Fig 1 - uploaded by Byung Mu Lee
Content may be subject to copyright.
Source publication
Di(2-ethylhexyl) phthalate (DEHP) used as a common plasticizer additive in the manufacture of plastics, such as polyvinyl chloride (PVC). This study examined the effect of DEHP on steroidogenesis or spermatogenesis in the testes of Sprague-Dawley male rats treated orally with 250, 500, 750 mg/kg over a 30-day period. The ex- pression levels of the...
Similar publications
Plasticizers added to polyvinylchloride (PVC) used in medical devices can be released into patients’ biological fluids. Di-(2-ethylhexyl)phthalate (DEHP), a well-known reprotoxic and endocrine disruptor, must be replaced by alternative compounds. Di-(2-ethylhexyl) terephthalate (DEHT) is an interesting candidate due to its lower migration from PVC...
Citations
... In mammals, previous studies indicate that DEHP has the potential to induce a wide range of reproductive impairments, including the disruption of spermatogenesis, imbalanced steroid hormone levels, and infertility in males [17][18][19][20][21][22][23][24][25][26]. However, very few studies have revealed the effects of DEHP on the male reproductive systems of aquatic organisms such as fish. ...
In this study, we evaluated gamete quality parameters of mature male koi carp (Cyprinus carpio)
exposed to three different concentrations (1, 10, and 100 µg/L) of di-(2-ethylhexyl) phthalate (DEHP).
After 60 days of exposure, there was a significant decrease in the gonadosomatic index (GSI) of
males exposed to 10 and 100 µg/L of DEHP. Histological analysis of the testes revealed impaired
histoarchitecture, including inflammatory cells, intratubular vacuoles, and swollen seminiferous
tubules in treatment groups. Gamete quality parameters like sperm production, motility, spermatocrit,
and sperm density values were significantly decreased at the 10 and 100 µg/L concentrations.
Biochemical compositions, including glucose, cholesterol, and total protein levels, were significantly
changed in the treatment groups. Similarly, the ionic compositions of seminal fluid (Na, K, Ca, and
Mg) also varied in the treatment groups. Furthermore, the 11-ketotestosterone levels were decreased,
and the 17-β estradiol levels were increased in the DEHP-treated groups. The mRNA expression
levels of reproduction-related genes, including Fshr, Lhr, Ar, Erα, and Erβ, were significantly changed
in the DEHP-treated males in a dose-dependent manner. In conclusion, the findings of this study
confirmed that environmentally relevant exposure to DEHP may contribute to a decline in the gamete
quality of male fishes.
... Similar phenotypes caused by DEHP exposure were found in both fish and mammals; Sprague-Dawley rats treated with DEHP (oral gavage of 250, 500, 750 mg/kg over a 30-day period) displayed decreased testicular sperm count, and reductions in daily sperm production (DSP), and serum testosterone levels [108]. Further studies in mice have indicated that these changes are the result of epigenetic changes in mouse sperm cells [109]. ...
Exposure to Endocrine Disrupting Chemicals (EDC) has been linked with several adverse outcomes. In this review, we examine EDCs that are pervasive in the environment and are of concern in the context of human, animal, and environmental health. We explore the consequences of EDC exposure on aquatic life, terrestrial animals, and humans. We focus on the exploitation of genomics technologies and in particular whole transcriptome sequencing. Genome-wide analyses using RNAseq provides snap shots of cellular, tissue and whole organism transcriptomes under normal physiological and EDC perturbed conditions. A global view of gene expression provides highly valuable information as it uncovers gene families or more specifically, pathways that are affected by EDC exposures, but also reveals those that are unaffected. Hypotheses about genes with unknown functions can also be formed by comparison of their expression levels with genes of known function. Risk assessment strategies leveraging genomic technologies and the development of toxicology databases are explored. Finally, we review how the Adverse Outcome Pathway (AOP) has exploited this high throughput data to provide a framework for toxicology studies.
... Different from the increased plasma T levels in our research, previous studies reported that exposure to DEHP could cause the decreased plasma T levels, which were accompanied by the down-regulated expression of genes encoding steroid biosynthesis proteins (star, cyp11a, 3bhsd, cyp17, and cyp19a) in fish (Ahmadivand et al., 2016;Ma et al., 2018). Interestingly, the decreased plasma T levels accompanied by significantly increased expression of steroidogenic genes, including star, have been reported in phthalate-exposure in rats (Culty et al., 2008;Lee et al., 2009). Therefore, other mechanisms of altered plasma hormone levels caused by phthalate exposure need to be further studied. ...
... PPARs showed upregulated mRNA expression in BPA treated groups in comparison to control but a dose-specific decrease in mRNA expression from lower to higher dose was observed. Similarly, Lee et al. (2009) have reported a significant decrease in expression of PPARs in relation to the effect of di-2ethylhexyl phthalate (DEHP) on the regulation of steroidogenesis and spermatogenesis in Sprauge Dawley rats. PPARs are reported as significant factors affecting sperm physiology, energy dissipation and motility indices Badr et al., 2018). ...
... Our findings suggest that exposure to DEHP may affect the estrous cycle and steroidogenesis, decrease sperm counts, sperm production and sperm cells viability in a dose dependent manner, these results being in accordance with the study carried out by Lee JY et al. (34). ...
Objective:
To study the effect of diethylhexyl phthalate (DEHP) alone or in combination with genistein (GEN) on the reproductive system of offspring rats, focus on the induction of reproductive outcomes.
Method:
180 Wistar rats were divided in 6 groups (30 animals per group): DEHP 250 mg/kg/day group, DEHP 1000 mg/kg/day group, DEHP 2500 mg/kg/day group treated with DEHP 2500 mg/kg/day, DEHP (2500 mg/kg) + GEN (50 mg/kg) group, DEHP (2500 mg/kg) + GEN (500 mg/kg) group and control group treated with the same quantity of corn oil. The differences in sperm quality and reproductive organs were observed.
Results:
After DEHP administration we observed an increase in rat's abestrus, metaestrus and all estrus cycle (P < 0.05), a decrease in rat testicle's organ coefficient and relative energy of testis Sertoli cells and an increase in the early, late and total apoptotic rate of testicular Sertoli cells in a dose dependent manner (P < 0.05). When combine DEHP with GEN the sperm density, sperm quality, the cell activity rate and testis tissue's changes will decrease compared with the group that receive only DEHP in a dose dependent manner.
Conclusion:
DEHP exposure induces cryptorchidism in offspring rats and this is aggravated by adding GEN.
... However, it is still unknown whether DEHP-reduced male fertility is corresponding to DEHP effects on sperm production, motility and velocity, which are key determinants for male fertility in fish (Billard et al., 1995;Alavi and Cosson, 2006;Linhart et al., 2008). In mammals, DEHP-reduced male fertility is associated with decrease in sperm production (Andrade et al., 2006a;Foster, 2006;Lee et al., 2009). Thibaut and Porte (2004) reported that DEHP inhibits 5␣dihydrotestosterone synthesis in fish in vitro; a potent androgen that binds to androgen receptor (ar). ...
... Overall, inhibitory effects of DEHP on androgen production are largely unknown in fish and none of the former studies have investigated 11-ketotestosterone (11-KT) levels, which is the major androgen in spermatogenesis (Miura and Miura, 2003). In mammals, in prepubertal and in utero DEHP exposure decreases T levels at 10-750 mg/kg/d in male rats which was associated with changes in circulatory luteinizing hormone (LH) levels and StAR mRNA levels (Parks et al., 2000;Akingbemi et al., 2001Akingbemi et al., , 2004Ge et al., 2007;Howdeshell et al., 2007;Culty et al., 2008;Lee et al., 2009;Hannas et al., 2012). ...
... However, DEHP does not affect the GnRH and Kiss-1/Gpr54 system. Sperm production was decreased in DEHP treated goldfish, which is consistent with earlier studies on mammals (Lee et al., 2009;Vo et al., 2009;Pocar et al., 2012). However, GSI in DEHP treated goldfish was not different from that of the control, while it was significantly decreased in E 2 treated goldfish. ...
... Finally, T can be transformed into E2 by 677 CYP19. Dramatic decreases in cyp19 transcript levels were 678 observed in a human adrenocortical carcinoma cell line, in rodents 679 treated with DEHP and MEHP (Gupta et al., 2010a;Lee et al., 2009;680 Lovekamp and Davis, 2001;Noda et al., 2007;Xu et al., 2010). In 681 addition, Wistar rat male pups exposed to DEHP during gestation 682 and lactation showed decreased CYP19 activity at low doses and 683 increased activity at high doses (Andrade et al., 2006). ...
... Several studies reviewed the effects of phthalates in mam-760 malian reproduction (Ema, 2002;Hotchkiss et al., 2008;Makris 761 et al., 2013;Talsness et al., 2009). In rats and rabbits, BzBP, DBP, 762 and DEHP reduced sperm synthesis, sperm concentration, sperm 763 motility, ejaculate volume, and number of motile sperms (Aso 764 et al., 2005;Giribabu et al., 2014;Gray et al., 2009;Higuchi 765 et al., 2003;Lee et al., 2009;Tyl et al., 2004). In invertebrates, 766 sperm cells exposed to 100 lg/L DMP also exhibited a low fertiliza-767 tion rate of 38.5% when compared to approximately 80% in control 768 abalone (Zhou et al., 2011b). ...
Due to their versatility, robustness, and low production costs, plastics are used in a wide variety of applications. Plasticizers are mixed with polymers to increase flexibility of plastics. However, plasticizers are not covalently bound to plastics, and thus leach from products into the environment. Several studies have reported that two common plasticizers, bisphenol A (BPA) and phthalates, induce adverse health effects in vertebrates; however few studies have addressed their toxicity to non-mammalian species. The aim of this review is to compare the effects of plasticizers in animals, with a focus on aquatic species. In summary, we identified three main chains of events that occur in animals exposed to BPA and phthalates. Firstly, plasticizers affect development by altering both the thyroid hormone and growth hormone axes. Secondly, these chemicals interfere with reproduction by decreasing cholesterol transport through the mitochondrial membrane, leading to reduced steroidogenesis. Lastly, exposure to plasticizers leads to the activation of peroxisome proliferator-activated receptors, the increase of fatty acid oxidation, and the reduction in the ability to cope with the augmented oxidative stress leading to reproductive organ malformations, reproductive defects, and decreased fertility.
... Suspicions that phthalate esters might be endocrine disruptors sparked a number of studies that investigated the ability of phthalates to disrupt testosterone production by Leydig cells 15 Today, the focus of study is elucidating the mode of action of phthalates in inducing testicular injury. A number of hypotheses exist, including the involvement of the peroxisome proliferator activated receptor (PPAR), a nuclear receptor 17 , oxidative stress 88 and the thyroid hormone receptor alpha 1 (TRĮ1) 89 . These hypotheses will be presented in greater detail in the discussion (section 4.5 Mechanism of Action). ...
... Several groups have detected elevated levels of free radicals in the testes, despite the reduced levels of steroidogenesis (a process which naturally produces free radicals 93 ). Kasahara et al. 101 89 . ...
... In addition to examining the expression of the genes involved in steroidogenesis, the group also looked at the expression of thyroid receptor alpha 1 (TRĮ1), as hormone receptor cross talk may be important in testes development. They found that TRĮ1 expression was significantly increased in DEHP treated rats, and propose that this receptor may play an important role in DEHP-induced testicular dysgenesis 89 . In addition, the expression of luteinizing hormone receptor (LHR) has been shown to be inhibited by DEHP 93 . ...
Phthalate plasticizers are used in the plastics industry to aid in processing and impart flexibility to plastics. Due to the broad use of plastics, and the tendency of plasticizers to leach out of polymers, plasticizers have become ubiquitous in the environment. Concerns about the testicular toxicity of phthalate plasticizers, in particular di-(2-ethylhexyl) phthalate (DEHP), have arisen due to their ability to cause male reproductive tract abnormalities in animal models. It has been assumed that the DEHP metabolite, mono-(2-ethylhexyl) phthalate (MEHP), is the active compound, however, metabolites such as 2-ethylhexanol, 2-ethylhexanal and 2-ethylhexanoic acid, have not been thoroughly investigated. The aim of this study was to evaluate the anti-androgenic potential of these metabolites in vitro with a mouse Leydig tumor cell line, MA-10 cells. DEHP, MEHP and 2-ethylhexanal were found to decrease cell viability, as well as steroidogenic potential. The latter was assessed using an enzyme-linked immunosorbent assay (ELISA) to quantify steroid production and quantitative real-time polymerase chain reaction (qRT-PCR) to assess gene expression analysis of key steroidogenic enzymes. 2-Ethylhexanal proved to be the most potent steroidogenic disruptor, offering intriguing implications in the search for the mechanism of phthalate testicular toxicity. Overall, the study suggests the involvement of multiple active metabolites in the testicular toxicity of DEHP.
... The DEHP-induced insulin deficiency and a decrease in the testosterone (T)/estradiol (E) ratio are suggestive of the diabetogenic effects of DEHP. DEHP exposure alters the expression of the spermatogenesisor steroidogenesis-related genes resulting in decreased sperm production in the testis (Lee et al., 2009). Oral administration of DEHP to rats significantly increased the serum marker enzymes, the level of total bilirubin and hepatic lipid peroxidation. ...
Diethyl hexyl phthalate (DEHP) is an endocrine disruptor, it influences various organ systems in human beings and experimental animals. DEHP reduced the serum testosterone and increased the blood glucose, estradiol, T(3) and T(4) in rats. However, the effect of DEHP on insulin signaling and glucose oxidation in skeletal muscle is not known. Adult male albino rats were divided into four groups: Group I: Control; Groups II and III: DEHP treated (dissolved in olive oil at a dose of 10 and 100mg/kg body weight, respectively, once daily through gastric intubation for 30 days); and Group IV: DEHP (100mg/kg body weight) plus vitamins E (50mg/kg body weight) and C (100mg/kg body weight) dissolved in olive oil and distilled water, respectively, once daily through gastric intubation for 30 days. On completion of treatment, animals were euthanized and perfused (whole body); gastrocnemius muscle was dissected out and subjected to assessment of various parameters. DEHP treatment increased the H(2)O(2), hydroxyl radical levels and lipid peroxidation which disrupt the membrane integrity and insulin receptor. DEHP impaired the insulin signal transduction, glucose uptake and oxidation through decreased expression of plasma membrane GLUT4, which may partly be responsible for the elevation of fasting blood glucose level. The present study suggests that DEHP exposure affects glucose oxidation in skeletal muscle and is mediated through enhanced lipid peroxidation, impaired insulin signaling and GLUT4 expression in plasma membrane. Antioxidant vitamins (C and E) have a protective role against the adverse effect of DEHP.
This review aims to understand the impacts of plasticizers on the thyroid system of animals and humans. The thyroid gland is one of the earliest endocrine glands that appear during embryogenesis. The thyroid gland synthesizes thyroid hormones (TH), triiodothyronine (T3), and thyroxine (T4) that are important in the regulation of body homeostasis. TH plays critical roles in regulating different physiological functions, including metabolism, cell growth, circadian rhythm, and nervous system development. Alteration in thyroid function can lead to different medical problems. In recent years, thyroid-related medical problems have increased and this could be due to rising environmental pollutants. Plasticizers are one such group of a pollutant that impacts thyroid function. Plasticizers are man-made chemicals used in a wide range of products, such as children's toys, food packaging items, building materials, medical devices, cosmetics, and ink. The increased use of plasticizers has resulted in their detection in the environment, animals, and humans. Studies indicated that plasticizers could alter thyroid function in both animals and humans at different levels. Several studies demonstrated a positive and/or negative correlation between plasticizers and serum T4 and T3 levels. Plasticizers could also change the expression of various TH-related genes and proteins, including thyroid-stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), and transporters. Histological analyses demonstrated thyroid follicular cell hypertrophy and hyperplasia in response to several plasticizers. In conclusion, plasticizers could disrupt TH homeostasis and the mechanisms of toxicity could be diverse.
