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ISSN : 2508-755X(Print)
ISSN : 2288-0178(Online)
Journal of Embryo Transfer Vol.28 No.2 pp.95-111
DOI : https://doi.org/10.12750/JET.2013.28.2.95

Environmental Chemical-Dioxin Impacts on Biological Systems: A Review

Eui-Bae Jeung2, *, Thuy Thi Bich Vo1, Binh Thi Nguyen Le1, Hai Van Nong1, Hyun Yang2
2Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, Cheongju 361-763, Republic of Korea
1Institute of Genome Research, Vietnam Academy of Science and Technology, No 18, Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam
(접수: 2013. 6. 13 / 심사: 2013. 6. 13 / 채택: 2013. 6. 27)

Abstract

Worldwide there is concern about the continuing release of a broad range of environmental endocrine disruptingchemicals, including polychlorinated biphenyls, dioxins, phthalates, polybrominated diphenyl ethers (PBDEs), and otherhalogenated organochlorines persistent organic pollutants (POPs) into the environment. They are condemned for healthadverse effects such as cancer, reproductive defects, neurobehavioral abnormalities, endocrine and immunologicaltoxicity. These effects can be elicited via a number of mechanisms among others include disruption of endocrine system,oxidation stress and epigenetic. However, most of the mechanisms are not clear, thus several number of studiesare ongoing trying to elucidate them in order to protect the public by reducing these adverse effects. In this review,we briefly limited review the process, the impacts, and the potential mechanisms of dioxin/dioxin like compound,particularly, their possible roles in adverse developmental and reproductive processes, diseases, and gene expressionand associated molecular pathways in cells.

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INTRODUCTION

 Several substances both natural and man-made are thought to be endocrine disrupting chemicals (EDCs). These reagents include pharmaceuticals, pesticides, dioxins, dioxin-like compounds, polychlorinated biphenyls, dichloro-diphenyl-trichloroethane (DDT), components of plastics such as bisphenol A (BPA), and other phthalates. EDCs interfere with the endocrine system and elicit adverse developmental, reproductive, neurological, cardiovascular, metabolic, and immune effects on humans and wildlife (Schug et al., 2011).

 Dioxins contain a heterocyclic 6-membered ring in which two carbon atoms have been replaced with oxygen atoms. Dioxins and dioxin-like compounds (DLCs) are known to exhibit toxicity. These include polychlorinated dibenzo-p-dioxins (PCDDs) known simply (but inaccurately) as dioxins, polychlorinated dibenzofurans (PCDFs) or furans, and polychlorinated biphenyls (PCBs). PCBs are not dioxins but twelve of them possess ‘dioxin-like’ properties. The term ‘dioxin’ may also refer to the basic chemical unit of more complex dioxin molecules (Pohjanvirta and Tuomisto, 1994).

 Recently, dioxins and DLCs have received much attention due to their widespread occurrence, high levels of toxicity, and the significant threat these compounds pose to humans (Slowinska et al., 2011). In 1998, the World Health Organization (WHO) reevaluated and identified a tolerable daily intake (TDI) of 1~4 pg Toxic Equivalents (TEQ)/kg body weight (bw)/day for coplanar PCBs, which would have a large impact worldwide (Kurokawa and Inoue, 1998). In Japan, the Ministry of Health and Welfare identified 10 pg TCDD/kg bw/day as the temporary TDI in 1996. Additionally, a 1998 survey of municipal incinerators revealed that 105 out of 1,641 produced more than the allowed emission level of WHO 80 ng TEQ/m3. Therefore, the Japanese government initiated a comprehensive survey to measure dioxin levels in milk and blood of residents around incinerators, and evaluate their health effects (Watanabe et al., 1999). In 1999~2000, the Centers for Disease Control and Prevention analyzed representative biological samples for dioxins/dioxin-like chemicals in the U.S. population. As a result, the 95th percentile estimates for total serum PCB levels (whole weight) in individuals 20 years and older was about 2.7 ng/g, and the 95th percentile estimates for serum dioxin total toxic equivalence was between 40 and 50 pg/g lipid basis. Generally, human exposure levels of PCB chemicals are decreasing over time in the U.S. population. This reflects the effects of legislation, industry, and changes in lifestyle or activity patterns on the population (Needham et al., 2005). In addition, the effects of dioxins and DLCs at low doses were also defined in the range of human exposures or traditional toxicological studies by the National Toxicology Program (USA) (Vandenberg et al., 2012).

 At the Stockholm Convention on POCs in 2001, 12 pollutants including dioxins, PCBs, and DDT were referred to as ‘the dirty dozen’ (Weiss et al., 2003). The world's highest dioxin levels in breast milk and blood was noted in inhabitants of Chapayevsk and Ufa (Russia). In these towns, changes in the population's health characteristic of exposure to organic pollutants was observed (Revich and Shelepchikov, 2008). Currently, European regulations limit the amount and type of contaminants that can appear in foodstuffs (Gueguen et al., 2011). In China, the presence of DDTs in some rivers may pose health risks to humans (Bao et al., 2011). A recent study in Vietnam also showed that samples of soil, mud, some local foods, blood, and breast milk taken around Da Nang Airbase contained dioxin concentrations exceeding current international environmental and food standards, and the main route of human exposure to dioxins was through the consumption of dioxin-contaminated foods (Muller JF, 2000).

 In recent years, both beneficial biomolecules and contaminants have been discovered. Dioxins and DLCs are some of the most toxic chemicals that persist in the environment (Long and Bonefeld-Jorgensen, 2012). PCDDs and PCBs are ubiquitous and come from many sources (e.g., industrial and human activities). Higher concentrations of these chemicals may be present in the soil in residential and recreational areas (Kimbrough et al., 2010). Dioxins and DLCs are also formed in the exhaust from controlled small-scale incinerators where experimental waste is burned (Shibamoto et al., 2007). Contamination with pesticides, mycotoxins, dioxins, acrylamide, Sudan red, melamine, and 4(5)-methylimidazole can be listed as one of the most significant problems related to food processing, cooking, and adulteration (da Rosa et al., 2012). For humans, food provides 80% of organochlorine (PCBs, DDT, and dioxins) contaminants, which meat, fish, dairy, and commercially produced fruit are the main sources (Hall, 1992).

 Human can be exposed to dioxins through environmental, occupational, or accidental pollution. In the human body, most dioxins are metabolized and eliminated while the rest are stored in body fat (Marinkovic N. et al., 2010). Many effects attributed to 2,3,7,8-tetrachlorodibenzodioxin (TCDD), such as lethality, lymphoid and gonadal atrophy, hepatotoxicity, adult neurotoxicity, and cardiotoxicity, are associated with high doses of the chemical. Exposure to dioxins also results in a broad spectrum of biological responses including altered metabolism, disruption of normal hormone signaling pathways, reproductive and developmental effects, cancer development (Spencer et al., 1999), and immune effects (Birnbaum and Tuomisto, 2000; Fracchiolla N. S. et al., 2011).

TFE EFFECTS OF DIOXINS AND DIOXIN-LIKE COMPOUNDS ON REPRODUCTION AND DEVELOPMENT

 Dioxins and DLCsas carcinogens and developmental toxicants presumably reflect the ability of these compounds to alter cell proliferation and differentiation. There are several biologicalmechanisms that are likely to differ according to tissue and developmental period. These mechanisms may also be modulated by distinct genetic and environmental factors (Whitlock, 1987).

Fig. 1 Chemical structures of dioxins and dioxin-like compounds.

1. Adverse Effects of Dioxins and DLCs on the Reproduction and Embryo Development

 Dioxin, an endocrine disruptor, causes reproductive and developmental toxic effects in pups following maternal exposure in a number of animal models (Koga et al., 2012). Previous study has raised two important issues that the rat fetus was about 100-fold more sensitive to TCDD exposure than the adult, and fetal sensitive to TCDD appeared to exist in the hamster even through adult life (Murray et al., 1979). In experimental animals, prenatal exposure to dioxin and DLCs was capable of causing endocrine related effects in offspring in the absence of overt signs of maternal toxicity (Feeley and Brouwer, 2000). Low single doses of TCDD administered the dam during gestation altereddevelopment of the fetal rodent reproductive system. Namely, in male rat and hamster offspring dosing with TCDD during gestation reduced epididymal and ejaculated sperm counts and delayed puberty, while female rats reduced ovarian weight and fecundity, induced cleft phallus and a persistent thread of tissue across the vaginal orifice (Wolf et al., 1999). Moreover, when a single dose of TCDD was administered in the ng/kg dose range to the rat on gestation day (GD) 15, the offspring display alterations of the reproductive system such as reduced ovarian weights, displayed malformations of the genitalia, including cleft phallus and a thread of tissue persists across the vaginal orifice, and affected a variety of androgenic status indices such as spermatogenesis, adult sexual behavior, luteinizing hormone (LH) secretion pattern in the male offspring (Bjerke et al., 1994; Gray et al., 1997). In utero TCDD exposure also caused abnormal ventral, dorsolateral, and anterior prostate develop- ment in mouse offspring (Lin et al., 2003). In addition, when TCDD was administered on GD 8, female offspring displayed a reduction in fecundity, an increased incidence of constant estrus, reduced ovarian size (Gray and Ostby, 1995) and reproductive histopathological alterations (Mann, 1997). A single oral dose of TCDD when administered to pregnant female rats (1.0 ug/kg) on GD 15 interfered with vaginal development by impairing regression of the Wolffian ducts, the size of interductal mesenchyme, and preventing fusion of the Mullerian ducts in exposed fetuses (Dienhart MK, 2000). Another study showed spermatogenesis in male offspring rats were sensitive to dam exposures to low dose levels of TCDD (64 ng/kg) on GD15, for instance, reductions in daily sperm production and sperm counts in the caudal epididymis continued to occur in the sexually mature (Feeley and Brouwer, 2000). Other consequences of maternal exposure of TCDD included deficits in androgen-dependent differentiation, neurologic development, and alterations in thyroid homeostasis in rodent offspring (Feeley and Brouwer, 2000). Previous study has demonstrated that TCDD imprints sexual immaturity by suppressing the expression of fetal pituitary gonadotropins, the regulators of gonadal steroidogenesis (Koga et al., 2012), or lead to the reduced expression of testicular steroidogenic proteins such as steroidogenic acute-regulatory protein (StAR) and cytochrome P450 (CYP) 17, or enhanced the steroidogenesis of the fetal adrenal gland and placenta in females (Takeda et al., 2011).

 The results obtained clearly demonstrate that exposure to TCDD at an early stage of embryogenesis affects steroid production and secretion by chicken gonads (Sechman et al., 2011). Particular concerns are TCDD exposures during the earliest stages of development embryogenesis, may have long term effects on newborns or adults. For instance, rat pre-implantation embryos following maternal exposure to TCDD disrupted morphogenesis at the compaction stage (8~16 cell), with defected including monopolar spindle formation, f-actin capping and fragmentation due to aberrant cytokinesis. Moreover, the size, shape and position of nuclei were modified in compaction stage pre-implantation embryos collected from treatment animals (Hutt et al., 2008). Addition, TCDD significantly increased the DNA methyltransferase activity of mouse preimplantation embryos (Wu et al., 2006). Li B et al. (2006) showed a result TCDD is a reproductive and developmental toxicant that can alter endocrine status, leading to decreased fertility and altered embryonic development. Namely, pregnant and pseudopregnant mice were exposed to TCDD orally during early GD 1~8, pre-implantation stages (days 1~3), and peri-implantation to early post-implantation stages (days 4~8) presented the number of implanted embryos was significantly reduced on GD 5, lower number of implantation sites on days 1~3 and days 4~8, and also inhibited decidualization in pseudopregnant mice (Li et al., 2006). In addition, TCDD interacts with estradiol in mobilizing specific fatty acids in chickens that may be a cause of cranial/beak malformations in this species. A single dose of 4 μg/kg BW TCDD on GD 15 or 20 exhibited embryo cellular changes, mainly increased cell death, and intercellular spaces in the neural tube (Moran et al., 2004). In study about the reproduction of white tailed sea eagles, PCBswere significantly higher in eggs with dead embryos compared to undeveloped eggs, implying lethal concentrations of PCBs such as LOEL of 320pg TEQ suggested for embryo mortality (Helander et al., 2002). The critical windows of vulnerability to TCDD have also been studied in human but very few (Lin et al., 2003). Tsang (2012) revealed TCDD affected on embryo development, implantation and fertility in humans (Tsang et al., 2012). All children are exposed to physical or biological TCDD chemicals that can result in adverse health effects before and after birth (Lund- qvist et al., 2006).

2. Adverse Effects of Dioxinsand DLCs on Male and Female Development and Reproductive Systems

 Environmental exposure to dioxinsresults in developmental and reproductive toxicity in fish, birds, and mammals (King-Heiden et al., 2012). Embryos, fetuses, and infants have been reported to be more sensitive to environmental or occupational chemicals through direct or indirect exposure compared to adults. Paternal and maternal exposure to some of these chemicals might affectgamete structure and function, potentially resulting in pregnancy complications (Kumar, 2011). Carpenter et al. (2006) showed that PCB exposure, especially during fetal development and early life reduces IQ and alters behavior. Moreover, PCBs affect thyroid and reproductive function in both males and females, and increase the risk of developing cardiovascular and liver disease as well as diabetes (Carpenter, 2006). In another study, detectable concentrations of PCBs and dioxins werefound in amniotic fluid, placenta, and fetal tissue samples, and breast-fed infants were able to obtain PCB blood levels greater than those of their mother (Feeley and Brouwer, 2000). Avariety of adverse mental and physical developmental abnormalities causing by these compounds including lower birth weight, changes in thyroid hormone production and lymphocyte subpopulations, and dysfunctional neurological development have also been observed (Feeley and Brouwer, 2000).

 A significant body of toxicology data from laboratory and wildlife studies suggests that exposure to certain endocrine disrupters (e.g., PCBs, DDT, dioxins, and some pesticides) is associated with reproductive toxicity including abnormalities of the male reproductive tract (cryptorchidism and hypospadias), reduced semen quality, and impaired fertility in adults (Phillips and Tanphaichitr, 2008; Sharpe, 2010; Kumar, 2011). These compounds mimic or inhibit natural hormones, alter the normal regulatory function of the endocrine system, and have potential hazardous effects on the male reproductive axis (thus causing infertility). For instance, exposure to endocrine disrupters is associated with altered pituitary and thyroid gland function, abnormal sexual development, chronic inflammation, testicular and prostate cancers, undescended testes, and hypospadias (Sikka and Wang, 2008). Furthermore, several lifestyle (e.g., obesity and smoking) and environmental factors also appear to negatively affect both the postnatal and adult testis function such as reduced sperm counts and Sertoli cell numbers in young men or dysfunctional spermatogenesis during adulthood (Sharpe, 2010).

 Kumar (2011) reported that some industrial pollutants (e.g., dioxins, organic solvents, and radioactive materials). Moreover, dioxins cause abnormal breast development in pre-pubescent girls (Roy et al., 2009). Associations have also been observed between serum TCDD levels and enzyme γ-glutamyl transferase, testosterone, luteinizing and follicle-stimulating hormones (Sweeney MH et al., 1997~1998).

3. Other Effects of Dioxins and DLCs on Human and Animal Health

 Aside from many studies analyzing the effects of TCDD exposure on the reproductive system, the impact of TCDD on other endocrine organs (particularly the thyroid gland) as well as the immune and neurological systems has also been evaluated (Papaleo et al., 2004).

Table 1 Assessing knowledge about toxicity activities of dioxin and DLCs in the development and reproduction of animals and mammals

Table 1 Continued

Table 1 Continued

1) Thyroid-disrupting Chemicals

 Exposure to specific environmental toxins including PCBs, PBDEs, dioxins, phthalates, and halogenated organochlorines have been shown to interfere with the production, transportation, and metabolism of thyroid hormones via a variety of mechanisms. Recent studies demonstrated that thyroid diseases (e.g., thyroid cancer and thyroid autoimmune disease) are increasing substantially, and neurodevelopmental damage due to thyroid-disrupting chemicals has also been observed (Langer, 2008; Radikova et al., 2008; Patrick, 2009). There is significant evidence that PCBs, dioxins, and furans cause hypothyroidism in animals and disrupthuman thyroid homeostasis, even small changes in thyroid homeostasis may adversely affect human health (Crofton et al., 2005; Suzuki et al., 2007; Boas et al., 2009). A previous study also uncovered possible effects of exposure to dioxin-like chemicals in maternal milk including reduced vitamin K levels, increased thyroxin concentrations, and mild liver enzyme changes in children (Pohl and Hibbs, 1996).

2) Chemicals that Disrupt the Immune System

 Immune system development is very sensitive to immunotoxicreagents. TCDD, a well-known immunotoxicant, has been shown to produce adverse effects in rodents and humans, and is considered a prototypical developmental immunotoxicant (Van Loveren et al., 2003). An array of toxic effects on the immune system has been described in experimental animals and humans accidentally exposed to PCBs and dioxins. Tryphonas (1998) suggested that the immune system of developing fetuses and newborns is particularly vulnerable to TCDD. In another study, TCDD exposure correlated with increased tumor necrosis factor á (TNFá) production in response to stimulation with T cell mitogen decreased Natural killer cell (NK) cytolytic activities were also observed (Rier and Foster, 2002). A recent investigation has expanded the physiological role of dioxin molecular pathways to include modulation of hematopoietic progenitor production and immune regulation (Smith et al., 2011). Ruby et al. (2002) also suggested that TCDD may alter the balance between nuclear factor kappa B/rel homology domain (NF-êB/Rel) heterodimers and transcription inhibitory p50 homodimers in dendritic cells, leading to defects in these cells and suppression of the immune response.

3) Chemicals that Disrupt the Neurological System

 The neurological effects of dioxins and DLCs in humans have been extensively studied and confirmed in several laboratory animal models. Several PCBs and dioxins have been found to affect nervous system function, possibly by acting on the endocrine system during development (Tilson and Kodavanti, 1997). Children born to women who accidentally consumed rice oil contaminated with relatively high amounts of PCBs during pregnancy had detrimental neurodevelopment changes, such as a decrease in dopamine content in basal ganglia and prefrontal cortex, and induced changes in specific neurotransmitters in specific brain areas. (Faroon et al., 2000). In addition, the effects of PCBs and dioxin pollutants on neurodevelopment in 134 Japanese pregnant women's peripheral blood and their 6 months old infants at low concentrations have been assessed (Nakajima et al., 2006). PCB was also found to affect calcium homeostasis in humans, thereby inducing behavioral and neurological changes observed in vivo after exposure during development (Costa, 2007). Moreover, altered levels of neurotransmitters in various brain areas have been found in monkeys, rats, and mice. For instance, decreased dopamine contents in the basal ganglia and prefrontal cortex were reported (Faroon et al., 2000).

 Other studies were performed to elucidate the molecular mechanisms and signaling pathways involved in TCDD-induced neurotoxicity, and define the molecular targets of this chemical in neurons. Results supported the hypothesis that TCDD toxicity in cerebellar granule cell (CGC) neurons involves aryl hydrocarbon receptor (AhR), and primarily involves an apoptotic process. AhR could therefore be considered as a novel target for neurotoxicity and neurodegeneration (Sanchez-Martin et al., 2011) whose down-regulation could block certain adverse xenobiotic-related effects in the central nervous system (CNS). Neurotoxicity caused by dioxin exposure also significantly increases expression of the activated C kinase-1 (RACK-1) receptor, a sensitive molecular target in neuronal cells (Monteiro et al., 2008).

4. Association of Dioxin Exposure with the Risk of Endometriosis, Diabetes, Cancer, and Cardiovascular Disease

 Dioxins are classified as human carcinogens but also cause noncancerous diseases like atherosclerosis, hypertension, and diabetes. Long-term exposure to dioxins results in disruption of the nervous, immune, reproductive, and endocrine systems (Marinkovic N. et al., 2010).

1) Endometriosis

 Endometriosis, a disease of the female reproductive tract, is potentially related to environmental chemical exposure and the subsequent dysregulation of estrogen metabolism along with inflammatory and immunological mechanisms (Tsuchiya et al., 2003). Several studies in animals and humans indicated a potential association between exposure to dioxins, endometriosis, and disruption of the immune system (Bruner-Tran and Osteen, 2010; Ding et al., 2011; Ballester et al., 2012). Bruner- Tran and Osteen (2010) discussed the potential importance of early life exposure to dioxin-like toxicantson subsequent development of endometriosis. Other animal studies have shown that rhesus monkeys exposed to dioxins have a high prevalence of endometriosis, and severity of the disease correlates with serum dioxin concentrations (Ballester et al., 2012). In addition, Rier and Foster (2002) provided evidence also suggesting that TCDD exposure and endometriosis in rhesus monkeysmay be associated with increased serum concentrations of specific coplanar PCB compounds and long-term alteations in systemic immunity. The precise relationship between organchlorine chemicals and endometriosis is still unclear. However, the effects of dioxins on growth factors, cytokines, and the immune and endocrine systems may promote endometriosis development (Birnbaum and Cummings, 2002).

2) Diabetes

 During the last decade, associations between persistent organic pollutants (POPs), including dioxins, furans, polychlorinated biphenyls, polybrominated biphenyls, polybrominated diphenyl ethers, or organochlorine pesticides, and diabetes have been reported in humans. In order to evaluate these relationships, several approaches have been used such as evaluating individuals involved in accidents leading to a high level of exposureor subjected occupational exposure, and geographical studies (Lind L., 2012). It is known the increased use of organochlorine POPs over the past few decades has occurred concurrently withan increased prevalence of type 2 diabetes (Lee et al., 2007). A previous study suggested that exposure to low levels of dioxins and PCBs, which mainly accumulate in adipose tissue, may play a role in the development of type 2 diabetes in the general population (Bonefeld-Jorgensen, 2010). An association between exposure to high concentrations of dioxins and type 2 diabetes was also reported in the U.S. (Uemura, 2012). A 2008’s survey on patients exposed during production of the herbicide trichlorophenoxyacetic acid in the period 1965~1968 showed that after forty years intoxication, the blood level of TCDD is still 100 times higher than in the general population (Pelclova et al., 2009), and it has been determined that exposure to TCDD increases the risk for diabetes mellitus in humans observed as hyperglycemia resulting from insulin resistance (Fried et al., 2010). Pelclova et al. (2007) evaluated patients with chronic health impairment due to TCDD exposure. Among these individuals, 91% were hyperlipidemic, 73% had hypertension, 55% had type 2 diabetes, 45% had ischemic heart disease, and 36% had psychological disorders (Pelclova et al., 2007). In another recent study, Zeliger (2013) showed that the development of type 2 diabetes rapidly increases with sequential exposure to lipophilic chemicals (POPs) and hydrophilic environmental pollutants. Ruzzin et al. (2010) also exposed Wistar rats to lipophilic POPs for 28 days, and observed that the animals developed insulin resistance, abdominal obesity, and steatosis. Another in vivo study suggested that exposure to TCDD affects glucose homeostasis and increases the incidence of type 2 diabetes (Alonso-Magdalena et al., 2011). Exposure to this compound was also found to impact the second phase of glucose-stimulated insulin secretion via the AhR signaling pathway (Kurita et al., 2009).

3) Cancer and Cardiovascular Disease

 The developing cardiovascular system is a sensitive target of many environmental pollutants including dioxins, dioxinlike chemicals, and some pesticides. Laboratory research has utilized a variety of vertebrate models to elucidate potential mechanisms that mediate this cardioteratogenicity and measure the sensitivity of different species for predicting potential risk to environmental and human health (Tuomisto and Tuomisto, 2012). It is notable that in all models, dioxin-associated cardioteratogenicity is associated with increased cardiovascular apoptosis and decreased cardiocyte proliferation (Kopf and Walker, 2009). In addition, research in animal has confirmed the human epidemiological finding that dioxin exposure during adulthood is associated with hypertension and cardiovascular disease (Kopf and Walker, 2009). For instance, dioxins and DCLs contamination in fish are associated with increased risk of cardiovascular disease (Bushkin-Bedient and Carpenter, 2010). Exposures to TCDD in utero and through breast milk in C57BL/6 mice alter cardiac gene expression as well as cardiac and renal morphology in adults, thus increasing the susceptibility to cardiovascular dysfunction (Aragon et al., 2008).

 To date, much of the research examining the health effects of environmental pollutants has focused on ascertaining whether compounds are carcinogenic. Numerous chemical contaminants are formed during the processing and cooking of foods (Borchers et al., 2010). The International Agency for Research on Cancer (IARC) has classified dioxins as a human carcinogen although they are not associated with the development of specific tumors (Donato and Zani, 2010). Recently, a prototypical dioxin was shown to be a developmental toxicant in the mammary gland as well as an sensitivity chemical to potential carcinogens in rodents (Birnbaum et al., 2003). TCDD also induce changes in estrogen metabolism and may alter the growth of hormone-dependent tumor cells, thus producing a potential carcinogenic effect (Gierthy et al., 1993). Furthermore, in vitro dioxin exposure leads to accelerated cell differentiation, increased cell proliferation, and decreased senescence in differentiation processes (Ahn et al., 2005; Kumar, 2011). These changes are accompanied by decreased levels of several regulatory proteins (e.g., p53), indicating that dioxins may exert cancer-promoting effects through this mechanism (Ray and Swanson, 2003). However, another study demonstrated that dioxins belong to a group of carcinogens, and induced cancer via non-genotoxic mechanisms. For instance, a integrated analysis identified unique pathway maps involved in receptor-mediated mechanisms, such as the G-protein coupled receptor protein (GPCR) signaling pathway maps (Jennen et al., 2011). Additionally, TCDD is a ligand of AhR, which is a key signaling molecule important for the toxic and carcinogenic properties of dioxins (Sanchez Martin et al., 2011).

5. The Effects of Dioxinsand Dioxin-like Chemicals on Gene Expression and Associated Molecular Pathways in Cells

1) Gene Expression

 Mechanistic studies have revealedthe biochemical pathways along with biological and molecular events that contribute to the adverse effectsof dioxins (Kimbrough and Krouskas, 2001). Previous studies showed the potential effects of dioxins on panels of biomarker genes or proteins in cells (Munoz and Albores, 2010). The toxicokinetic characteristics of dioxins and related chemicals depend on three major properties: lipophilicity, metabolism, and binding to the cytochrome P450 enzymes (CYP1A2) in the liver (Van Birgelen and Van den Berg, 2000). In vivo exposure to TCDD for 10 days leads to a significant change in the abundance of 18 individual proteins mostly involved in cytoskeleton organization and biogenesis, actin filament-based processes, protein transport and folding, and calcium binding (Carpi et al., 2009). DNA microarray and quantitative real time-PCR analyses revealed changes in the expression of genes involved in the circadian rhythm, cholesterol biosynthesis, fatty acid synthesis, and glucose metabolism in the liver after TCDD exposure (Sato et al., 2008). Embryonic TCDD exposure was found to alter the expression of 113 genes in ovaries and 56 in testes with seven genes common to both sex organs (Magre et al., 2012).

 In addition, TCDD alters the expression of genes associated with gluose and lipid metabolism, GABAergic transmission, and fertility in males and females, thus providing a possible explanation of the diabetogenic, dyslipidemic, neurologic, and fertility effects induced by TCDD following in vivo exposure (Fracchiolla N. S. et al., 2011). Fetal exposure to dioxins affects brain development, and influences behavior in humans and laboratory animals. A previous analysis revealed that the expression of two chemokine genes (Cxcl4 and Cxcl7) is upregulated by in utero TCDD exposure and later effect on adults (Mitsui T. et al., 2011). Exposure to TCDD in utero and through breast milk results in differential mRNA expression associated with fibrosis, inflammatory responses, and disruption of cellular components (Arima A. et al., 2010).

 Another investigation demonstrated that TCDD treatment enhances TNFá-induced cell death by affecting the transcription of several genes involved in apoptosis (Ruby et al., 2005). Jenny et al. (2012) reported that TCDD exposure causes modest changes in the expression of some genes which regulate the critical stage of hematopoiesis and cardiovascular development. Furthermore, over 100 genes respondto TCDD during adipogenesis including ones that contain AhR response elements, affect oxidative processes, and involve in cell signaling. In immature ovariectomized Sprague Dawley rats and C57BL/6 mice exposed to TCEE, responses of conserved genes associated with xenobiotic/chemical- induced stress and amino acid metabolism, cellular growth, lipid metabolism, and immune responses were observed (Boverhof et al., 2006). Moreover, significantly altered expression of variousgenes involved in xenobiotic metabolism, cardiac homeostasis, extracellular matrix production/remodeling, and cell cycle regulation in fetal animal exposed to TCDD was reported (Thackaberry et al., 2005).

 In vitro exposure to different PCB congeners leads to observe gene expression in peripheral blood cells. These changes were related to hepatotoxicity, immune and inflammatory responses, and disturbances of lipid and cholesterol homeostasis (Wens et al., 2011). Microarray analysis also identified 104 TCDD-responsive genes, which 98 genes were upregulated, and 69 genes were associated with AhR and aryl hydrocarbon receptor nuclear translocator protein (ARNT) signaling in breast cancer cells (Lo and Matthews, 2012). Another microarray analysis identified 1,896 TCDD-responsive genes, which 625 differentially expressed genes involved an AhR interaction at a dioxin response element in the steatosis mouse liver (Dere et al., 2011). In addition, TCDD was found to activate Akt and extracellular signal-regulated kinase 2 (ERK2), and increased the expression of CYP1A1, plasminogen activator inhibitor-2 (PAI-2), and human interleukin-1P (IL-lb) mRNA along with ERK2 protein. These genes are intrinsically associated with breast epithelial cell proliferation and survival clearly suggests that they may be involved in TCDD induced breast tumorigenesis (Ahn et al., 2005). Hsu et al. (2007) found that dioxins down-regulate messenger RNA expression of the G-protein-coupled receptor CXCR4 as well as its unique chemokine ligand CXCL12 in MCF-7 breast cancer cells (Hsu et al., 2007).

2) Nuclear Receptor Signaling Pathways

 Many toxicology studies have evaluated the effects of exposure to various chemicals, but few have identified molecular targets associated with specific toxicity endpoints. The endpoints of dioxin toxicity for which downstream molecular targets have begun to be identified are observed in developmental or tissue regeneration processes (Yoshioka et al., 2011). The toxicological effects of dioxins are mediated via cytosolic AhR, which functions as a ligand-dependent transcription factor in partnership with ARNT (Long and Bonefeld-Jorgensen, 2012). The key role of AhR in promoting the effects of dioxin and related compounds has been substantiated by four different lines of research: structure/activity relation- ships, responsive versus nonresponsive mouse strains, mutant cell lines, and the development of transgenic mice in which the AhR gene has been knocked out (Lahvis and Bradfield, 1998). Several experimental animals have demonstrated that the AhR mediates different biological effects of TCDD and functions as a ligandactivated transcription factor by control- ling the expression of specific genes via interaction with defined nucleotide sequences in the promoter regions (Peters et al., 2006).

 Analyses of polymorphisms in genes encoding human AhR and ARNT have the potential to identify genotypes associated with higher (or lower) sensitivities to dioxin-related effects (Sweeney and Mocarelli, 2000). Species-specific AhR molecular structures indicate that this receptor is a member of a family of transcription-activating proteins that contain a basic helix-loop-helix (bHLH) DNA binding motif, per ARNT single-minded protein (PAS) domain for dimerization and ligand binding, and a C-terminal transactivation domain associated with transcription induction and a variety of toxic endpoints (Korkalainen et al., 2001). Another potential mechanism by which TCDD can be involved the protein/protein interactions of AhR. When not bound to a ligand, the AhR exists in a multimeric protein complex containing two molecules of heat shock protein 90 as well as other proteins including Aryl hydrocarbon receptor interacting protein/ X-associated protein 2/aryl hydrocarbon receptor-associated protein 9 (AIP/XAP2/ara9), ara3, ara6, Src tyrosine kinase, Rel homology domain, and retinoblastoma protein (Rb) (Puga et al., 2000). Similarly, several investigators have demonstrated an association between the AhR and retinoblastoma protein that affects cell cycling (Ganguly and Shields, 2010; Lindsey and Papoutsakis, 2012). Thus, the AhR in an unbound state may act as a negative regulator of key molecules involved in the control of phosphorylation, cell cycling, and apoptosis in the presence of dioxins (Puga et al., 2000).

 The ARNT protein is a common co-transcriptional factor in the TCDD-AhR transcription pathway (Nie et al., 2001). This complex is bound by other nuclear co-activators and/or co-repressors that regulate transcription. ARNT has many other binding partners that control neuronal differentiation, morphological branching, and responses to hypoxia (Gu et al., 2000). This protein dimerizes with other receptor/transcription pathways in the nucleus, indicating its importance and fundamental role in regulating DNA transcription (Tian et al., 1999). However, it cannot be assumed that increasedreceptor occupancy will necessarily elicit a proportional increase in all biological response(s) because numerous molecular factors (e.g., cofactors, other transcription factors, and genes) that contribute to reaching the endpoints can affect the overall response (Pohjanvirta et al., 1999).

 Other molecular pathways affected by dioxins and DLCs in cells have also been described. For instance, previous studies revealed a general inverse relationship between high serum POP concentrations and estrogen receptor (ER) and AhR transactivation (Lo and Matthews, 2013). A different investigation provided evidence of an opposite relationship between dioxinlike AhR and ER activity supporting the hypothesis that dioxins exert anti-estrogen effects (Bonefeld-Jorgensen, 2010). Moreover, Swedenborg and Pongratz (2010) described some effects of AhR on the estrogen system. The molecular mechanisms as well as potential adverse effects of AhR, ER, and dioxin activities on human health have been identified. There is also accumulating evidence that intricate interplay exists between AhR and ER pathways at multiple levels of molecular mechanisms underlying the effects dioxins on cells (Swedenborg E. and Pongratz I., 2010).

CONCLUSION

 Understanding the biochemical pathways that influence TCDD responsiveness may allow us to more clearly identify the risks associated with dioxin exposure. Furthermore, it is important to further elucidate the mode of action of these environmental pollutants not only to help protect the health of exposed individuals, but also to identify novel targets for the development of diagnostic biomarkers and new drugs that can prevent the adverse effects of dioxins in humans and animals. Other strategies for preventing damage due to dioxins include education, techniques that reduce pollution, and a better use of natural resources.

ACKNOWLEDGEMENT

 This work was supported by the research grant of Chungbuk National University in 2012.

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