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B6C3F1 mice were treated with 0, 100, 500, 1500, or 6000 ppm di(2-ethylhexyl)phthalate (DEHP) in the diet for up to 104 weeks. Blood and urine were analyzed at Weeks 26, 52, 78, and 104 from 10 animals per sex per group. Body weights and food consumption were measured weekly for the first 16 weeks, then monthly thereafter. Survival was reduced for...
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Context 1
... 104 weeks of exposure, increased incidence of hepa- tocyte pigmentation and cytoplasmic eosinophilia in the liver were observed for the 6000-ppm groups, compared with the (Table 6). The incidence of chronic inflammation in the liver for male 6000-ppm mice was significantly higher than for controls. ...
Citations
... Although the use of DEHP has been restricted by regulations in many countries and substitutes have been provided, DEHP is still the predominant environmental PAE contaminant (Gao et al., 2019), and its concentration in human body has been reported to keep increasing in some regions, such as China in recent years (Domínguez-Romero et al., 2023). In 2012, the International Agency for Research on Cancer (IARC) defined DEHP as possibly carcinogenic to humans (Group 2B) (Grosse et al., 2011), emphasizing that although several studies have linked DEHP to tumors of the reproductive system and liver (David et al., 2000a;David et al., 2000b;Kim et al., 2010), the effects of DEHP on the carcinogenicity of mammary gland are still short of large-scale longitudinal epidemiological evidence (Dueñas-Moreno et al., 2023). ...
... The LOAEL and the NOAEL for tumour induction (total male mice with hepatocellular neoplasms) in this study were 1500 and 500 ppm DEHP in the diet, respectively (corresponding to 292 and 98 mg/kg/day for males of the two dose groups respectively). The LOAEL and the NOAEL for non-neoplastic effects on the liver in this study was 98 mg/kg/day and 19 mg/kg/day of DEHP in the diet, respectively for males of the two dose groups (28,29) . ...
... The LOAEL for tumour induction (total male rats with hepatocellular neoplasms and MCL) and for the effects on the liver, kidney and testis in this rat study was 2500 ppm DEHP in the diet (147 mg/kg/day for males). An overall NOAEL for the tumour induction and for the effects on the liver, kidney and testis was established as 28.9 mg/kg/day for male rats (28,29) . ...
... Rats and mice are responsive to carcinogenic effects of peroxisome proliferators, while guinea pigs, dogs, non-human primates, and humans are non-responsive. This difference is due to marked interspecies variations in the expression of PPAR-α (18,28,29) . Therefore, evidence for occurrence of carcinogenicity in humans is very low. ...
... 21 Chronically high DEHP levels have also been shown to result in various biological effects, including testicular atrophy, proliferation of peroxisomes, and potential liver tumors in mice. 22 Harmful effects related to DEHP exposure in children have also been reported, including reproductive-related toxicity and cardiotoxic effects of DEHP and its metabolites, 2-4 increased incidence of asthma and allergies, 5-7 precocious puberty, 23 liver toxicity, 8 acute irritant symptoms, 8 abnormal neurodevelopment, 9,10 and high blood pressure. 11,12 Our results reveal the potential for DEHP exposure during admission for cardiac catheterization, an issue which deserves more attention. ...
Background:
Di(2-ethylhexyl) phthalate (DEHP) may produce toxicity, posing a risk to human health. Medical devices composed of DEHP are frequently used in catheterization, but few studies have investigated DEHP exposure during catheterization. The aim of this prospective series was to characterize the exposure pattern of DEHP during catheterization.
Methods:
We enrolled 16 patients with congenital heart disease undergoing catheterization. Collection of urine was done to measure DEHP metabolites on hospitalization, before catheterization, after catheterization, and at discharge. The following DEHP metabolites were measured: mono-(2-ethylhexyl) phthalate (MEHP), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and the ratio of MEHP to overall metabolites (MEHP%) was determined. DEHP exposure from polyvinyl chloride (PVC)-containing catheter and infusion systems were recorded in detail. Differences in DEHP levels before and after catheterization were analyzed.
Results:
Urinary levels of MEHP, MEHHP, and MEOHP significantly decreased from before catheterization to after catheterization (all p < 0.01), but did not change significantly from initial hospitalization to before catheterization. Urinary MEHP% significantly decreased from initial hospitalization to before catheterization (p < 0.001), then increased after catheterization (p < 0.001), and decreased gradually at discharge (p = 0.03). Urinary MEHP% after catheterization and at discharge was significantly positively related to the duration of using PVC-containing catheter systems. There was a significant positive correlation between urinary MEHP% and the duration of using PVC-containing infusion system before catheterization, and a borderline significant correlation at both post-catheterization time slots.
Conclusions:
Our results demonstrated that urinary MEHP% may be a potential biomarker of DEHP contamination from the use of PVC-containing catheters or infusion systems.
... Limited data on DEHP exposure in mice and rats point to an association with nephropathy and progression of the chronic kidney disease (CKD) (49)(50)(51). One animal study (52) has shown that DEHP, but not its metabolite MEHP, induced epithelialmesenchymal transition (EMT) and renal fibrosis in renal tubular cells, and that these effects were associated with the downregulation of peroxisome proliferator-activated receptors (PPARs). ...
Phthalates are a group of phthalic acid esters used as plasticisers in a large number of products to improve their flexibility, softness, and extensibility. Their wide use in medical devices, however, raises a lot of concern, as they can enter the organism and have toxic effects on human liver, thyroid, kidneys, lungs, reproductive, endocrine, nervous, and respiratory system and are associated with asthma, obesity, autism, and diabetes. The aim of this review is to summarise current knowledge about phthalate migration from medical devices during different medical procedures and possible impact on patient health. It also looks at alternative plasticisers with supposedly lower migration rates and safer profile. Not enough is known about which and how many phthalates make part of medical devices or about the health impacts of alternative plasticisers or their migration rates.
... Due to their reversible combination with plastic matrix, phthalates can leach out of plastics and contaminate the environment, such as indoor dust (Matsumoto et al. 2008;Abdi et al. 2021). In addition to their well-known endocrine-disrupting effects, phthalates also have kidney toxicity (David et al. 2000;Ward et al. 1986;Wood et al. 2014). Some epidemiologic studies have shown that phthalates exposure was associated with markers of early kidney impairment in children and adults (Chang et al. 2020;Chen et al. 2019Chen et al. , 2020Lee et al. 2020;Trasande et al. 2014;Wu et al. 2018). ...
Melamine (MEL), cyanuric acid (CYA), and phthalates have kidney toxicity, respectively. Still, no study has explored whether there is an interaction of co-exposure to MEL, CYA, and phthalates on early kidney impairment, including cystatin C (CYST), beta 2-microglobulin (β2-MG), albumin creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR). Urine samples were collected from 333 adults in the National Health and Nutrition Examination Survey (NHANES) 2003–2004, and urinary MEL, CYA, and ten metabolites of phthalates were quantified. The multiple markers of early kidney impairment were also measured, including serum CYST, β2-MG, urinary ACR, and eGFR. Their associations were explored by multiple linear and multivariate logistic regression models. Meanwhile, the interactions of co-exposure to MEL, CYA, and phthalates on early kidney impairment were analyzed by Wilcoxon rank-sum test combined with the LSD test. In the multiple linear regression model, urinary concentrations of monobenzyl phthalate (MBzP), mono(3-carboxypropyl) phthalate (MCPP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), and mono(2-ethylhexyl) phthalate (MEHP) were positively associated with urinary ACR, serum β2-MG, and CYST, respectively. Urinary concentrations of MBzP and MCPP were negatively associated with eGFR. In the multivariate logistic regression model, increased urinary CYA concentration was the risk factor of CYST abnormality with an odds ratio (OR) (95% confidence interval, 95% CI) of 2.38 (1.01, 5.60) (P = 0.047) and increased urinary MBzP concentration was the risk factor of ACR abnormality with an OR of 2.59 (1.41, 4.75) (P = 0.002). The co-exposure to MEL, CYA, and four phthalate metabolites (MEHP, MBzP, MCPP, and MECPP) presented significantly interactive effects on the markers of early kidney impairment, respectively. There were the independent and interactive effects of exposure to MEL, CYA, and specific phthalate metabolites on early kidney impairment. Due to co-exposure to multiple environmental chemicals in our daily life, more attention should be paid to the health damage raised by the synergistic effects of environmental chemicals.
... DEHP also impairs the migration and colony-forming capacity of human CD34 + HSPCs [6]. Highdosage and long-term dietary DEHP uptake causes chronic progressive nephropathy and significantly reduces hemoglobin (Hgb) production in rodents [7,8]. However, DEHP has no effect in male cynomolgus monkeys that were treated with 500 mg/kg/day DEHP for 14 days [9]. ...
Di(2-ethylhexyl)phthalate (DEHP) is the most widely used phthalate to manufacture various plastic products. However, the potential effects of DEHP on erythropoiesis have not been investigated comprehensively. Here, we aimed to investigate whether DEHP modulated the function of hematopoietic stem and progenitor cells (HSPCs) to influence erythropoiesis, and to explore the associated mechanisms. In the present study, human cell lines with a capacity to differentiate into erythroid cells and murine bone marrow cells were treated with DEHP. DEHP not only impaired HSPC function, but also suppressed erythroid differentiation in a dose-dependent manner. In addition, DEHP removal restored HSPC activity. To explore how DEHP interfered with erythroid differentiation, we focused on energy metabolism and Klotho expression. DEHP suppressed erythroid differentiation via upregulating Klotho expression, while it did not via modulating cellular bioenergetics. Therefore, our results provided a novel insight into the pathophysiological link between phthalates and dysregulated erythroid differentiation.
... Po dawce 1 266 mg/kg mc./dzień spadła przeżywalność zwierząt (z powodu neoplazji wątrobowokomórkowej). Po największej ze stosowanych w doświadczeniu dawek (1 458 mg/kg mc./dzień) obserwowano zmniejszenie masy macicy (Dawid i in. 1999;2000b). ...
... W kolejnym badaniu przeprowadzonym przez David i in. (1999;2000b) 6-tygodniowe samce i samice szczurów F344 (w grupach liczących 50 ÷ 80 osobników) narażano z paszą na ftalan bis(2--etyloheksylu) o stężeniach: 0 (kontrola), 100, 500, 2 500 lub 12 500 ppm. Dawki ftalanu bis(2-etyloheksylu) obliczono na podstawie średniego spożycia paszy przez zwierzęta. ...
Ftalan bis(2-etyloheksylu) (DEHP) był powszechnie stosowany w przeszłości, głównie jako plastyfikator. Narażenie zawodowe na DEHP występuje w czasie jego produkcji oraz stosowania, zaś narażenie środowiskowe jest związane z produktami zawierającymi ten związek oraz ze spożywaniem zanieczyszczonej żywności lub wody. Unia Europejska wprowadziła zakaz obrotu produktów zawierających DEHP w stężeniu ≥0,1%. Wchłanianie tego flatalanu może zachodzić drogą pokarmową i inhalacyjną, przechodzi on również przez barierę łożyskową oraz do mleka matki. Dane epidemiologiczne wskazują na związek między narażeniem na DEHP (zarówno zawodowym, jak i środowiskowym) a funkcjonowaniem męskiego układu rozrodczego. Nie wykazano bezpośredniej zależności między narażeniem na DEHP a bezpłodnością. W badaniach na zwierzętach za najczulszy skutek toksyczności przewlekłej tego związku uznano zaburzenia spermatogenezy u szczurów. Jako podstawę do zaproponowania wartości NDS dla ftalanu bis(2-etyloheksylu) przyjęto toksyczne działanie na męski układ rozrodczy obserwowane u szczura (NOAEL = 5,8 mg/kg mc./dzień). Proponuje się przyjęcie wartości NDS dla ftalanu bis(2-etyloheksylu) na poziomie 0,8 mg/m3 . Brak jest podstaw do ustalenia wartości NDSCh oraz DSB. Proponuje się notację „Ft” – substancja działająca szkodliwie na rozrodczość. Z powodu niewielkiego wchłaniania DEHP drogą dermalną brak jest podstaw do przyjęcia notacji „skóra”. Zakres tematyczny artykułu obejmuje zagadnienia zdrowia oraz bezpieczeństwa i higieny środowiska pracy będące przedmiotem badań z zakresu nauk o zdrowiu i inżynierii środowiska.
... In the animal study, PAE exposure has been reported to lower kidney weight, and further inducing chronic progressive nephropathy in rats (animal study) (David et al., 2000). Similarly, Wei et al. (2012) found that maternal rat exposure to PAE (DEHP) reduced the number of nephrons, increased glomerular volume, and resulted in a smaller Bowman capsule in DEHP-treated offspring at weaning, glomerulosclerosis, and interstitial fibrosis, further resulting in renal disease . ...
Phthalate esters (PAEs) are one of the most widely used plasticizers in polymer products and humans are increasingly exposed to them. The constant exposure to PAEs-contained products has raised some concerns against human health. Thus, the impacts of PAEs and their metabolites on human health require a comprehensive study for a better understanding of the associated risks. Here, we attempt to review eight main health effects of PAE exposure according to the most up-to-date studies. We found that epidemiological studies demonstrated a consistent association between PAE exposure (especially DEHP and its metabolites) and a decrease in sperm quality in males and symptom development of ADHD in children. Overall, we found insufficient evidence and lack of consistency of the association between PAE exposure and cardiovascular diseases (hypertension, atherosclerosis, and CHD), thyroid diseases, respiratory diseases, diabetes, obesity, kidney diseases, intelligence performance in children, and other reproductive system-related diseases (anogenital distance, girl precocious puberty, and endometriosis). Future studies (longitudinal and follow-up investigations) need to thoroughly perform in large-scale populations to yield more consistent and powerful results and increase the precision of the association as well as enhance the overall understanding of potential human health risks of PAEs in long-term exposure.
... Phthalates are endocrine disruptors, and studies on human biomonitoring have reported ubiquitous phthalate exposure in the general population in the United States., Canada, Europe, South Korea, and Taiwan (Frederiksen et al., 2010(Frederiksen et al., , 2013Goen et al., 2011;Huang et al., 2015;Kim et al., 2016;Koch et al., 2017;Saravanabhavan et al., 2013;Schwedler et al., 2017;Zota et al., 2014). Several animal studies have revealed that exposure to high doses of di-2-ethylhexyl phthalate (DEHP) may cause renal tubular damage, chronic progressive nephropathy, renal tubular degeneration, and decreased kidney weight (David et al., 2000;Ward et al., 1986;Wood et al., 2014;Wu et al., 2018). Moreover, mono-ethylhexyl phthalate (MEHP) was discovered to have an obvious nephrotoxic effect on cultured kidney epithelial cells in vitro, as experimental studies (Rothenbacher et al., 1998;Wu et al., 2018) reported chronic progressive nephropathy and renal tubule pigmentation in rats with chronic DEHP exposure (David et al., 2000). ...
... Several animal studies have revealed that exposure to high doses of di-2-ethylhexyl phthalate (DEHP) may cause renal tubular damage, chronic progressive nephropathy, renal tubular degeneration, and decreased kidney weight (David et al., 2000;Ward et al., 1986;Wood et al., 2014;Wu et al., 2018). Moreover, mono-ethylhexyl phthalate (MEHP) was discovered to have an obvious nephrotoxic effect on cultured kidney epithelial cells in vitro, as experimental studies (Rothenbacher et al., 1998;Wu et al., 2018) reported chronic progressive nephropathy and renal tubule pigmentation in rats with chronic DEHP exposure (David et al., 2000). ...
... Previously, a correlation was observed between the subacute or chronic kidney toxicity or lesions caused by DEHP exposure and peroxisome proliferator-activated receptor (PPAR)-α mediation as a result of peroxisome proliferation (Ward et al., 1998). Animal studies have reported that chronic DEHP exposure could cause chronic progressive nephropathy and the growth of lesions on the kidney, such as the mineralization of renal tubules and papilla (David et al., 2000). As demonstrated by in vitro and in vivo studies, DEHP treatment could cause epithelial-to-mesenchymal transition and the progression of renal fibrosis in renal tubular cells through PPAR downregulation. ...
... The study further found that highly exposed children (with an average daily DEHP intake of 0.05 mg/kg/day) were 10.39% prone to the risk of microalbuminuria. Female mice exposed to 1500 and 6000 ppm of DEHP had a significantly higher proportion of chronic progressive nephropathy (CPN) cases than those in the control group [72]. In the same study, male and female mice exposed to the same concentration of DEHP experienced a reduction in kidney weight [72]. ...
... Female mice exposed to 1500 and 6000 ppm of DEHP had a significantly higher proportion of chronic progressive nephropathy (CPN) cases than those in the control group [72]. In the same study, male and female mice exposed to the same concentration of DEHP experienced a reduction in kidney weight [72]. CPN in male rats was reported to be aggravated following exposure to 12,500 ppm of DEHP [72]. ...
... In the same study, male and female mice exposed to the same concentration of DEHP experienced a reduction in kidney weight [72]. CPN in male rats was reported to be aggravated following exposure to 12,500 ppm of DEHP [72]. A separate report indicated that exposure to 3147 mg/kg/day of DEHP in mice resulted in the degeneration of the renal tubule and reduced kidney weight [73]. ...
Endocrine-disrupting chemicals (EDCs) are hormonally active compounds in the environment that interfere with the body's endocrine system and consequently produce adverse health effects. Despite persistent public health concerns, EDCs remain important components of common consumer products, thus representing ubiquitous contaminants to humans. While scientific evidence confirmed their contribution to the severity of Influenza A virus (H1N1) in the animal model, their roles in susceptibility and clinical outcome of the coronavirus disease (COVID-19) cannot be underestimated. Since its emergence in late 2019, clinical reports on COVID-19 have confirmed that severe disease and death occur in persons aged ≥65 years and those with underlying comorbidities. Major comorbidities of COVID-19 include diabetes, obesity, cardiovascular disease, hypertension, cancer, and kidney and liver diseases. Meanwhile, long-term exposure to EDCs contributes significantly to the onset and progression of these comorbid diseases. Besides, EDCs play vital roles in the disruption of the body's immune system. Here, we review the recent literature on the roles of EDCs in comorbidities contributing to COVID-19 mortality, impacts of EDCs on the immune system, and recent articles linking EDCs to COVID-19 risks. We also recommend methodologies that could be adopted to comprehensively study the role of EDCs in COVID-19 risk.
