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Environment International Jun 2022The obesity pandemic is presumed to be accelerated by endocrine disruptors such as phthalate-plasticizers, which interfere with adipose tissue function. With the...
Di-(2-ethylhexyl) phthalate substitutes accelerate human adipogenesis through PPARγ activation and cause oxidative stress and impaired metabolic homeostasis in mature adipocytes.
The obesity pandemic is presumed to be accelerated by endocrine disruptors such as phthalate-plasticizers, which interfere with adipose tissue function. With the restriction of the plasticizer di-(2-ethylhexyl)-phthalate (DEHP), the search for safe substitutes gained importance. Focusing on the master regulator of adipogenesis and adipose tissue functionality, the peroxisome proliferator-activated receptor gamma (PPARγ), we evaluated 20 alternative plasticizers as well as their metabolites for binding to and activation of PPARγ and assessed effects on adipocyte lipid accumulation. Among several compounds that showed interaction with PPARγ, the metabolites MINCH, MHINP, and OH-MPHP of the plasticizers DINCH, DINP, and DPHP exerted the highest adipogenic potential in human adipocytes. These metabolites and their parent plasticizers were further analyzed in human preadipocytes and mature adipocytes using cellular assays and global proteomics. In preadipocytes, the plasticizer metabolites significantly increased lipid accumulation, enhanced leptin and adipsin secretion, and upregulated adipogenesis-associated markers and pathways, in a similar pattern to the PPARγ agonist rosiglitazone. Proteomics of mature adipocytes revealed that both, the plasticizers and their metabolites, induced oxidative stress, disturbed lipid storage, impaired metabolic homeostasis, and led to proinflammatory and insulin resistance promoting adipokine secretion. In conclusion, the plasticizer metabolites enhanced preadipocyte differentiation, at least partly mediated by PPARγ activation and, together with their parent plasticizers, affected the functionality of mature adipocytes similar to reported effects of a high-fat diet. This highlights the need to further investigate the currently used plasticizer alternatives for potential associations with obesity and the metabolic syndrome.
Topics: Adipocytes; Adipogenesis; Diethylhexyl Phthalate; Homeostasis; Humans; Lipids; Obesity; Oxidative Stress; PPAR gamma; Phthalic Acids; Plasticizers
PubMed: 35567983
DOI: 10.1016/j.envint.2022.107279 -
Environmental Health Perspectives Jul 2023We have previously shown that chronic exposure of adult male mice to low doses of di(2-ethylhexyl) phthalate (DEHP) altered male sexual behavior and induced...
BACKGROUND
We have previously shown that chronic exposure of adult male mice to low doses of di(2-ethylhexyl) phthalate (DEHP) altered male sexual behavior and induced down-regulation of the androgen receptor (AR) in the neural circuitry controlling this behavior.
OBJECTIVES
The cellular mechanisms induced by chronic exposure of adult male mice to low doses of DEHP alone or in an environmental phthalate mixture were studied.
METHODS
Two-month-old C57BL/6J males were exposed orally for 8 wk to DEHP alone (0, 5, or ) or to DEHP () in a phthalate mixture. Behavior, dendritic density per length, pre-/postsynaptic markers, synapse ultrastructure, and bioenergetic activity were analyzed.
RESULTS
Mice exposed to DEHP either alone or in a phthalate mixture differed in mating, emission of ultrasonic vocalizations, and the ability to attract receptive females in urinary preference tests from control mice. Analyses in the medial preoptic area, the key hypothalamic region involved in male sexual behavior, showed lower dendritic spine density and protein levels of glutamate receptors and differences in other postsynaptic components and presynaptic markers between the treated groups. Ultrastructural observation of dendritic synapses by electron microscopy showed comparable morphology between the treated groups. Metabolic analyses highlighted differences in hypothalamic metabolites of males exposed to DEHP alone or in a phthalate mixture compared to control mice. These differences included lower tryptophan and higher levels, respectively, a precursor and end product of the kynurenine pathway of tryptophan metabolism. The protein amounts of the xenobiotic aryl hydrocarbon receptor, one of the targets of this metabolic pathway and known negative regulator of the AR, were higher in the medial preoptic area of exposed male mice.
DISCUSSION
Differences in behavior of male mice exposed to environmental doses of phthalates were associated with differences in neural structure and metabolism, with possibly a key role of the kynurenine pathway of tryptophan metabolism in the effects mediated by these substances. https://doi.org/10.1289/EHP11514.
Topics: Female; Mice; Animals; Male; Diethylhexyl Phthalate; Tryptophan; Kynurenine; Mice, Inbred C57BL; Phthalic Acids
PubMed: 37458746
DOI: 10.1289/EHP11514 -
Environment International Mar 2023Di-2-ethylhexyl phthalate (DEHP) and its substitute 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) are widely used as plasticizers but may have adverse...
Di-2-ethylhexyl phthalate (DEHP) and its substitute 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) are widely used as plasticizers but may have adverse health effects. Via hydrolysis of one of the two ester bonds in the human body, DEHP and DINCH form the monoesters MEHP and MINCH, respectively. Previous studies demonstrated binding of these metabolites to PPARγ and the induction of adipogenesis via this pathway. Detailed structural understanding of how these metabolites interact with PPARγ and thereby affect human health is lacking until now. We therefore characterized the binding modes of MINCH and MEHP to the ligand binding domain of PPARγ by X-ray crystallography and molecular dynamics (MD) simulations. Both compounds bind to the activating function-2 (AF-2) binding site via an interaction of the free carboxylates with the histidines 323 and 449, tyrosine 473 and serine 289. The alkyl chains form hydrophobic interactions with the tunnel next to cysteine 285. These binding modes are generally stable as demonstrated by the MD simulations and they resemble the complexation of fatty acids and their metabolites to the AF-2 site of PPARγ. Similar to the situation for these natural PPARγ agonists, the interaction of the free carboxylate groups of MEHP and MINCH with tyrosine 473 and surrounding residues stabilizes the AF-2 helix in the upward conformation. This state promotes binding of coactivator proteins and thus formation of the active complex for transcription of the specific target genes. Moreover, a comparison of the residues involved in binding of the plasticizer metabolites in vertebrate PPARγ orthologs shows that these compounds likely have similar effects in other species.
Topics: Humans; Plasticizers; Diethylhexyl Phthalate; PPAR gamma; Furylfuramide; Phthalic Acids
PubMed: 36841188
DOI: 10.1016/j.envint.2023.107822 -
Ecotoxicology and Environmental Safety Apr 2023Diisononyl phthalate (DINP), a mixture of chemical compounds composed of diverse isononyl esters of phthalic acid, is commonly applied as a plasticizer to substitute for...
Diisononyl phthalate (DINP), a mixture of chemical compounds composed of diverse isononyl esters of phthalic acid, is commonly applied as a plasticizer to substitute for di (2-ethylhexyl) phthalate (DEHP). It has been demonstrated that DINP exposure impairs the functions of kidney and liver in animals. However, the effects and potential mechanisms of DINP exposure on the female reproduction, especially the oocyte quality are still poorly understood. Here, we discovered that DINP exposure weakened the porcine oocyte meiotic competency (78.9% vs 53.6%, P < 0.001) and fertilization ability (78.5% vs 34.1%, P < 0.0001) during in vitro maturation. Specifically, DINP exposure induced the persistent spindle assembly checkpoint (SAC) activation caused by the disorganized spindle/chromosome apparatus (spindle: 20.0% vs 83.3%, P < 0.001; chromosome: 20.0% vs 80.0%, P < 0.01) to arrest meiotic progression of oocytes at metaphase I stage. In addition, DINP exposure disturbed the dynamics of sperm binding (146.7 vs 58.6, P < 0.0001) and fusion proteins (19.5 vs 11.6, P < 0.0001) in oocytes to compromise their fertilization ability. In particular, transcriptome data uncovered that the action mechanism of DINP on the oocyte maturation was associated with oxidative phosphorylation, apoptosis and autophagy pathways. Lastly, we validated that DINP exposure resulted in the mitochondrial dysfunction (27.2 vs 19.8, P < 0.0001) and elevated levels of reactive oxygen species (ROS; 8.9 vs 19.9, P < 0.0001) to trigger the occurrence of apoptosis (7.2 vs 13.1, P < 0.0001) and protective autophagy (68.6 vs 139.3, P < 0.01). Altogether, our findings not only testify that DINP has a potentially adverse impact on the mammalian oocyte quality, but also provide a scientific reference regarding how environment pollutants act on the female germ cell development.
Topics: Male; Female; Swine; Animals; Diethylhexyl Phthalate; Semen; Phthalic Acids; Oocytes; Apoptosis; Mammals
PubMed: 36917878
DOI: 10.1016/j.ecoenv.2023.114768 -
Reproductive Toxicology (Elmsford, N.Y.) Mar 2022Phthalates are chemicals used in products including plastics, personal care products, and building materials, leading to widespread contact. Previous studies on prenatal...
Phthalates are chemicals used in products including plastics, personal care products, and building materials, leading to widespread contact. Previous studies on prenatal exposure to Di-(2-ethylhexyl) phthalate (DEHP) in mice and humans demonstrated pubertal timing and reproductive performance could be affected in exposed offspring. However, the impacts at the pituitary, specifically regarding signaling pathways engaged and direct effects on the gonadotropins LH and FSH, are unknown. We hypothesized prenatal exposure to DEHP during a critical period of embryonic development (e15.5 to e18.5) will cause sex-specific disruptions in reproduction-related mRNA expression in offspring's pituitary due to interference with androgen and aryl hydrocarbon receptor (AhR) signaling. We found that prenatal DEHP exposure in vivo caused a significant increase in Fshb specifically in males, while the anti-androgen flutamide caused significant increases in both Lhb and Fshb in males. AhR target gene Cyp1b1 was increased in both sexes in DEHP-exposed offspring. In embryonic pituitary cultures, the DEHP metabolite MEHP increased Cyp1a1 and Cyp1b1 mRNA in both sexes and Cyp1b1 induction was reduced by co-treatment with AhR antagonist. AhR reporter assay in GHFT1 cells confirmed MEHP can activate AhR signaling. Lhb, Fshb and Gnrhr mRNA were significantly decreased in both sexes by MEHP, but co-treatment with AhR antagonist did not restore mRNA levels in pituitary culture. In summary, our data suggest phthalates can directly affect the function of the pituitary by activating AhR signaling and altering gonadotropin expression. This indicates DEHP's impacts on the pituitary could contribute to reproductive dysfunctions observed in exposed mice and humans.
Topics: Animals; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1B1; Diethylhexyl Phthalate; Female; Follicle Stimulating Hormone, beta Subunit; Gene Expression; Luteinizing Hormone, beta Subunit; Male; Maternal-Fetal Exchange; Mice; Pituitary Gland; Plasticizers; Pregnancy; Prenatal Exposure Delayed Effects; Receptors, Aryl Hydrocarbon; Reproduction
PubMed: 34954075
DOI: 10.1016/j.reprotox.2021.12.008 -
Environmental Health Perspectives Feb 2003Phthalates are high-production-volume synthetic chemicals with ubiquitous human exposures because of their use in plastics and other common consumer products. Recent... (Review)
Review
Phthalates are high-production-volume synthetic chemicals with ubiquitous human exposures because of their use in plastics and other common consumer products. Recent epidemiologic evidence suggests that women have a unique exposure profile to phthalates, which raises concern about the potential health hazards posed by such exposures. Research in our laboratory examines how phthalates interact with the female reproductive system in animal models to provide insights into the potential health effects of these chemicals in women. Here we review our work and the work of others studying these mechanisms and propose a model for the ovarian action of di-(2-ethylhexyl) phthalate (DEHP). In vivo, DEHP (2 g/kg) causes decreased serum estradiol levels, prolonged estrous cycles, and no ovulations in adult, cycling rats. In vitro, monoethylhexyl phthalate (MEHP; the active metabolite of DEHP) decreases granulosa cell aromatase RNA message and protein levels in a dose-dependent manner. MEHP is unique among the phthalates in its suppression of aromatase and in its ability to activate peroxisome proliferator-activated receptors (PPARs). We hypothesize that MEHP activates the PPARs to suppress aromatase in the granulosa cell. MEHP-, PPAR alpha-, and PPAR gamma-specific ligands all similarly decreased estradiol production and RNA message levels of aromatase in vitro. Our model shows that MEHP acts on the granulosa cell by decreasing cAMP stimulated by follicle stimulating hormone and by activating the PPARs, which leads to decreased aromatase transcription. Thus, the environmental contaminant DEHP, through its metabolite MEHP, acts through a receptor-mediated signaling pathway to suppress estradiol production in the ovary, leading to anovulation.
Topics: Animals; Cyclic AMP; Diethylhexyl Phthalate; Disease Models, Animal; Esters; Estradiol; Estrus; Female; Granulosa Cells; Humans; Ovary; Ovulation; Phthalic Acids; Rats
PubMed: 12573895
DOI: 10.1289/ehp.5658 -
Molecules (Basel, Switzerland) Jun 2022The concentration levels of thirteen organic pollutants and selected heavy metals were investigated in 40 plastics bottled and tap water samples. Some of the selected...
The concentration levels of thirteen organic pollutants and selected heavy metals were investigated in 40 plastics bottled and tap water samples. Some of the selected contaminants have an ascertained or suspected endocrine disrupting activity, such as Bisphenol A (BPA) and its analogs, and Bis 2-ethylhexyl phthalate (DEHP), which are used by industries as plasticizers. The most frequently detected pollutants were Bisphenol AF (BPAF) (detection frequency (DF) = 67.5%, mean 387.21 ng L), DEHP (DF = 62.5%, mean 46.19 µg L) and BPA (DF = 60.0%, mean 458.57 ng L), with higher concentration levels found in tap waters. Furthermore, a possible level of exposure to thirteen pollutants via drinking water intake was calculated. Our findings show that, even though the occurrence of contaminants and heavy metals in drinking waters does not pose an immediate, acute health risk for the population, their levels should be constantly monitored and "hard-wired" into everyday practice. Indeed, the health impact to the continuous and simultaneous intake of a huge variety of xenobiotics from various sources by humans is complex and still not fully understood.
Topics: Benzhydryl Compounds; Diethylhexyl Phthalate; Drinking Water; Endocrine Disruptors; Environmental Pollutants; Humans; Plasticizers; Plastics; Water Pollutants, Chemical
PubMed: 35807230
DOI: 10.3390/molecules27133990 -
Journal of Insect Physiology Sep 2023Environmental plastic pollution has significantly increased in the recent decades, and severely impacts economies, human and biodiversity health. Plastics are made of...
Environmental plastic pollution has significantly increased in the recent decades, and severely impacts economies, human and biodiversity health. Plastics are made of several chemical additives, including bisphenol and phthalate plasticizers such as bisphenol A (BPA) and Di(2-ethylhexyl)phthalate (DEHP). In some animal species, both BPA and DEHP are known as endocrine disruptor compounds, and can alter physiological and metabolic homeostasis, reproduction, development and/or behavior. To date, the impacts of BPA and DEHP have mainly focused on vertebrates, and to a lesser extent, on aquatic invertebrates. Yet, the few studies which examined the effects of DEHP on terrestrial insects also revealed the impacts this pollutant can have on development, hormone titrations, and metabolic profiles. In particular, it has been hypothesized in the Egyptian cotton leafworm Spodoptera littoralis that the observed metabolic alterations could result from the energetic costs necessary for DEHP detoxification or to the dysregulation of hormonally-controlled enzymatic activities. To get additional insights into the physiological effects of bisphenol and phthalate plasticizers on the moth S. littoralis, larvae were fed with food contaminated by BPA, DEHP, or the mixture of both compounds. Then, activities of four glycolytic enzymes, hexokinase, phosphoglucose isomerase, phosphofructokinase, and pyruvate kinase were measured. BPA and/or DEHP had no effects on the activities of phosphofructokinase and pyruvate kinase. Conversely, BPA-contaminated larvae were characterized by a 1.9-fold increase in phosphoglucose isomerase activity, and BPA + DEHP-fed larvae had highly variable hexokinase activity. Overall, since no disruption of glycolytic enzyme was observed in DEHP-contaminated larvae, our work tended to demonstrate that exposure to bisphenol and DEHP increased the amount of oxidative stress experienced.
Topics: Humans; Animals; Plasticizers; Diethylhexyl Phthalate; Spodoptera; Moths; Pyruvate Kinase; Glucose-6-Phosphate Isomerase; Hexokinase; Larva; Phosphofructokinases
PubMed: 37380125
DOI: 10.1016/j.jinsphys.2023.104533 -
Journal of Toxicology and Environmental... 2018Male reproductive alterations found in animals and humans following in utero phthalate exposure include decreased anogenital distance (AGD) and other reproductive-tract... (Meta-Analysis)
Meta-Analysis
Male reproductive alterations found in animals and humans following in utero phthalate exposure include decreased anogenital distance (AGD) and other reproductive-tract malformations. The aim of this investigation was to conduct systematic reviews of human and animal evidence of the effect of in utero exposure to diethylhexyl phthalate (DEHP) on anogenital distance (AGD) in males. PubMed, Embase, and Toxline were searched for relevant human and experimental animal studies on August 15, 2016. Search results were screened for relevance, and studies that met the inclusion criteria were evaluated for quality and data extracted for analysis. Confidence in the human and animal bodies of evidence was assessed and hazard conclusions reached by integrating evidence streams. The search yielded 6 relevant human studies and 19 animal studies. Meta-analysis of 5 human observational prospective cohort studies showed that increased maternal urinary concentrations of DEHP metabolites were associated with decreased AGD in boys (-4.07 [CI, -6.49 to -1.66] % decrease per log rise in DEHP metabolites). Meta-analysis and meta-regression of the 19 experimental animal studies found reduced AGD with DEHP treatment, with a dose-response gradient, and with heterogeneity explained by species and strain. There is a moderate level of evidence from human investigations and a high level of data from animal studies that in utero exposure to DEHP decreases AGD. Based upon the available human and animal evidence, and consideration of mechanistic data, DEHP is presumed to be a reproductive hazard to humans on the basis of effects on AGD.
Topics: Animals; Diethylhexyl Phthalate; Environmental Pollutants; Female; Genitalia, Male; Humans; Male; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 30199328
DOI: 10.1080/10937404.2018.1505354 -
Environment International Nov 2020Infantile development of phthalate metabolism is crucial for risk assessment of endocrine disruption and has important toxico/pharmacokinetic implications.
BACKGROUND
Infantile development of phthalate metabolism is crucial for risk assessment of endocrine disruption and has important toxico/pharmacokinetic implications.
OBJECTIVES
To characterize temporal variability in urinary phthalate metabolites in infants and to examine their growth-dependent detoxification.
METHODS
In this cohort study, urine samples (n = 876) from 155 healthy Chinese infants were collected serially at eight time points from birth to one year old. Free and total (i.e., free plus glucuronide conjugated) phthalate metabolites (PMEs) were measured by LC/MS/MS. Time variability in PMEs and PME metabolism capacity was characterized using intraclass correlation coefficients (ICCs) and linear mixed regression models.
RESULTS
Concentrations of most PMEs changed significantly, with ICCs ranging from 0.213 to 0.318, and trends increased significantly over time (p < 0.001), while MEHP showed fair reproducibility (ICC = 0.480). Glucuronidation increased considerably (ICC ≤ 0.250; p < 0.001) for most PMEs but not for MMP or MEHP. Ester-chain ω-/ω-1-oxidation and α-/β-oxidation patterns of MEHP steeply increased from 3 months to 8 months, where they peaked, resulting in a molar percentage of MEHP in ΣDEHP showing the inversion pattern. MEHP detoxification through oxidation of the hydrophobic ester-chain is apparently a priority for carboxyl glucuronidation in infants.
CONCLUSIONS
Infant phthalate exposure is prevalent, but they cannot metabolize or eliminate these compounds as efficiently as adults, especially during the first 6 months of life. From an environmental biomonitoring view, age-dependent phthalate metabolism provides crucial implications for infantile ontogeny and health risk assessment within the first year of life.
Topics: Adult; Cohort Studies; Diethylhexyl Phthalate; Environmental Exposure; Environmental Pollutants; Humans; Infant; Phthalic Acids; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 32822925
DOI: 10.1016/j.envint.2020.106052