feminino , Camundongos , Ácidos Ftálicos , RNA Ribossômico 16S , Reprodução
7.
Mol Med Rep ; 23(4)2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33649816

RESUMO

Di (2­ethylhexyl) phthalate (DEHP), an environmental pollutant, is widely used as a plasticizer and causes serious pollution in the ecological environment. As previously reported, exposure to DEHP may cause thyroid dysfunction of the hypothalamic­pituitary­thyroid (HPT) axis. However, the underlying role of DEHP remains to be elucidated. The present study performed intragastrical administration of DEHP (150, 300 and 600 mg/kg) once a day for 90 consecutive days. DEHP­stimulated oxidative stress increased the thyroid follicular cavity diameter and caused thyrocyte oedema. Furthermore, DEHP exposure altered mRNA and protein levels. Thus, DEHP may perturb TH homeostasis by affecting biosynthesis, biotransformation, bio­transportation, receptor levels and metabolism through disruption of the HPT axis and activation of the thyroid­stimulating hormone (TSH)/TSH receptor signaling pathway. These results identified the formerly unappreciated endocrine­disrupting activities of phthalates and the molecular mechanisms of DEHP­induced thyrotoxicity.


Assuntos
Dietilexilftalato/toxicidade , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Animais , Poluentes Ambientais/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/crescimento & desenvolvimento , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Plastificantes/toxicidade , Ratos Wistar , Receptores da Tireotropina/genética , Receptores da Tireotropina/metabolismo , Receptores do Hormônio Liberador da Tireotropina/genética , Receptores do Hormônio Liberador da Tireotropina/metabolismo , Glândula Tireoide/crescimento & desenvolvimento , Glândula Tireoide/metabolismo , Hormônios Tireóideos/sangue , Hormônios Tireóideos/metabolismo , Fator Nuclear 1 de Tireoide/genética , Fator Nuclear 1 de Tireoide/metabolismo , Tireotropina Subunidade beta/genética , Tireotropina Subunidade beta/metabolismo
8.
Sci Total Environ ; 777: 146146, 2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-33684750

RESUMO

Prenatal exposure to di(2-ethylhexyl) phthalate (DEHP) may cause adverse health outcomes. However, trimester-specific impacts of DEHP exposure on offspring growth from fetal to early childhood stage have not been thoroughly evaluated. In this study, participants who provided a full series of urine specimens at three trimesters were selected from a birth cohort conducted at Wuhan, China from 2014 to 2015. 814 mother-offspring pairs were included in the study. Urinary concentrations of DEHP metabolites were determined using liquid chromatography-tandem mass spectrometry. Z-scores for ultrasound-measured fetal growth parameters at 14.0-18.9, 22.6-27.0, and 29.0-33.9 weeks of gestation, were calculated. Weight, height, and body mass index (BMI) at 6, 12, and 24 months were standardized to z-scores using sex-specific and age-specific WHO child growth standards. Linear regressions with generalized estimating equations were used to assess the relationships of DEHP levels per trimester to fetal growth, birth size, and growth at 6, 12, and 24 months to explore the trimester-specific impacts of DEHP exposure on offspring development. Among males, the1st-trimester DEHP was negatively related to fetal growth (ß < 0, p < 0.05), but positively related to 24-month BMI. The 2nd-trimester DEHP was negatively related to birth weight and birth length, but positively related to weight gain rates from birth to 24 months old. The 3rd-trimester DEHP was positively (ß > 0, p < 0.05) associated with birth weight and BMI at 6 and 12 months. Among females, the 1st-trimester DEHP was associated with increased birth length, while the 2nd-trimester DEHP was negatively associated with BMI at 6 and 12 months. A negative association between DEHP and weight gain rates at 6 months was noted among females. This prospective cohort revealed the sex-specific and trimester-specific relationships of DEHP exposure to offspring growth from fetal to early-childhood stage.


Assuntos
Dietilexilftalato , Ácidos Ftálicos , Efeitos Tardios da Exposição Pré-Natal , Criança , Pré-Escolar , China/epidemiologia , Estudos de Coortes , Dietilexilftalato/toxicidade , Feminino , Desenvolvimento Fetal , Humanos , Masculino , Exposição Materna/efeitos adversos , Gravidez , Estudos Prospectivos
9.
Environ Int ; 151: 106440, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33640694

RESUMO

BACKGROUND: Parental preconception exposure to select phenols and phthalates was previously associated with increased risk of preterm birth in single chemical analyses. However, the joint effect of phenol and phthalate mixtures on preterm birth is unknown. METHODS: We included 384 female and 211 male (203 couples) participants seeking infertility treatment in the Environment and Reproductive Health (EARTH) Study who gave birth to 384 singleton infants between 2005 and 2018. Mean preconception urinary concentrations of bisphenol A (BPA), parabens, and eleven phthalate biomarkers, including di(2-ethylhexyl) phthalate (DEHP) metabolites, were examined. We used principal component analysis (PCA) with log-Poisson regression and Probit Bayesian Kernel Machine Regression (BKMR) with hierarchical variable selection to examine maternal and paternal phenol and phthalate mixtures in relation to preterm birth. Couple-based BKMR model was fit to assess couples' joint mixtures in relation to preterm birth. RESULTS: PCA identified the same four factors for maternal and paternal preconception mixtures. Each unit increase in PCA scores of maternal (adjusted Risk Ratio (aRR): 1.36, 95%CI: 1.00, 1.84) and paternal (aRR: 1.47, 95%CI: 0.90, 2.42) preconception DEHP-BPA factor was positively associated with preterm birth. Maternal and paternal BKMR models consistently presented the DEHP-BPA factor with the highest group Posterior Inclusion Probability (PIP). BKMR models further showed that maternal preconception BPA and mono(2-ethyl-5-hydroxyhexyl) phthalate, and paternal preconception mono(2-ethylhexyl) phthalate were positively associated with preterm birth when the remaining mixture components were held at their median concentrations. Couple-based BKMR models showed a similar relative contribution of paternal (PIP: 61%) and maternal (PIP: 77%) preconception mixtures on preterm birth. We found a positive joint effect on preterm birth across increasing quantiles of couples' total mixture concentrations. CONCLUSION: In this prospective cohort of subfertile couples, maternal BPA and DEHP, and paternal DEHP exposure before conception were positively associated with preterm birth. Both parental windows jointly contributed to the outcome. These results suggest that preterm birth may be a couple-based pregnancy outcome.


Assuntos
Dietilexilftalato , Exposição Materna/efeitos adversos , Exposição Paterna/efeitos adversos , Ácidos Ftálicos , Nascimento Prematuro , Teorema de Bayes , Compostos Benzidrílicos/toxicidade , Dietilexilftalato/toxicidade , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenol , Fenóis/toxicidade , Ácidos Ftálicos/toxicidade , Gravidez , Nascimento Prematuro/induzido quimicamente , Nascimento Prematuro/epidemiologia , Estudos Prospectivos
10.
Toxicology ; 453: 152734, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33631300

RESUMO

Estrogen receptors are involved in regulating the proliferation and invasion process of neuroblastoma. As a kind of estrogen-like environmental endocrine disruptors (EEDs), whether mono-2-ethylhexyl phthalate (MEHP) can affect the proliferation and invasion of neuroblastoma cells via ERs is unknown. The present study aimed to explore the role of ERα in MEHP-induced proliferation, migration, and invasion of SH-SY5Y cells. SH-SY5Y cells were cultured in DMEM with 10 % FBS. Wild-type SH-SY5Y cells and ERα-knockdown SH-SY5Y cells were treated with MEHP (0, 10, 50, and 250 µM) for 12 h and 24 h. The viability of SH-SY5Y cells was detected with a CCK8 kit and cell cycle was measured by flow cytometry. Cell migration was measured using a scratch assay, and cell invasion was tested using a Transwell migration assay. The expression levels of proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of matrix metalloproteinase 2 (TIMP-2), ERα, and ERß were detected with real-time qPCR and western blotting. MEHP promoted the proliferation of SH-SY5Y cells. The results also showed that MEHP significantly increased the relative migration distance of wild-type SH-SY5Y cells. Conversely, MEHP treatment did not increase the relative migration distance of ERα-knockdown SH-SY5Y cells, suggesting that MEHP promotes the migration of neuroblastoma through ERα. Similarly, MEHP significantly increased the relative number of invaded wild-type SH-SY5Y cells, while the MEHP-induced invasion effect was significantly decreased in ERα-knockdown SH-SY5Y cells. Moreover, the expression levels of PCNA, MMP-2, MMP-9, and ERα cells were upregulated by MEHP in wild-type SH-SY5Y, and the expression level of its tissue inhibitor TIMP-2 was downregulated. In contrast, the expression of PCNA, MMP-2, MMP-9, and ERα was significantly downregulated in ERα-knockdown SH-SY5Y cells, while the expression of TIMP-2 was significantly upregulated. In conclusion, MEHP can upregulate PCNA, MMP-2, and MMP-9, and downregulate TIMP-2, further promoting proliferation, migration, and invasion of neuroblastoma through ERα.


Assuntos
Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Dietilexilftalato/análogos & derivados , Receptor alfa de Estrogênio/fisiologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Dietilexilftalato/toxicidade , Relação Dose-Resposta a Droga , Receptor alfa de Estrogênio/deficiência , Receptor alfa de Estrogênio/genética , Técnicas de Silenciamento de Genes/métodos , Humanos , Invasividade Neoplásica/patologia
11.
ACS Chem Neurosci ; 12(2): 311-322, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33411500

RESUMO

Exposure to di-(2-ethylhexyl) phthalate (DEHP), a widely used kind of plasticizer, can result in neurodevelopment impairments and learning and memory disorders. We studied the effects and possible mechanisms of maternal DEHP treatment on hippocampal synaptic plasticity in offspring. Pregnant Wistar rats were randomly divided into four groups and received 0, 30, 300, 750 (mg/kg)/d DEHP by gavage from gestational day (GD) 0 to postnatal day (PN) 21. Our data showed that DEHP exposure impaired hippocampal synaptic plasticity, damaged synaptic ultrastructure, and decreased synaptic protein levels in male pups. Furthermore, DEHP decreased the density of dendritic spines, affected F-actin polymerization, and downregulated the Rac1/PAK/LIMK1/cofilin signaling pathway in male offspring. However, the alterations in the hippocampi of female offspring were not observed. These results illustrate that maternal DEHP exposure could impair hippocampal synaptic plasticity by affecting synaptic structure and dendritic spine development in male offspring, which may be attributed to altered cytoskeleton construction induced by downregulation of the Rac1/PAK/LIMK1/cofilin signaling pathway.


Assuntos
Dietilexilftalato , Efeitos Tardios da Exposição Pré-Natal , Animais , Espinhas Dendríticas , Dietilexilftalato/toxicidade , Feminino , Hipocampo , Humanos , Masculino , Exposição Materna , Plasticidade Neuronal , Ácidos Ftálicos , Gravidez , Ratos , Ratos Wistar
12.
J Agric Food Chem ; 69(4): 1291-1299, 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33475360

RESUMO

Lycopene (Lyc) as a natural antioxidant has attracted widespread attention. Di(2-ethylhexyl) phthalate (DEHP) can cause serious spleen injury in animals via the environment and food chain. For investigation of whether Lyc could alleviate DEHP-exerted pyroptosis in spleen through inhibiting the Caspase-1/NLRP3 pathway activation, 140 male mice were randomly divided into 7 groups: control group, vehicle control group, Lyc group (5 mg/kg BW/day), DEHP-exposed group (500 or 1000 mg/kg BW/day, respectively), and DEHP + Lyc groups by daily administration for 28 days. Pathological results showed that the supplementation of Lyc alleviated DEHP-induced inflammatory infiltration. Moreover, the addition of Lyc inhibited DEHP-induced Caspase-1, NLRP3, ASC, NF-κB, IL-1ß, and IL-18 overexpression and GSDMD down-expression. These results indicate that Lyc could inhibit DEHP-induced Caspase-1-dependent pyroptosis and the inflammatory response. Taken together, the study provided new evidence that Lyc may be a strategy to mitigate spleen injury induced by DEHP.


Assuntos
Caspase 1/metabolismo , Dietilexilftalato/toxicidade , Licopeno/administração & dosagem , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/efeitos dos fármacos , Baço/efeitos dos fármacos , Animais , Caspase 1/genética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Baço/metabolismo
13.
Toxicol Appl Pharmacol ; 414: 115411, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33476678

RESUMO

Di-2-ethylhexyl phosphate (DEHP) and its main toxic metabolite mono-2-ethylhexyl phthalate (MEHP) are the typical endocrine disrupting chemicals (EDCs) and widely affect human health. Our previous research reported that synthetic nonionic dietary emulsifier polysorbate 80 (P80, E433) had the promotional effect on the oral absorption of DEHP in rats. The aim of this study was to explore its mechanism of promoting oral absorption, focusing on the mucus barrier and mucosal barrier of the small intestine. A small molecule fluorescent probe 5-aminofluorescein-MEHP (MEHP-AF) was used as a tracker of MEHP in vivo and in vitro. First of all, we verified that P80 promoted the bioavailability of MEHP-AF in the long-term and low-dose exposure of MEHP-AF with P80 as a result of increasing the intestinal absorption of MEHP-AF. Afterwards, experimental results from Western blot, qPCR, immunohistochemistry, and immunofluorescence showed that P80 decreased the expression of proteins (mucus protein mucin-2, tight junction proteins claudin-1 and occludin) related to mucus barrier and mucosal barrier in the intestine, changed the integrity of intestinal epithelial cell, and increased the permeability of intestinal epithelial mucosa. These results indicated that P80 promoted the oral absorption of MEHP-AF by altering the intestinal mucus barrier and mucosal barrier. These findings are of great importance for assessing the safety risks of some food emulsifiers and clarifying the absorption mechanism of chemical pollutants in food, especially for EDCs.


Assuntos
Dietilexilftalato/análogos & derivados , Emulsificantes/toxicidade , Células Epiteliais/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Polissorbatos/toxicidade , Animais , Disponibilidade Biológica , Células CACO-2 , Claudina-1/metabolismo , Dietilexilftalato/farmacocinética , Dietilexilftalato/toxicidade , Células Epiteliais/metabolismo , Fluoresceínas/metabolismo , Corantes Fluorescentes/metabolismo , Células HT29 , Humanos , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Masculino , Camundongos Endogâmicos ICR , Mucina-2/metabolismo , Ocludina/metabolismo , Permeabilidade , Ratos Sprague-Dawley , Distribuição Tecidual , Toxicocinética
14.
Environ Sci Pollut Res Int ; 28(18): 23501-23509, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33449321

RESUMO

Di-(2-ethylhexyl)-phthalate (DEHP) is the most commonly used plasticizer and it has been a ubiquitous environmental contaminant which affects health. The purpose of this study was to investigate the protective effect of the Lycium barbarum polysaccharide (LBP) at dosages of 100, 200, and 300 mg/kg bw on DEHP-induced (3000 mg/kg) toxicity in rat liver through a 28-day animal experiment. The results showed that LBP attenuated oxidative stress slightly by lowering the production of ROS and improving the activity of SOD and GSH-Px in liver and serum of DEHP treatment rats. At the same time, the levels of PXR, CYP450, CYP2E1, CYP3A1, UGT1, and GST were reduced after LBP treatment. Moreover, LBP decreased the mRNA expression of PXR, UGT1, and GST significantly. These findings suggested that LBP might ameliorate DEHP-induced liver injury by down-regulating the expression of PXR in liver, further down-regulating the downstream phase I and II detoxification enzymes, thus reducing the damage caused by DEHP. Therefore, LBP may have the potential to become an auxiliary therapeutic agent as a natural ingredient of health food.


Assuntos
Dietilexilftalato , Medicamentos de Ervas Chinesas , Lycium , Ácidos Ftálicos , Animais , Dietilexilftalato/metabolismo , Dietilexilftalato/toxicidade , Medicamentos de Ervas Chinesas/farmacologia , Fígado/metabolismo , Estresse Oxidativo , Ácidos Ftálicos/metabolismo , Ratos
15.
Environ Sci Technol ; 55(3): 1842-1851, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33459556

RESUMO

Chemical proteomics methods have been used as effective tools to identify novel protein targets for small molecules. These methods have great potential to be applied as environmental toxicants to figure out their mode of action. However, these assays usually generate dozens of possible targets, making it challenging to validate the most important one. In this study, we have integrated the cellular thermal shift assay (CETSA), quantitative proteomics, metabolomics, computer-assisted docking, and target validation methods to uncover the protein targets of monoethylhexyl phthalate (MEHP). Using the mass spectrometry implementation of CETSA (MS-CETSA), we have identified 74 possible protein targets of MEHP. The Gene Ontology (GO) enrichment integration was further conducted for the target proteins, the cellular dysregulated proteins, and the metabolites, showing that cell cycle dysregulation could be one primary change due to the MEHP-induced toxicity. Flow cytometry analysis confirmed that hepatocytes were arrested at the G1 stage due to the treatment with MEHP. Subsequently, the potential protein targets were ranked by their binding energy calculated from the computer-assisted docking with MEHP. In summary, we have demonstrated the development of interactomics workflow to simplify the redundant information from multiomics data and identified novel cell cycle regulatory protein targets (CPEB4, ANAPC5, and SPOUT1) for MEHP.


Assuntos
Dietilexilftalato , Ácidos Ftálicos , Ciclo Celular , Dietilexilftalato/toxicidade , Proteínas , Proteômica
16.
Environ Sci Pollut Res Int ; 28(17): 21696-21705, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33411269

RESUMO

Di-(2-ethylhexyl) phthalate (DEHP) is a male reproductive toxicant. This research is aimed at investigating the effect of pubertal DEHP exposure on testicular endoplasmic reticulum (ER) stress and germ cell apoptosis. Five-week-old male mice were orally administered with DEHP (0, 0.5, 50, or 500 mg/kg/day) for 35 days. Testis weight and sperm count were reduced in mice exposed to 500 mg/kg/day DEHP. The number of seminiferous tubules in stages VII-VIII, mature seminiferous tubules, was reduced and the number of seminiferous tubules in stages IX-XII, immature seminiferous tubules, was elevated in mice treated with 500 mg/kg/day DEHP. Numerous apoptotic germ cells were observed in mouse seminiferous tubules exposed to 50 and 500 mg/kg/day DEHP. Moreover, cleaved caspase-3 was elevated in mouse testes exposed to 500 mg/kg/day DEHP. In addition, Bcl-2 was reduced and Bax/Bcl-2 was elevated in mouse testes exposed to 500 mg/kg/day DEHP. Additional experiment showed that GRP78, an ER molecular chaperone, was downregulated in mouse testes exposed to 500 mg/kg/day DEHP. Testicular p-IRE-1α, p-JNK, and CHOP, three markers of ER stress, were upregulated in mice exposed to 500 mg/kg/day DEHP. These results suggest that pubertal exposure to high doses of DEHP induces germ cell apoptosis partially through initiating ER stress in testes.


Assuntos
Dietilexilftalato , Testículo , Animais , Apoptose , Dietilexilftalato/toxicidade , Estresse do Retículo Endoplasmático , Células Germinativas , Masculino , Camundongos , Ácidos Ftálicos
17.
Environ Sci Pollut Res Int ; 28(21): 26961-26974, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33496947

RESUMO

Bisphenol A (BPA) and di(2-ethylhexyl)phthalate (DEHP) are abundant endocrine disrupting chemicals (EDCs). In recent years, studies showed that EDCs may lead to neurodevelopmental diseases. The effects of prenatal exposure to these chemicals may have serious consequences. Moreover, exposure to EDCs as a mixture may have different effects than individual exposures. The present study aimed to determine the toxicity of BPA and/or DEHP on central nervous system (CNS) and neuroendocrine system in prenatal and lactational period in Sprague-Dawley rats. Pregnant rats were randomly divided into four groups: control (received vehicle); BPA group (received BPA at 50 mg/kg/day); DEHP group (received DEHP at 30 mg/kg/day); and combined exposure group (received both BPA at 50 mg/kg/day and DEHP at 30 mg/kg/day) during pregnancy and lactation by oral gavage. At the end of lactation, male offspring (n = 6) were randomly grouped. The alterations in the brain histopathology, neurotransmitter levels and enzyme activities in the cerebrum region, oxidative stress markers, and apoptotic effects in the hippocampus region were determined at adulthood. The results showed that exposure to EDCs at early stages of life caused significant changes in lipid peroxidation, total GSH and neurotransmitter levels, and activities of neurotransmitter-related enzymes. Moreover, BPA and/or DEHP led to apoptosis and histopathologic alterations in the hippocampus. Therefore, we can suggest that changes in oxidant/antioxidant status, as well as in neurotransmitters and related enzymes, can be considered as the underlying neurotoxicity mechanisms of BPA and DEHP. However, more mechanistic studies are needed.


Assuntos
Dietilexilftalato , Disruptores Endócrinos , Efeitos Tardios da Exposição Pré-Natal , Animais , Compostos Benzidrílicos , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Feminino , Lactação , Masculino , Sistemas Neurossecretores , Fenóis , Ácidos Ftálicos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos Sprague-Dawley
18.
Int Immunopharmacol ; 91: 107323, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33385713

RESUMO

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder which manifests itself in early childhood and is distinguished by recurring behavioral patterns, and dysfunction in social/communication skills. Ubiquitous environmental pollutant, di-2-ethylhexyl phthalate (DEHP) is one of the most frequently used plasticizers in various industrial products, e.g. vinyl flooring, plastic toys, and medical appliances. DEHP gets easily released into the environment and leads to human exposure through various routes. DEHP has been described to be linked with oxidative stress in various organs in animal/human studies. Increased concentration of DEHP has also been detected in ASD children which indicates an association between phthalates exposure and ASD. However, effect of DEHP on autism-like behavior has not been investigated previously. Therefore, this study probed the effect of DEHP on autism-like behavior (marble burying, self-grooming and sociability) and innate immune cells (dendritic cells/neutrophils)/cerebellar oxidant-antioxidant balance (NFkB, iNOS, NADPH oxidase, nitrotyrosine, lipid peroxides, Nrf2, SOD, GPx) in BTBR and C57 mice. Our data show that DEHP treatment causes worsening of autism-like behavior in BTBR mice which is associated with enhancement of oxidative stress in innate immune cells and cerebellum with concomitant lack of antioxidant protection. DEHP also causes oxidative stress in C57 mice in both innate immune cells and cerebellar compartment, however there is Nrf2-mediated induction of enzymatic antioxidants which protects them from upregulated oxidative stress. This proposes the notion that ubiquitous environmental pollutants such as DEHP may be involved in the pathogenesis/progression of ASD through dysregulation of antioxidant-antioxidant balance in innate immune cells and cerebellum.


Assuntos
Transtorno Autístico/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Dietilexilftalato/toxicidade , Poluentes Ambientais/toxicidade , Imunidade Inata/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Plastificantes/toxicidade , Animais , Antioxidantes/metabolismo , Transtorno Autístico/enzimologia , Transtorno Autístico/imunologia , Transtorno Autístico/psicologia , Cerebelo/enzimologia , Cerebelo/imunologia , Modelos Animais de Doenças , Asseio Animal/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Comportamento Social
19.
Chemosphere ; 263: 128191, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33297156

RESUMO

Reproductive behaviors are tightly regulated by sex steroid hormones. Interference with these hormones or their neural signaling pathways leads to behavioral alterations. We have previously shown that oral exposure of adult male mice to di(2-ethylhexyl) phthalate (DEHP), an organic environmental endocrine disruptor, altered sexual behavior. In this study, we examined the effects of pubertal exposure to DEHP and analyzed whether pubertal and adult exposures to DEHP trigger long-term effects. For pubertal exposure, male mice were exposed orally to the vehicle or DEHP at 5 or 50 µg/kg/d from postnatal day (PND) 30 to PND60. Exposure was arrested and animals were analyzed on PND120. They exhibited normal olfactory preference but showed modified emission of ultrasonic vocalizations. DEHP exposure also affected partner preference and mating components. These modifications were associated with normal circulating testosterone levels and weight of androgen-sensitive tissues. In contrast, androgen receptor (AR) protein amount was reduced in the hypothalamic preoptic area in particular for the DEHP-50 group. Pubertal exposure also increased the anxiety-state level without changing circadian activity. When adult male mice were exposed to DEHP at the same doses from PND60 to PND105 and analyzed two months later, no effects of treatment on reproductive and anxiety-related behaviors or hypothalamic AR protein amount were seen. Our data show that pubertal exposure of male mice to DEHP induces long-term behavioral changes in contrast to the adult exposure. This highlights the sensitivity of the nervous system to low doses of DEHP during the critical period of puberty.


Assuntos
Dietilexilftalato , Disruptores Endócrinos , Ácidos Ftálicos , Animais , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Masculino , Camundongos , Reprodução
20.
Chemosphere ; 263: 128307, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33297244

RESUMO

Bisphenol A (BPA) and Diethylhexyl Phthalate (DEHP) are well-studied endocrine disrupting chemicals (EDCs), however, the effects of mixtures of these EDCs are not. To assess the consequences of prenatal exposure to a mixture of these EDCs, dams were orally administered either saline (control), BPA (5 µg/kg BW/day), high dose DEHP (HD-D; 7.5 mg/kg BW/day), or a combination of BPA with HD-D in experiment 1; saline, BPA (5 µg/kg BW/day), low-dose DEHP (LD-D; 5 µg/kg BW/day) or a combination of BPA with LD-D in experiment 2. Gestational weights, number of abortions, litter size and weights, number of live births and stillbirths were recorded. Morphometric measures were obtained at birth and body weight, food and water intake were monitored weekly from postnatal weeks 3-12. Offspring were sacrificed at 16-24 weeks of age and organ weights were measured. The abortion rate of dams exposed to HD-D and the mixtures, BPA + LD-D and BPA + HD-D were higher at 9, 14 and 27% respectively. Prenatal exposure to BPA or HD-D significantly decreased relative thymus weights in male but not female offspring. Apoptotic cells were detected in thymus sections of both male and female offspring prenatally exposed to DEHP. Relative heart weights increased in BPA + HD-D exposed male offspring compared to the other groups. The results indicate that a mixture of BPA and DEHP, produced a pronounced effect on pregnancy outcomes. Male offspring appear to be more susceptible to the programming effects of these EDCs or their mixture suggesting a need to reconsider the possible additive, antagonistic or synergistic effects of EDC mixtures.


Assuntos
Dietilexilftalato , Disruptores Endócrinos , Efeitos Tardios da Exposição Pré-Natal , Animais , Compostos Benzidrílicos/toxicidade , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Feminino , Humanos , Masculino , Fenóis , Gravidez , Resultado da Gravidez , Ratos , Ratos Sprague-Dawley
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