Determination of the half-life of di(2-ethylhexyl) phthalate (DEHP) in a preterm neonate using blood transfusion as the source of intravenous exposure

Our previous studies found that di (2-ethylhexyl) phthalate (DEHP) could disorder lipid metabolism in adolescents but the mechanisms underlying this association remained unclear. This study was undertaken to clarify the mediating effect of JAK3/STAT5/PPARγ on disorder lipid levels induced by DEHP in adolescents. We recruited 478 adolescent students (median age 18.1 years). The mRNA expression and DNA methylation levels of JAK3/STAT5/PPARγ were detected by real-time PCR and the MethylTarget, respectively. We used multiple linear regression to analyze the association between DEHP metabolites (MEHP, MEOHP, MEHHP, MECPP, MCMHP, and ΣDEHP) levels, mRNA expression, and DNA methylation levels. The mediating effect of JAK3/STAT5/PPARγ mRNA expression levels was examined by mediation analysis. We found that all DEHP metabolite levels were positively correlated with TC/HDL-C and LDL-C/HDL-C (P < 0.05). The MEOHP level was negatively associated with DNA methylation levels and positively associated with mRNA levels of PPARγ and STAT5b (P < 0.05). The MEHP level was negatively associated with the DNA methylation level and positively associated with the mRNA level of JAK3 (P < 0.05). Higher MEOHP was associated with a higher level of TC/HDL-C, the mediation analysis showed the mediation effect was 17.18% for the JAK3 level, 10.76% for the STAT5b level, and 11% for the PPARγ level. Higher MEHP was associated with a higher level of LDL-C/HDL-C, the mediation effect was 14.49% for the JAK3 level. In conclusion, DEHP metabolites decreased the DNA methylation levels, inducing the increase of the mRNA levels of JAK3/STAT5/PPARγ. In addition, the mRNA levels mediated the association between DEHP exposure and disorder lipid levels.

Premature neonates who spend time in a neonatal intensive care unit may be at increased risk of adverse health effects from exposure to di-(2-ethylhexyl) phthalate (DEHP) because of their increased risk of high exposure, their small body size, and their physical condition. DEHP, a reproductive toxicant in animals, is a major component in polyvinyl chloride (PVC) plastics, which are frequently used in medical tubing and blood storage bags. DEHP is not covalently bound to PVC, and it may be easily released from the PVC medical devices. The objective of this study was to determine whether premature infants who undergo medical procedures, such as blood transfusions, intravenous therapy, enteral and parenteral nutrition support, and dialysis, are at increased risk of exposure to DEHP than the general population. Because of their smaller size, children and especially premature and small infants may receive a larger dose of DEHP on a milligram per kilogram basis than adults when the same-size medical device is used for all ages. Premature neonates who seemed to have the potential to be on intravenous infusion for >2 weeks and were expected to survive were eligible for enrollment in the study. We assessed exposure to DEHP in 6 premature newborns by measuring in 41 urine samples the levels of 3 DEHP metabolites: mono-(2-ethylhexyl) phthalate (mEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), and mono-(2-ethyl-5-oxohexyl) phthalate (mEOHP). mEHHP and mEOHP were detected in all 41 urine samples, and mEHP was detected in 33. Because only 33 of the samples had detectable amounts for all 3 metabolites, statistical analyses were limited to those 33. The levels of all 3 DEHP metabolites varied widely, and the urinary mean and median concentrations of mEOHP and mEHHP were 1 order of magnitude higher than those for mEHP. Furthermore, the geometric mean urinary concentrations of mEOHP (1617 ng/mL), mEHHP (2003 ng/mL), and mEHP (100 ng/mL) in these 6 premature infants who underwent intensive therapeutic interventions were found to be severalfold higher than in the US general population (for mEHP, geometric mean in those 6 years and older was 3.43 ng/mL). This study provides the first quantitative evidence confirming that newborns who undergo intensive therapeutic medical interventions are exposed to higher concentrations of DEHP than the general population. Although the overall benefits of medical procedures using PVC devices outweigh the risks associated with exposure to DEHP, more research is needed to determine whether infants and children who undergo intensive therapeutic interventions using DEHP-containing devices are at higher risk for altered health outcomes than infants and children who undergo similar treatments but are not potentially exposed to DEHP.

The main objective of the Endosulfan Manufacturers and Formulators Welfare Association in India is disseminating scientific facts concerning the use of endosulfan. Because endosulfan is used in several countries, the association watches for global news and information relevant to endosulfan.

Background: Di-2-ethylhexyl phthalate (DEHP), a phthalate compound found in medical devices, may cause toxic effects in premature infants. In this study, the objective is to quantify DEHP exposures from various intravenous and respiratory therapy devices, and to use these values to predict typical exposure for an infant in a neonatal unit. Methods: Common IV products used on infants are directed through various types of IV tubing (IVT) and analyzed for DEHP content. DEHP exposure for infants receiving respiratory therapy was determined indirectly through analysis of urine DEHP metabolites. By deriving these values for DEHP we calculated the daily exposure to DEHP from common IV fluids (IVF) and respiratory devices during hospitalization in a neonatal unit. Results: IVF labeled DEHP-positive showed very high concentrations of DEHP, but when passed through IVT, substantial amounts were adsorbed. DEHP was undetectable with all DEHP-negative IVF tests, except when passed through DEHP-positive IVT. The DEHP leached from most respiratory devices was relatively modest, except that detected from bubble CPAP. In 14 very low birthweight infants, the mean DEHP exposure was 182,369 mcg/kg over 81.2 days of the initial hospitalization. Ninety-eight percent of the exposure was from respiratory devices, with bubble CPAP accounting for 95% of the total DEHP exposure in these infants. Conclusions: The DEHP exposure in our neonatal unit can be reduced markedly by avoiding or modifying bubble CPAP equipment and avoiding IV tubing containing DEHP.

Di (2-ethylhexyl) phthalate (DEHP) is a widely used plastic additive. As an environmental endocrine disruptor, it has been shown to be harmful to the mammalian reproductive system. Previous studies indicated that DEHP inhibited the development of mouse ovarian follicles. However, the mechanisms by which DEHP affects ovarian antral follicle development during the pre-puberty stage are poorly understand. Thus, we investigated the effects of direct DEHP exposure on antral follicle growth in pre-pubescent mice by use of intraperitoneal injection. Our results demonstrated that the percentage of large antral follicles was significantly reduced when mice were exposed to 20 or 40 μg/kg DEHP every 5 days from postnatal day 0 (0 dpp) to 15 dpp. In 20 dpp, we performed microarray of these ovaries. The microarray results indicated that mRNA levels of apoptosis related genes were increased. The mRNA levels of the apoptosis and cell proliferation (negative) related genes Apoe, Agt, Glo1 and Grina were increased after DEHP exposure. DEHP induced the differential gene expression of Hsp90ab1, Rhoa, Grina and Xdh which may play an important role in this process. In addition, TUNEL staining and immunofluorescence showed that DEHP exposure significantly increased the number of TUNEL, Caspase3 and γH2AX positive ovarian somatic cells within the mouse ovaries. Flow cytometer analyses of redox-sensitive probes showed that DEHP caused the accumulation of reactive oxygen species. Moreover, the mRNA expression of ovarian somatic cell antioxidative enzymes was down-regulated both in vivo and in vitro. In conclusion, our data here demonstrated that DEHP exposure induced oxidative stress and ovarian somatic cell apoptosis, and thus may impact antral follicle enlargement during the pre-pubertal stage in mice.

Increased plasma levels of phthalate esters in women with advanced-stage endometriosis: a prospective case-control study

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. 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. 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. Our results demonstrated that urinary MEHP% may be a potential biomarker of DEHP contamination from the use of PVC-containing catheters or infusion systems.

Exposure to Phthalate Esters

Di (2-ethylhexyl) phthalate reduces sperm motility by decreasing sperm tail energy supply.

Di(2-ethylhexyl) phthalate (DEHP), an environmental endocrine disruptor, has hormone-like activity and endocrine-disrupting effects. However, the types of reproductive hormones associated with DEHP vary across the studies. Thus, we conducted a systematic review and meta-analysis to pool existing epidemiological evidence. We searched three databases up to January 31, 2024, for eligible original studies to ultimately include 37 studies from eight countries with a total of 28 911 participants. DEHP exposure was evaluated with urinary metabolites. Since the main types, production sites, blood concentrations, and functions of reproductive hormones differ between men and women, we reported the combined effect values by gender. Subgroup analyses were conducted by age, subfertility status, and the national sociodemographic index (SDI) level. Furthermore, the effect of maternal exposure during pregnancy on children's reproductive hormone levels was analyzed separately. Overall, in general, in men, DEHP was positively correlated with sex hormone binding-globulin (SHBG) and adversely correlated with total testosterone (TT), free androgen index (FAI), and follicle-stimulating hormone (FSH). Results indicated that among men of reproductive age, DEHP exposure was associated with more significant hormonal suppression in infertile men compared with fertile men. Notably, age subgroup analysis among women revealed that postmenopausal women were more vulnerable to DEHP, which was related to lower TT and estradiol (E2). However, this study did not observe a significant association between prenatal DEHP metabolites and reproductive hormone levels in children. Our research identifies the most susceptible hormones (androgen suppression) after DEHP exposure and suggests that infertile men and postmenopausal women are in great need of more attention as sensitive populations.

The male reproductive system has been the subject of considerable attention in recent years due to the adverse effects of Di (2-ethylhexyl) phthalate (DEHP). Although previous research has suggested that DEHP exposure hinders the early meiotic progression of male germ cells, the underlying mechanisms are still not well understood. The transcriptomic changes in testicular cells of postnatal male rodents following DEHP exposure were meticulously analyzed using 10X Genomics single-cell RNA sequencing in this study. For downstream analysis, we acquired 42,000 cells and generated 3172,754,990 reads. DEHP exposure at concentrations of 40 μg/kg/day (DEHP40) and 80 μg/kg/day (DEHP80) substantially decreased the proportion of pachytene and diplotene spermatocytes, indicating a shared inhibitory effect on early meiosis, as demonstrated by our findings. In addition, DEHP exposure disrupted the cellular communication between Sertoli cells and germ cells, which had a significant impact on the p38-MAPK signaling pathway. The expression of key ligand genes Tgfb1 and Tgfb3 in Sertoli cells was significantly reduced. DEHP exposure resulted in a substantial decrease in the expression of the Trp53 gene, which in turn down-regulated three critical downstream genes (Stmn1, Tubb5, and Ccnb1) that are implicated in spindle organization from a mechanistic perspective. This study offers the first comprehensive evidence that DEHP inhibits early meiotic progression in male germ cells through the Trp53-mediated p38-MAPK pathway, providing crucial insights into the molecular mechanisms underlying DEHP-induced male reproductive toxicity. Our results emphasize the enduring negative effects of DEHP exposure on male fertility, which have substantial ramifications for the comprehension and mitigation of the influence of environmental estrogens on reproductive health.

This research was performed to estimate the potential effects of Di (2-ethylhexyl) phthalate (DEHP) on changes of ovarian miRNA expression profile during mouse primordial follicle assembly using miRNAs-seq analysis. The ovaries of newborn mice were collected and in vitro cultured with different concentration of DEHP for 72 h. Then they were prepared for miRNAs-seq analysis. The results indicated that DEHP exposure altered ovarian miRNA expression profile of newborn mice. Eighteen differentially expressed miRNAs were screened after 100 μM DEHP exposure. The target mRNAs of differentially expressed miRNAs were predicted and further analyzed through gene ontology (GO) enrichment analysis and pathway enrichment analysis. Our results showed that the differentially expressed miRNAs from DEHP exposure can regulate ovarian development by targeting mRNAs involved in MAPK, mTOR, FoxO signaling pathways. Three miRNAs of miR-32-5p, miR-19a-3p, and miR-141-3p were randomly selected from the differentially expressed miRNAs to quantify their expression level by miRNA qRT-PCR. The results of qRT-PCR and miRNA-seq were consistent. Considering one of its target gene PTEN of miR-19a-3p and the decreased level of pAKT and increased Bax/Bcl-2 under DEHP exposure, we speculated that the altered expression of miR-19a-3p by DEHP exposure affected mouse primordial follicle assembly via PI3K/AKT1/mTOR signaling pathway. Epigenetic changes are one of the most important targets of toxicant exposure. The effects of DEHP exposure on microRNA (one of the epigenetic regulators) expression profile were uncovered to enrich the research on relationship of epigenetics and toxicant exposure.

Human Exposure Estimates for Phthalates

Animal studies have linked di(2-ethylhexyl) phthalate (DEHP) with reproductive and developmental toxicity, and have demonstrated an especially pronounced effect on testicular development when administered postnatally. Previous research has shown that newborns treated at neonatal intensive care units (NICUs) may receive doses of DEHP at 2–3 times the average daily adult exposure, and that these infants have relatively high urinary levels of the DEHP metabolite mono(2-ethylhexyl) phthalate (MEHP). Now researchers, using urinary MEHP as a biomarker of DEHP exposure, demonstrate for the first time that the more DEHP-containing devices are used in treating an infant, the more DEHP makes its way into the infant’s body [EHP 113:1222–1225]. Human DEHP exposure is widespread but generally much lower than the levels causing harm in animal studies. However, certain circumstances such as intensive medical treatment can result in higher-than-average exposure, which may be a particular risk for newborn males. DEHP is added to polyvinyl chloride (PVC) plastics for use in medical equipment including IV bags, blood bags, and various types of tubing, as well as many industrial and consumer PVC products. DEHP does not chemically link to PVC and leaches into fluids (such as blood and saline solution) that contact the plastic. The amount of leaching depends upon factors such as type of fluid, length of storage, and temperature. The study involved 54 newborn girls and boys receiving treatment at two Boston-area NICUs between 1 March and 30 April 2003. The infants had been admitted for various reasons, and treatment included procedures such as mechanical ventilation, enteral feedings, and cardiac catheterization. Prior to visiting the NICUs, the researchers defined low, medium, and high DEHP exposure categories based upon typical NICU procedures and equipment. Infants whose treatment consisted primarily of bottle and/or gavage feedings composed the low-exposure group. Infants in the medium-exposure group received more invasive therapies involving equipment such as an indwelling gavage tube or umbilical vein catheter. High-exposure infants experienced multiple and simultaneous invasive treatments, including endotracheal intubation and continuous umbilical vein catheterization. One researcher visited the NICUs and observed each infant for 3–12 hours over the course of 1–3 days (more than one infant was observed at a time). During the observational visits, the researcher noted the equipment being used for each infant, then assigned the infant to an exposure group accordingly. At the end of each visit, urine samples were collected for MEHP measurement. The researchers detected 10 phthalate metabolites in the samples, including 3 associated with DEHP, but focused on MEHP for data analysis since this metabolite is well studied and a proven biomarker of DEHP exposure. MEHP levels ranged from less than the level of detection to 758 nanograms per milliliter and did not vary substantially between multiple individual samples. Between the two NICUs there were 13, 24, and 17 infants in the low-, medium-, and high-exposure groups, respectively. The researchers found that infants in the high-exposure group had MEHP levels five times higher than those in the low-exposure group. MEHP levels for medium-exposure infants were twice those of the low-exposure group. The researchers indicate that the MEHP levels seen in this study are similar to those previously reported for NICU infants and higher than those reported for older children; no data are available for infants who did not need NICU care. The relevance of these exposures to health effects is unknown, and the researchers urge larger, more comprehensive studies with follow-up to determine consequences of DEHP exposure related to NICU treatment.

Di (2-ethylhexyl) phthalate (DEHP), is the most common member of the class of phthalates that are used as plasticizers and have become common environmental contaminants. A number of studies have shown that DEHP exposure impacts reproductive health in both male and female mammals by acting as an estrogen analog. Here, we investigated the effects of DEHP on meiotic progression of fetal mouse oocytes by using an in vitro model of ovarian tissue culture. The results showed that 10 or 100 μM DEHP exposure inhibited the progression of oocytes throughout meiotic prophase I, specifically from the pachytene to diplotene stages. DEHP possibly impairs the ability to repair DNA double-strand breaks induced by meiotic recombination and as a consequence activates a pachytene check point. At later stages, such defects led to an increased number of oocytes showing apoptotic markers (TUNEL staining, expression of pro-apoptotic genes), resulting in reduced oocyte survival, gap junctions, and follicle assembly in the ovarian tissues. Microarray analysis of ovarian tissues exposed to DEHP showed altered expression of several genes including some involved in apoptosis and gonad development. The expression changes of some genes clustered in cell-cell communication and signal transduction, along with plasma membrane, extracellular matrix and ion channel function classes, were dependent on the DEHP concentration. Together, these results bring new support to the notion that exposure to DEHP during gestation might exert deleterious effects on ovary development, perturbing germ cell meiosis and the expression of genes involved in a wide range of biological processes including ovary development.