Stockholm Convention defined polychlorinated biphenyls (PCBs) as a group of persistent organic pollutants (POPs) such as dioxin/furan, dichlorodiphenyltrichloroethane, polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, aldrin, polychlorinated dibenzofurans and organometallic compounds (such as organotin and organomercury) which share the same characteristics of being persistent, bioaccumulative and toxic and can travel long distance through various media. They have diverse health impacts with different underlined molecular mechanisms. Recently, PCBs were referred as potent carcinogens with persistent existence in the environment. As the liver is the organ of detoxification, it is the major target organ for toxic effects induced by environmental contaminants, including PCBs. PCBs, furan and dioxin exert their hepatocarcinogenic effect through different mechanisms such as induction of oxidative stress, an increase of reactive oxygen species (ROS), mutagenic induction to oncogenes and epigenetic alteration to hepatic cells. In this chapter, we will provide an updated overview about PCBs, furan and dioxins, their impact on liver cancer initiation and progression on various in vivo and in vitro systems and its underlined molecular mechanisms. Also, a special emphasis will be directed to highlight zebrafish as in vivo model system to analyse the hepatocarcinogenic effect of these pollutants.
- polychlorinated biphenyls
Polychlorinated biphenyls (PCBs) are related to a larger group of environmental pollutants named persistent organic pollutants (POPs) with intense ecological burden and toxicological problems [1, 2]. PCBs are halogenated aromatic hydrocarbons with special chemical formulas encompassing 209 congeners . Based on the number of chlorine atoms and their location at the biphenyl, PCBs can be divided into lower and higher chlorinated congeners. Lower and higher chlorinated PCBs have different bioaccumulation rates . PCBs are made of two cis-carbon rings linked by a single carbon bond and biphenyl molecule. Each PCB molecule consists of 12 carbon atoms alongside chlorine atoms substituted for hydrogen ones at any of 10 possible positions. Hence, theoretically, 209 possible PCB congeners can be found . Due to their chemical characteristics, they have been used extensively in the industry as electric insulators, plasticizers, heat exchange and hydraulic fluids. The main problem of PCBs lies in their persistent nature, high degree of lipophilicity, slow transformation rate and low environmental degradation, which made them associated with a broad spectrum of human diseases such as reproductive, immunological and carcinogenic [3, 6, 7, 8]. In 1987, International Agency for Research on Cancer and in 1996, the US environmental Protection Agency reported that PCBs are carcinogen in laboratory and wild animals and a possible carcinogen in humans [9, 10, 11, 12, 13, 14, 15].
Absorption of PCBs is feasible through ingestion, inhalation and dermal routes. The highest exposure pattern occurs through inhalation and skin absorption . Once inside the body PCBs are transported to the liver. The main target of PCBs metabolism is the liver by the action of hepatic cytochrome p450 (CYP450). According to their chemical structure, PCBs can bind to different receptors  such as aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) and pregnane X receptor (PXR) . Therefore, research was focused to study the impact of PCBs on liver function alteration and carcinogenicity . Based on PCBs’ chemical structure and receptor affinity, they can be categorized into dioxin-like and non-dioxin-like PCBs. Among different PCBs, Aroclors 1016, 1242, 1254 and 1260 are the most produced and used PCBs in the US during the 1958–1977 period .
One of the earliest incidences of human direct PCB ingestion was reported in Japan in 1968 and known as Yusho accident (oil syndrome in Japanese). This incident affected more than 1800 people who ingested rice oil contaminated with kanechlor-400 . The average intake of PCBs in Yusho patients was 633 mg. The PCB concentration in adipose tissue was 46–76 ppm. After 34 years, the titre of non-ortho and mono-ortho PCBs in the blood of those patients reached 320 and 76 pg./g lipid, respectively . Another famous PCB toxicity outbreak was reported a few years later after the Yusho incident in 1979 in Taiwan, known as the Yucheng incident (oil syndrome in Chinese). In this incident, around 2000 individuals consumed the same rice oil contaminated with Kanechlor-500 from one store . Later, they developed skin problems and various health diseases. The concentration of PCBs in blood ranged from 3 to 1156 ppb . A meta-analysis study of Yusho and Yucheng incidents showed that most patients exhibit a high degree of mortality due to lung, liver and skin cancers in both men and women [24, 25].
Before 1996, different assumptions have been made regarding PCBs’ carcinogenicity. Sometimes all PCBs were considered carcinogens. Other assumptions indicated that mixtures with high chlorine content are only carcinogenic . The carcinogenic potential of different PCBs is attributed to PCBs potency, which is affected by environmental processes (partitioning, chemical reaction, transformation and preferential bioaccumulation). Partitioning includes the fractionation of PCB mixture into different environmental compartments (air, water, sediment and soil). PCBs adsorption rate increases proportionally with their chlorine and organic content where low-chlorine content PCBs tend to be more volatile and hydrophilic and high-chlorine content is more persistent and lipophilic. Chemical transformation of PCBs in the environment occurs through the biodegradation process by the action of anaerobic bacteria in the sediments. These bacteria remove chlorines from
Based on several reports from different agencies, PCBs were referred as possible human carcinogens . This assumption is based on experimental data from rodents where PCBs treatment increased neoplasm formation in different rodent tissues.
Commercial PCB mixtures such as Aroclors 1016, 1242, 1254 and 1260 (dietary PCBs concentration ranged from 25 to 200 ppm over a period of 24-month treatment) were found to induce not only alteration in liver function tests (AST, ALT and GGT) but also liver tumours with bile duct carcinoma (cholangiocarcinoma) in rats (female tumour incidence higher than male rats) after long-term feeding regime . In addition, rats exposed to commercial mixtures with 60% chlorine through a dietary lifetime regime developed benign liver tumours that eventually progressed to malignant ones . Furthermore, a mixture of PCB126 and PCB153 caused a mild increase in neoplastic liver lesions in mice. This was accompanied by an up-regulation of Cyp1a1 and Cyp2b10 (RNA and protein level) . The same promotion of liver carcinogenesis was observed in partially hepatectomized rats challenged with a single DEN dose and subsequent intraperitoneal injection of PCB105, 126 or 153 . Moreover, rats receiving a single dose of DEN followed by intraperitoneal injection of PCB77 or PCB153 (150 μmol/kg) alongside selenium-enriched diets feeding developed hepatic neoplasm. Selenium administration enhances the carcinogenic induction of PCB77 more than that of PCB153 as the number of positive placental glutathione s0transferase (PGST+) hepatic regions was higher in the former than the latter, respectively .
Single PCB compounds have a preferential binding affinity to different receptors. For example, PCB126 binds to AhR while PCB153 binds to CAR. Rats treated with a single dose of DEN followed by PCB126, PCB153 or in combination developed hepatic neoplasms most profoundly in single PCBs treatment only (PCBs combination treatments showed antagonistic results on liver neoplasm formation) as indicated with positive GST-P liver areas . Cultured mouse hepatocytes treated with PCB126 exhibited reduced hepatocyte glycogen content in a dose-dependent manner and suppressed forskolin-stimulated gluconeogenesis from lactate. Interestingly, glycogen treatment of cells restored PCB127 effects, indicating that PCB127 could affect the terminal players in the gluconeogenesis cycle. Finally, PCB126 could activate AhR and its downstream effector phosphoenolpyruvate carboxylase. This suggests a possible role of PCBs as energy metabolism disruptor agents . Other studies showed that PCB153 could induce hepatocarcinoma through induction of NF-kB in mice (this was inhibited by deleting the p50 subunit of NF-kB)  or induce mutation in β-catenin (
PCBs administration could interfere with metals accumulation in the liver and affect their transport and excretion through kidneys. Mice fed different concentrations of PCBs with Cadmium (Cd)-enriched diets showed a reduction of Cd concentration in the liver. Also, liver histology of those mice revealed a characterized centrilobular enlargement of hepatocytes, hepatic focal necrosis and clear cytological signs of malignancy than the control group . On the other hand, female rats fed a diet enriched with high-dose Aroclor-1254 and Aroclor-1260 for 78 weeks developed initial iron accumulation in the liver by week 52, induced hepatocyte proliferation and eventually liver carcinoma by the 78th week, indicating that iron accumulation in the liver is an early sign of hepatic neoplasm transformation induced by PCBs .
Human exposure cohort studies were also conducted to monitor the pathological aspects of PCBs. Workers in capacitor factories exposed to Aroclors mixtures with 41–54% chlorine content had increased mortality rates from liver tumours (gall bladder and biliary tract) . The same finding was reported in HCC Italian patients settled in areas highly polluted with PCBs [46, 47]. The burden of PCBs concentration in liver, lung and kidney tissues of Chinese cancer patients residing near e-waste disassembly sites was very high (257.9 to 455.1 ng g−1), indicating a possible correlation between PCBs exposure and cancer incidence in those patients . Another long-term cohort study was conducted in Germany in former PCB-exposed workers. The study linked the change in liver enzymes and morphology with PCB exposure level. There was a significant inverse connection between PCB concentration and ɤGT and a significant association between liver enlargement and PCBs level . Another cohort study in the USA linked elevated levels of ortho-substituted PCBs and liver toxicant-associated steatohepatitis (TASH) in the former worker of PCB manufacturing complex. The authors reported that the increase in PCBs exposure was connected with an increase in liver disease burden, inflammation, steatohepatitis induction and hepatocyte apoptosis and fibrosis . A large and extensive cohort study was conducted on 138,905 electricity workers exposed to insulating liquids of PCBs at five different electricity companies between the period of 1950 and 1986. Poisson regression was utilized to examine mortality of skin cancer (melanoma) and liver cancer in relation to PCBs exposure. Results showed that PCBs exposure was linked to melanoma development and in some workers hepatic cancers . A controlled study was nested with two large prospective cohorts (one from Northern California Multiphasic Health Check-up (MHC) comprising 408 HCC cases and Norwegian Janus group comprising 84 HCC cases) from 1960 to 1980. Measuring 37 different congeners with GC-MS, the authors found that among measured congeners, PCBs (151, 170, 172,180,177 and 195) congeners were the highest with a concentration in HCC patients 1.3 to 1.4 ng/g lipid for the first group and 1.9 ng/g lipid for the second group, confirming a significant link between PCBs levels and HCC development .
PCBs can be indirectly accumulated in the human body through food chain by ingestion of aquatic animals contaminated with PCBs. For example, Delistraty study showed that PCBs titre in different aquatic animals in Columbia River, USA was significantly high. Sturgeon liver, whitefish fillet, carbs and smallmouth bass all showed significant high level of dioxin-like PCBs, non-dioxin like PCBs and total PCBs . Another study showed that Bottlenose dolphin was stranded alive with high levels of different PCBs such as PCB 153,180, 187 and 138. Finally, large cell immunoblastic lymphoma was observed in the hepatic sinuses of these dolphins accompanied with liver enlargement. All previous studies indicate a direct correlation between carcinogenesis induction and levels of PCBs in those dolphins .
1.1 Possible hepatocarcinogenic mechanisms of PCBs
PCBs mode of action and the underlined molecular mechanisms of toxicity and carcinogenicity have not been deciphered so far . Yet, studies on different animal models,
2,3′4,4′,5-Pentachlorobiphenyl known as PCB118, one of the most persistent congener members, was found to promote hepatocellular carcinoma SMMC-7721 cell proliferation and glycolysis through AhR, which subsequently elevates the expression of pyruvate kinase M2 (PKM2) and stimulation of reactive oxygen species (ROS) production through nicotinamide adenine dinucleotide phosphate (NADPH). These effects were inhibited by treating cells with PKM2 shRNA and superoxide dismutase, respectively .
PCB126 (3,3′,4,4′,5-Pentachlorobiphenyl), a non-ortho-chlorinated congener, was found to increase the synthesis of ROS specifically. Treatment of HepG2 cells with this congener enhance their carcinogenicity by inducing an oxidative stress response that was underlined by activation of mitogen-activated protein kinases (extracellular signal-regulated kinase 1/2), p38, c-Jun phosphorylation, activating protein-1 (AP-1) and finally an expression of antioxidant-responsive element (ARE)-dependent genes . In addition, Faust
PCB47, 49, 52, 77 and 153 have a tumour promoting activity . Also, some PCBs induce liver toxicity through induction of mixed function oxidases (phenobarbital, 3-methylcholanthrene)  and inhibition of anti-oxidant production such as PCB154, 155, 184 and 153 inhibit paraoxonase 1 (PON1) in treated rats .
Most PCBs mixtures with high chlorine content and their derived metabolites showed superior tumour-promoting characteristics. Yet, concern over low-chlorine content PCBs was raised after experiments showing that dihydroxy metabolites induce breast cancer by inducing oxidative DNA damage in breast cancer cells . Another possible mechanism of PCBs carcinogenicity is their ability to suppress the immune system and cause endocrine disruption . PCB104, 188 and their hydroxylated forms 4′-50, 4′-30, 4′-72, 4′-112 and 4′-121 disturb endocrine pathways in rainbow trout cultured hepatocytes and induced vitellogenin synthesis indicating altered liver physiology . Human MCF-7 cells exposed to PCBs analogues showed a reduction in catechol-O-methyltransferase (COMT) activity on the transcriptional and translational level
HepG2 cells co-treated with benzo-a-pyrene and different doses of Aroclor 1254 had a high degree of DNA damage (as indicated by DNA migration assay and formation of 8-hydroxy-2′-deoxyguanosine (8-OHdG)), oxidative stress and elevated CYP1A activity . In another experiment, HepG2 cells exposed to various PCBs concentration (0.01-10µM) exhibit aggressive carcinogenic behavious underlined by pERK Tyr204 and pMdm2 Ser166 which attenuated P53 activity in those cells .
Dioxin-like PCBs such as PCB 77 and 81 were shown to have direct genotoxic effects on Chinese hamster V79-derived cell line by inducing micronuclei formation, and induced expression of CYP1A1, CYP2E1 and γ-H2AX protein (a marker of DNA double-strand breaks) [65, 66].
Another surprising finding of PCBs-induced hepatic carcinogenicity is their ability to inhibit intercellular community between liver cells. Mouse hepatoma cell line (Hepa1c1c7) treated with TCDD and different PCBs showed a rapid intercellular inhibition after 2 hrs. of treatment accompanied with AhR activation and induction of ethoxyresorufin O-deethylase (EROD) activity (an early marker of PCBs induced oxidative stress) . Moreover, by using a quantitative polymerase chain reaction (qPCR) to quantify relative telomere length in lung and liver samples collected from rats treated with different PCBs (126, 153 and a mixture of them) showed larger relative telomere length, which is an early indication of euplastic or non-neoplastic pathogenic disease development .
Furan, a heterocyclic organic chemical, is considered as a human carcinogen and a liver toxicant in rodents . It is found in a broad spectrum of common heat-treated and jarred foods in addition to tobacco smoke. It is also generated from numerous precursors such as amino acids, ascorbic acid and carbohydrates . Infants received the highest furan exposure from ready-to-eat meals, while adults are exposed to furan by the dietary intake of coffee . Furan is found mainly in the liver and is metabolized to the reactive metabolite, cis-but-2-ene-1,4-dialdehyde (BDA) through cytochrome P450 2E1 (CYP2E1). Reported studies have indicated that humans can convert furan to its reactive metabolite and cis-2-butene-1,4-dial (BDA), and consequently may be subjected to furan toxicity .
Being hepatotoxic, researchers  stated that furan is associated with cholangiofibrosis in rats and HCC & adenomas in mice. They also indicated that oxidative stress, alterations in gene expression, epigenetic modifications, inflammation and increased cell proliferation represent indirect mechanisms that are included in carcinogenesis. The carcinogenic effects of furan have been referred to as genotoxic and non-genotoxic modes of action. Epigenetic alterations are among the most important non-genotoxic alterations induced by furan since they are related to all other non-genotoxic events . As a genotoxic furan could be linked to furan-into carcinogenicity, current human exposure levels to this hepatotoxicant may represent a risk to human health and required the necessity for its mitigation .
2.1 Possible hepatocarcinogenic mechanisms of furan
Metabolism of furan leads to the formation of protein adducts in the target organ. The first bioactivation step comprises the oxidation of cytochrome P450-catalysed of furan, which generates cis-2-butene-1,4-dial (BDA). BDA can react with lysine to form pyrrolin-2-one adducts . This metabolite directly reacts with DNA nucleophiles and proteins . It is also known as a bacterial mutagen in Ames assay strain TA104. According to metabolic studies, this reactive metabolite is formed
Being a hepatocarcinogen in mice and rats, furan induced an enhancement for cytotoxic pathways represented by signalling of stress-activated protein kinase (SAPK) and death receptor (DR5 and TNF-alpha), and proliferation through extracellular signal-regulated kinases (ERKs) and TNF-α. In addition, NF-kappa B and c-Jun (genes essential for liver regeneration) were involved in response to furan . Previous studies applying furan high doses revealed that it induced tumours at nearly 100% incidence at all doses . Fraction of H-ras codon 61 CAA to AAA mutation was increased in liver tumours of furan-treated mice . Besides, furan has a deleterious impact on the activity of crucial target enzymes included in ATP synthesis, glycolysis, redox regulation as well as b-oxidation in rat liver. After treatment with a high dose of furan, it was found that glyceraldehyde-3-phosphate dehydrogenase was significantly inhibited and observed some metabolic changes reliable to blockage of the glycolytic breakdown of glucose in the liver of the rat. Despite an increase in enoyl-CoA hydratase activity, an enhancement of ketone bodies production and a reduction in the activity of succinate dehydrogenase were recorded as a result of furan treatment. These enzymatic changes were linked to impairments occurring in cellular processes affecting the metabolic pathways and antioxidant defence and indicate mitochondrial dysfunction as a serious incident in furan toxicity . Moreover, targets of putative protein of furan reactive metabolites induced functional damage of numerous individual proteins and interference with pathways, especially that of mitochondrial energy production, redox regulation, and protein folding. This damage represented critical targets of furan toxicity and can combine together to disturb cell homeostasis and cause the cell death of hepatocytes .
The liver is the main target organ affected by furan as indicated by serum biomarkers changes, change in liver weights and histological lesions after exposure to furan. Accordingly, a dose of 0.03 mg/kg bw of furan was proposed to be the non-detectable serious effect for hepatic toxicity . In addition, Selmanoğlu
In addition, analysis of liver rats treated with furan by Comet assays showed breaks in both strands of DNA, an increase in oxidized purines and pyrimidines at cancer bioassay dosage represented by a near-linear dose-responsive manner . Consequently, these findings postulated that furan induces cancer mainly in rats’ liver through a secondary genotoxic mechanism including oxidative stress, a down-regulation in the expression of apoptotic, cell-cycle checkpoints as well as DNA-repair genes accompanied by inflammation and cell proliferation dosage .
Furthermore, glutathione S-transferase placental form-positive (GST-P) foci are considered as preneoplastic lesions markers in the hepatocarcinogenic rats. Using reporter gene transgenic rats, it was found that furan rapidly induces GST-Pþ foci formation without reporter gene mutation after short exposure . On the other hand, GST-P foci development is probably due to cell proliferation other than the genotoxic mode of action in furan-treated rats. Based on the close association between neoplastic hepatocytes and GST-P, Hibi
Cholangiofibrosis is defined as a physical anomaly that occurs before cholangiocarcinoma development in some rodents. Some reports explained that severely affected areas of the liver representing injury due to furan administration were extended into the portal and capsular parts, resulting in a rapid ductular cells proliferation that extended into the parenchyma accompanied by a subtype of liver fibroblasts. These ductules were differentiated into hepatocytes lacking fibroblasts or developed to form tortuous ductular structures replacing much of the parenchyma, leading to cholangiofibrosis . Moreover, furan-induced cholangiocarcinomas were proposed to develop from cholangiofibrosis areas as a consequence of indirect and chronic damage to DNA through oxygen radicals joined with persistent proliferative signals, including loss of connexin 32, which acts to translate this DNA damage to fixed mutations .
2.1.1 Epigenetic alterations and the non-genotoxic mechanism of furan in liver
The carcinogenic effect of furan has been referred to as a genotoxic and non-genotoxic mechanism comprising epigenetic alterations in liver tissue . Some reports postulated that furan carcinogenicity is caused by a non-genotoxic mechanism since it was not genotoxic in
In addition, epigenetic alterations involving DNA and microRNA (miRNA) methylation play a fundamental role in inducing furan carcinogenicity. It was indicated that DNA methylation changes and miRNA modulation followed by a DNA-damage response are the most pronounced alterations resulted from the use of 3-month furan treatment at a carcinogenic dose suggesting that non-genotoxic mechanisms are crucial for furan carcinogenicity . It was found that gene-specific DNA methylation alterations have an essential role in the contribution of furan hepatotoxicity and hepatocarcinogenicity . Other studies indicated that aberrations in microRNAs (miRNAs) expression are one of the non-genotoxic alterations induced by furan exposure, which highlighted the role of epigenetic impairments in the furan hepatotoxicity mechanism .
Since the mammalian genome is transcribed into mRNAs that code for protein and other non-coding RNA products . Long non-coding-RNAs (lncRNA) are known as ncRNA species >200 nucleotides long, which represent significant epigenetic regulators of gene expression and are included in a wide spectrum of biological processes related to toxicology. Recio
Dioxins are considered as representative toxic agents among persistent organic pollutants and a large family of halogenated aromatic hydrocarbons, which composed of tricyclic aromatic compounds . These compounds are produced by industrial wastes and can accumulate in soil, sediments as well as food chains with long half-life of numerous years, affecting human health . 2,3,7,8-Tetrachlorodibenzo -p-dioxin (TCDD) is a typical representative and the most toxic substance of dioxins, which exhibits systemic hepatotoxicity, carcinogenicity, immunotoxicity, teratogenicity, endocrine disruption and also affects pathology and physiology of human skin . Being with four chlorine atoms in lateral positions, 2,3,7,8 Tetrachlorodibenzop-dioxin (TCDD) is the most biologically active isomer of dioxins . It is a widespread and persistent pollutant in the environment originated from waste incineration or metal industries, plastics manufacturing and paper processing . Moreover, it plays a significant role by binding to AhR for endocrine changes in experimental animals . Besides, Türkez, Türkez
3.1 TCDD exposure and dioxin receptor
The aryl hydrocarbon receptor (AhR) is considered as a ligand-activated receptor which enables environmental pollutant toxicity like 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) . It is also known as xenobiotic receptor or dioxin receptor and is a member of the basic helix-loop-helix/period AhR nuclear translocator single-minded family . AhR translocates to the nucleus after binding to TCDD, dimerizes with AhR nuclear-translocator protein, binds to dioxin-responsive elements and up-regulates a series of genes expression that encode xenobiotic-metabolizing enzymes, such as cytochrome P450s (e.g. CYP1A1, CYP1A2), NAD(P)H quinone oxidoreductase as well as a form of UDPglucoronosyl-transferase-6 . Even though AhR may serve as part of an adaptive chemical response, numerous studies reported that this dioxin receptor has important functions in liver, cell proliferation, cardiac development [104, 105] and the ubiquitin-proteasome system . AhR plays a fundamental role in three biological aspects including xenobiotics metabolism, the toxic responses related to TCDD (dioxin) exposure and the vascular remodelling of the developing embryo. Using
Being a generally expressed ligand-dependent transcription factor, AhR mediates cellular responses to dioxins. Boutros
In response to dioxin, Kennedy
TCDD can induce hepatic fibrosis through a sequential events of steatosis followed by steatohepatitis. Lee, Wada  investigated the role of AhR in liver steatosis in wild type and transgenic mice. They concluded that AhR activated in liver cells induced CD36 expression, enhanced the uptake of fatty acids and steatosis induciton .
Cytochrome P4502E1 (CYP2E1) mainly expressed in liver, is involved in the metabolic activation of carcinogens and hepatotoxins such as TCCD and CCl4. At post-transcriptional levels, CYP2E1 is induced and exerted mostly through mRNA and protein stabilization, while xenobiotic induction is found to be very limited at the transcriptional level . Since the effect of xenobiotics on CYP2E1 liver, expression is of significant attention. Therefore, Mejia-Garcia
Recent studies revealed that TCDD exposure had caused increased productions of lipid peroxidation, reactive oxygen species and histopathological injury in the liver of both rats and mice . This exposure also enhances oxidative stress and diminishes the fluidity of hepatic membrane and glutathione (GSH) content, as well as imbalances the antioxidant enzymes in the liver [112, 113]. Moreover, an increase in the relative weight of the liver, a significant increase in all of the hepatic biomarker levels (glucose, cholesterol, triglycerides, AST, ALT and LDH) in the serum and a decrease of the antioxidant enzyme activities (catalase, glutathione peroxidase and superoxide dismutase) were observed under dioxin effect in hepatic tissue of rat . Additionally, Bentli
4. Zebrafish models of PCBs-, furan- and dioxin-induced hepatocarcinogenesis
Viluksela and Pohjanvirta  reported that paternal exposure to TCDD was considered as the most effective congenator of dioxins in laboratory rodents and zebrafish as it can lower the reproductive performance and reduce the male/female ratio of offspring. Therefore, it will affect subsequent generations
Besides, previous studies have demonstrated that dioxins broadly alter hepatic mRNA levels . Unexpectedly, Boverhof, Burgoon  found that responses of mouse and rats to TCDD exposure revealed that rat and mouse responses diverge significantly through analysis of a limited portion of their transcriptome. Accordingly, it was suggested that both mice and rat models should be applied to detect the acute hepatotoxicity of xenobiotics .
Under fabp10a promoter, Zhang  also established a line of transgenic zebrafish line (LiPan) characterized with the expression of liver-specific red fluorescent protein (DsRed), which enables the observation of liver in live LiPan fry. They revealed that TCDD could significantly increase both liver red fluorescence and size in LiPan fry. Thus, LiPan transgenic fry offers a suitable and rapid hepatotoxicity assay
Furthermore, by using the inducible
Environmental pollutants are a severe persistent burden, which cause a broad spectrum of health problems not only to aquatic animals but also to humans. Among them, PCBs, furan and dioxin are organic pollutants that were widely used in different applications before they were banned due to their carcinogenic potential. Different studies using different model animals and screening systems (