New papers and results are presented so fast that it is impossible to give a complete review of this emerging research field. View via Publisher. Open Access. Save to Library. Create Alert. Share This Paper. Figures and Tables from this paper. Figures and Tables. Citations Publications citing this paper. Francis , E. By the progression of technology and increase in the global population growth, plastic materials are now widely used and have very different application fields [ 19 ]. Phthalates are dialkyl or alkyl aryl esters of phthalic acid and are abundantly used to make plastic materials more flexible.
Their main use is for the softening of rigid plastics and polymers. Phthalates were first synthesized in the s.
DEHP was first used in in United States and has been the most abundantly used phthalate derivative in the Twentieth century. In , the consumption of phthalates were 3. Phthalates migrate out PVC-containing items into food, air, dust, water, and soils and cause human exposure in various ways [ 23 ]. Several studies were conducted in different parts of the world, and human blood and urine mostly spot urine samples were used as biological fluids to evaluate the exposure to phthalates.
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The results of these studies revealed that humans are ubiquitously exposed to different phthalates, mostly in industrialized countries [ 24 — 27 ]. On the contrary, workplace inhalation is also of concern as phthalates; particularly, DEHP has low vapor pressure [ 28 ]. Diet is the main source of phthalate exposure in the general population. Particularly, fatty food e.
One other major source is medical exposure by blood storage bags and blood transfusion equipment during receiving blood transfusion [ 31 , 32 ] or hemodialysis dialysis bags [ 33 , 34 ]. Based on the number of carbon atoms in their alcohol chain, phthalates are divided into two distinct groups, with very different applications, toxicological properties, and classification: high molecular weight MW phthalates and low MW phthalates.
Their use largely depends on their MW. Higher MW phthalates, such as DEHP, are used in construction materials and in numerous PVC products, including clothing, food and beverage packaging, children products toys, grip bumpers , and biomedical equipment e. In a study by Lawrence et al. Autian [ 37 ] concluded that this was because biotransformation was required before DEHP produces toxic effects. The oral administration LD 50 value for rats Wistar, male was suggested to be between Phthalates are not covalently bound to plastic products and therefore may leak out to contaminate blood or food products and can be ingested.
When administered orally to humans and rodents, phthalates are rapidly hydrolyzed by esterases in the gut and other tissues to produce the corresponding active monoesters and their further oxidized metabolites. During phase I biotransformation, the relatively polar and low MW phthalates e. In contrast, the high MW phthalates are first metabolized to their respective hydrolytic monoesters and then, after enzymatic oxidation of the alkyl chain, to more hydrophilic, oxidative metabolites [ 39 ]. Some phthalates are subject to phase II particularly to glucuronidation and, to a lesser extent, sulfation metabolic reactions.
Glucuronidation not only provided higher urinary excretion of phthalate metabolites but also can reduce their biological activity. The biological effects of phthalates are of major concern but so far elusive. Phthalates are shown to cause cytogenetic damage to animals and humans. In s, phthalates were evaluated as epigenetic carcinogens because of their peroxisome proliferative effects.
However, in the s and in the Twenty first century, several studies confirmed their genotoxic effects [ 41 — 43 ]. Chromosomal aberration test, unscheduled DNA synthesis UDS , Ames test, micronucleus test, and hypoxanthine guanine phosphoribosyltransferase HPRT mutation test were applied to evaluate the genotoxic potentials of phthalates.
Besides, DEHP caused lymphatic mitotic inhibition after 4 h of exposure and caused an increase in the doubling time of human lymphocytes [ 44 ]. Later, Stenchever et al. Phillips et al. However, S-9 mix a mix of cytosolic and microsomal drug-metabolizing enzymes and cofactors had no effect on the chromosome damage produced by MEHP in CHO cells [ 48 ].
A study using mouse hepatocytes evaluated the genotoxicity of these compounds i. No changes were observed in DNA repair capacity. Lindahl-Kiessling et al. Kim et al. McKee et al. Using Ames test, Lee and Lee [ 54 ] observed that the phthalic acid and terephthalic acid did not produce any mutagenic responses in the absence or presence of S9 mix on the Salmonella typhimurium strains in Ames test. Besides, phthalic acid and terephthalic acid did not show any significant cytogenetic effect on CHO cells in the chromosomal aberration test and in the mouse micronucleus test [ 54 ].
Many studies are performed on the genotoxicity of phthalates using Comet assay in the last 30 years. Anderson et al.
Kleinsasser et al. The same researchers also determined the correlation between the genotoxic sensitivities to DBP and its isomer DiBP in mucosal epithelial cells or lymphocytes using Comet assay, and both phthalates showed significant genotoxicity on both cells and lymphocytes where the genotoxic effect of DiBP was higher than DBP in both cell types [ 57 ].
Biscardi et al. In a recent study performed on HepG2 cells exposed to various concentrations of DEHP for 24 or 48 h, DNA damage increased significantly in a dose-dependent manner [ 60 ]. The correlation between urinary phthalate levels and sperm DNA damage is being investigated by several studies. Duty et al. Hauser et al. Recently, Ahbab et al. Male rats were allowed to grow until different ages prepubertal, pubertal, and adulthood.
The results of many studies strongly point out that that EDC exposure can caused by epigenetic mechanisms, which can lead to cumulative adverse effects on future generations. These permanent changes will result in adverse health effects, such as neural and immune disorders, infertility, and late-onset complex diseases cancers and diabetes [ 64 ]. Phthalates are long suggested to be epigenetic carcinogens because of their peroxisome proliferator effects. Fetal testis is suggested to be the main target for DEHP. During the period of embryonic sex determination, transient exposure to a plastic mixture BPA and phthalates of gestating female rats was shown to promote early-onset puberty transgenerationally F 3 generation and decrease the pool size of ovarian primordial follicles in female pups.
On the contrary, in male pups, spermatogenic cell apoptosis was also affected transgenerationally, and differential DNA methylation of the F 3 generation sperm promoter regions was also observed [ 67 ]. Phthalates are well-known peroxisome proliferators that can alter gene and protein expressions. This capability may result in the promotion of hepatic carcinogenesis in rodents [ 68 ]. On the contrary, there are data in the literature that indicate that phthalates increase oxidative stress in the rodent liver even before peroxisomal oxidases are induced.
In addition, Kupffer cells have been suggested to be a potential source of oxidants in rodent liver after treatment with DEHP [ 69 , 70 ]. It appears that molecular events, which may be a consequence of increase oxidative stress, could interact with other pathways activated by peroxisome proliferation in rodent liver [ 69 , 70 ]. Although several studies including the studies by our group in the last decade pointed out that DEHP can induce reactive oxygen species ROS production and lead to increased cellular oxidative stress both in vivo and in vitro , there are no convincing data to prove whether the induction of ROS production is a one of the major pathways or whether ROS elimination is not efficiently achieved after a series of molecular events induced by phthalates, particularly by DEHP [ 42 , 43 , 70 , 71 ].
In the s, the hepatocarcinogenic effects of DEHP, due to its peroxisome proliferator effect, was shown by several studies. Back then, some concerns started rising about the safety of this substance. Therefore, the mechanism by which DEHP increases the incidence of hepatocellular tumors in rats and mice is not relevant to humans.
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Blom et al. This effect is suggested to be related to a direct ER binding of some, but not all, phthalates [ 76 , 77 ]. Recent in vivo and in vitro studies on phthalates are mainly focusing on their reproductive toxicity potential. Phthalates were suggested to target mainly male reproductive system. There is a decline in male fertility and increase in the number of cases with TDS in the last decades, and phthalates are suggested to be the major underlying factors. In testis, Leydig and Sertoli cells are the main targets of phthalates.
Many researchers observed that DEHP caused disruption in the function of both cell types. Tay et al. We also determined that DEHP exposure caused disruption and collapse of vimentin filaments and significantly induced apoptotic death of germ cells [ 82 ]. Exposure to phthalates, particularly to DEHP, resulted in decreased testicular testosterone production in rodents, and most of the reprotoxic effects are suggested to be related to their antiandrogenic potential [ 83 , 84 ].
In our studies, we determined that DEHP caused abnormal sperm production, decreases in sperm count, and motility when administered to week-old rats at ppm dose for 10 days. These substances were shown to cause both hepatocellular carcinomas and adenomas [ 86 — 88 ]. There are a number of molecular events that underlie the hepatocarcinogenic potential of these substances: Their genotoxicity, peroxisome proliferative property, and epigenetic effects are the most studied mechanisms.
Collectively, it appears that, in rodent liver, oxidative stress-related molecular events could interact with other pathways that can be activated by peroxisome proliferation. Previously, we have also shown that DEHP caused peroxisome proliferation, alterations in antioxidant enzyme activities decreases in glutathione peroxidase 1, glutathione peroxidase 4, superoxide dismutase, and glutathione S -transferase activities; increase in thioredoxin reductase activity , and liver enzymes when administered to week-old rats at ppm dose for 10 days.
Other than testis and liver, phthalates were suggested to be toxic to kidneys and thyroid [ 90 , 91 ].
Environmental Endocrine Disruptors
In the last five decades, a gradual decline in global semen quality has been reported [ 95 ]. Semen quality defines the sperm count, motility, and morphology. Seminal DBP levels were associated with decreased sperm concentration, and an overall analysis indicated a positive association between DBP and sperm concentration [ 95 ]. Among the infertile men, seminal phthalates were associated with increased sperm abnormality but not with sperm count or motility [ 96 ]. A positive association between sperm motility and phthalic acid was found, and this finding suggested that an increased ability to metabolize phthalates may be protective.
Besides, the researchers reported a cross-sectional association between urinary MEP concentrations and decreased LH levels when comparing the quartile of highest exposure to the lowest [ 97 ]. The majority of studies of phthalate exposure and semen quality have been conducted among infertile populations.
In , an American study was conducted on men undergoing infertility therapy. Higher urinary MBP levels were associated with decreased sperm concentration and motility after adjusting for age, abstinence time, and smoking status. Pant et al. The final selection, based on 1, publications, identifies endocrine disruptors. The identified endocrine disruptors have been classed according to different criteria. Their effects may have been observed in vivo in human beings Category I: 7 substances identified , in vivo in rodents and in vitro in experiments with human cells Category II: substances identified , solely on in vivo in rodents Category III: substances identified , or solely in vitro with human cells Category IV: substances identified.
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Seven general categories of effects of disruptors linked to the hormonal system were established: reproduction, development, metabolism, the hepatic system, immunology and neurology, as well as cancers relating to the hormonal system. For each of these categories, the database can be used to verify if specific effects have already been identified in the scientific literature regarding particular substances.
A third possible research approach is by the use of substances. The database distinguishes seven major categories: consumer products, agriculture, industry, medicine and healthcare, pollutants, natural sources, and intermediate inputs in production processes.
A particularly high number of endocrine disruptors were identified in categories where there is decisive occupational exposure for agriculture, for industry, and for healthcare.
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