Developmental effects of trichloroacetate in Zebrafish embryos: Association with the production of superoxide anion.

To assess the developmental toxicity of trichloroacetate (TCA), zebrafish embryos were exposed to 8 to 48 mM of TCA and evaluated for developmental milestones from 8- to 144-hour postfertilization (hpf). All developmental toxicities are reported in this paper. Embryos were found to have developed edema in response to 16 to 48 mM of TCA exposure at 32- to 80-hpf, experienced delay in hatching success in response to 24 to 48 mM at 80-hpf. Lordosis was observed in developing embryos exposed to 40 to 48 mM at 55- to 144-hpf. The observed toxic effects of TCA exposure were found to be concentration and exposure period independent. Effects were found to be associated with increases in superoxide anion production, but these increases were also found to be concentration and time independent. TCA resulted in concentration-dependent increases in embryonic lethality at 144-hpf, with an LC50 determined to be 29.7 mM.

Comparative toxicity studies on bromochloroacetate, dibromoacetate, and bromodichloroacetate in J774A.1 macrophages: Roles of superoxide anion and protein carbonyl compounds.

The brominated and mixed bromo-chloro-haloacetates, such as dibromoacetate (DBA), bromochloroacetate (BCA), and bromodichloroacetate (BDCA), are by-products of water chlorination and are found at lower levels than the fully chlorinated acetates in the drinking water. The toxicities of the compounds were assessed in J774A.1 cells and were found to induce concentration-dependent increases in cell death and superoxide anion and protein carbonyl compounds production. Compared to the previously tested concentrations of dichoroacetate (DCA) and trichloroacetate (TCA) in the same cell line, the tested haloacetates induced similar effects on cellular viability and superoxide anion production but at DBA and BCA concentrations that were approximately 40-160 times lower than those of DCA and TCA, and at BDCA concentrations that were 4-16 times lower than those of DCA and TCA. Also, production of super oxide anion, protein carbonyl compounds, and induction of phagocytic activation are suggested to play a role in their toxicity.

Identification and characterization of the zebrafish glutathione S-transferase Pi-1.

Zebrafish has in recent years emerged as a popular vertebrate model for use in pharmacological and toxicological studies. While there have been sporadic studies on the zebrafish glutathione S-transferases (GSTs), the zebrafish GST gene superfamily still awaits to be fully elucidated. We report here the identification of 15 zebrafish cytosolic GST genes in NCBI GenBank database and the expression, purification, and enzymatic characterization of the zebrafish cytosolic GST Pi-1 (GSTP1). The cDNA encoding the zebrafish GSTP1 was cloned from a 3-month-old female zebrafish, expressed in Eschelichia coli host cells, and purified. Purified GSTP1 displayed glutathione-conjugating activity toward 1-chloro-2,4-dinitrobenzene as a representative substrate. The enzymatic characteristics of the zebrafish GSTP1, including pH-dependency, effects of metal cations, and kinetic parameters, were studied. Moreover, the expression of zebrafish GSTP1 at different developmental stages during embryogenesis, throughout larval development, onto maturity was examined.

The induction of phagocytic activation by mixtures of the water chlorination by-products, dichloroacetate- and trichloroacetate, in mice after subchronic exposure.

In this study, groups of B6C3F1 male mice were treated with dichloroacetate (DCA), trichloroacetate (TCA), and mixtures of the compounds (Mix I, II, and III) daily by gavage, for 13 weeks. The tested doses were 7.5, 15, and 30 mg DCA/kg/day and 12.5, 25, and 50 mg TCA/kg/day. The DCA: TCA ratios in Mix I, II, and III were 7.5:12.5, 15:25, and 30:50 mg/kg/day, respectively. Peritoneal lavage cells were collected at the end of the treatment period and assayed for the biomarkers of phagocytic activation, including superoxide anion and tumor necrosis factor-alpha production, and myeloperoxidase activity. The mixtures produced nonlinear effects on the biomarkers of phagocytic activation, with Mix I and II effects were found to be additive, but Mix III effects were found to be less than additive.

Vitamin E restriction in the diet enhances phagocytic activation by dichloroacetate and trichloroacetate in mice.

The effects of a vitamin E-restricted diet on the induction of phagocytic activation by dichloroacetate (DCA) and trichloroacetate (TCA) was investigated. Groups of B6C3F1 male mice were either kept on standard diet (Std diet group) or diet that had the vitamin provided only by its natural ingredients (Low-E diet group). The animals in each diet group were administered 77 mg of DCA or TCA/ kg/day, or 5 ml/kg water (controls), by gavage, for 13 weeks. Thereafter, peritoneal lavage cells (PLC) were assayed for superoxide anion (SA), tumor necrosis factor (TNF)-α, and myeloperoxidase (MPO), as well as for the activities of the anti-oxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). SA and TNFα production, as well as MPO, SOD, CAT and GSH-Px activities were significantly increased in the cells from the Low-E diet group treated with the compounds as compared with cells from hosts in the Std-diet group that received the corresponding treatments. The results indicate that consumption of a Vitamin E-restricted diet enhances the induction of phagocytic activation by DCA and TCA, a mechanism that was previously suggested to be an initial adaptive/protective response against the compounds long-term effects.

Dichloroacetate- and Trichloroacetate-Induced Modulation of Superoxide Dismutase, Catalase, and Glutathione Peroxidase Activities and Glutathione Level in the livers of Mice after Subacute and Subchronic exposure.

Dichloroacetate (DCA) and trichloroacetate (TCA) were previously found to induce various levels of oxidative stress in the hepatic tissues of mice after subacute and subchronic exposure. The cells are known to have several protective mechansims against production of oxidative stress by different xenobiotics. To assess the roles of the antioxidant enzymes and glutathione (GSH) in DCA- and TCA-induced oxidative stress, groups of B6C3F1 mice were administered either DCA or TCA at doses of 7.7, 77, 154 and 410 mg/kg/day, by gavage for 4 weeks (4-W) and 13 weeks (13-W), and superoxide dismutase (SOD) catalase (CAT) and glutathione peroxidase (GSH-Px) activities, as well as GSH were determined in the hepatic tissues. DCA at doses ranging between 7.7-410, and 7.7-77 mg/kg/day, given for 4-W and 13-W, respectively, resulted in either suppression or no change in SOD, CAT and GSH-Px activities, but doses of 154-410 mg DCA/kg/day administered for 13-W were found to result in significant induction of the three enzyme activities. TCA administration on the other hand, resulted in increases in SOD and CAT activities, and suppression of GSH-Px activity in both periods. Except for the DCA doses of 77-154 mg/kg/day administered for 13-W that resulted in significant reduction in GSH levels, all other DCA, as well as TCA treatments produced no changes in GSH. Since these enzymes are involved in the detoxification of the reactive oxygen species (ROS), superoxide anion (SA) and H(2)O(2), it is concluded that SA is the main contributor to DCA-induced oxidative stress while both ROS contribute to that of TCA. The increases in the enzyme activities associated with 154-410 mg DCA/kg/day in the 13-W period suggest their role as protective mechanisms contributing to the survival of cells modified in response to those treatments.

The induction of tumor necrosis factor-alpha, superoxide anion, myeloperoxidase, and superoxide dismutase in the peritoneal lavage cells of mice after prolonged exposure to dichloroacetate and trichloroacetate.

The induction of phagocytic activation in response to prolonged treatment with different doses of dichloroacetate (DCA) and trichloroacetate (TCA) has been investigated in mice. Groups of B6C3F1 male mice were administered 7.7, 77, 154, and 410 mg of DCA or TCA/kg/day, postorally, for 4- and 13-weeks. Peritoneal lavage cells (PLCs) were isolated and assayed for the different biomarkers of phagocytic activation, including superoxide anion (SA), tumor necrosis factor-alpha (TNF-alpha), and myeloperoxidase (MPO). In addition, the role of superoxide dismutase (SOD) in the SA production was also assessed. DCA and TCA produced significant and dose-dependent increases in SA and TNF-alpha production and in MPO activity, but the increases in response to the high doses of the compounds (>77 mg/kg/day) in the 13-week treatment period were less significant than those produced in the 4-week treatment period. Also, dose-dependent increases in SOD activity were observed in both periods of treatments. In general, the results demonstrate significant induction of the biomarkers of phagocytic activation by doses of DCA and TCA that were previously shown to be noncarcinogenic, with significantly greater increases observed at the earlier period of exposure, as compared with later period. These findings may argue against the contribution of those mechanisms to the hepatotoxicity/hepatocarcinogenicity of the compounds and suggest them to be early adaptive/ protective mechanisms against their long-term effects.

Dichloroacetate- and trichloroacetate-induced oxidative stress in the hepatic tissues of mice after long-term exposure.

Dichoroacetate (DCA) and trichloroacetate (TCA) were found to be hepatotoxic and hepatocarcinogenic in rodents. To investigate the role of oxidative stress in the long-term hepatotoxicity of the compounds, groups of mice were administered 7.7, 77, 154 and 410 mg kg(-1) per day, of either DCA or TCA, by gavage, for 4 weeks (4-W) and 13 weeks (13-W), and superoxide anion (SA), lipid peroxidation (LP) and DNA-single strand breaks (SSBs) were determined in the hepatic tissues. Significant increases in all of the biomarkers were observed in response to the tested doses of both compounds in the two test periods, with significantly greater increases observed in the 13-W, as compared with the 4-W, period. Hepatomegaly was only observed with a DCA dose of 410 mg kg(-1) per day in the 13-W treatment period, and that was associated with significant declines in the biomarkers, when compared with the immediately lower dose. With the exception of LP production in the 13-W treatment period that was similarly induced by the two compounds, the DCA-induced increases in all of the biomarkers were significantly greater than those of TCA. Since those biomarkers were significantly induced by the compounds' doses that were shown to be carcinogenic but at earlier periods than those demonstrating hepatotoxicity/haptocarcinogencity, they can be considered as initial events that may lead to later production of those long-term effects. The results also suggest LP to be a more significant contributing mechanism than SA and DNA damage to the long-term hepatotoxicity of TCA.

Assessment of the roles of antioxidant enzymes and glutathione in 3,3',4,4',5-Pentachlorobiphenyl (PCB 126)-induced oxidative stress in the brain tissues of rats after subchronic exposure.

The abilities of various doses of 3,3',4,4',5-pentachlorobiphenyl (PCB126) to induce changes in antioxidant enzyme activities and glutathione levels in the brain tissues of rats were examined in rats after subchronic exposure. Groups of rats were administered 10,30, 100, 300, 550 or 1000 ng PCB 126/kg/day, p.o., for 13 weeks and the activities of supeoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), as well as (GSH) levels were determined in the brain tissue homogenates. Treatment resulted in significant and dose-dependent increases in the activities of the three tested enzymes. While maximal increase GSH-Px activity was achieved with a dose of 100-175 mg/kg/day, CAT and SOD activities continued to increase in response to maximal dose used for this study. GSH levels on the other hand, were suppressed significantly in a dose-dependent fashion. Data suggest that previously observed increase in oxidative stress production by PCB-126 in the brain tissues of rats is associated with dose-dependent rise in antioxidant enzyme activities and GSH depletion. However, the increases in the antioxidant enzyme activities can not provide full protection against oxidative damage induced by the same doses. In addition, GSH depletion plays a critical role in the previously observed oxidative stress in response to this compound.

Dichloroacetate-induced modulation of cellular antioxidant enzyme activities and glutathione level in the J774A.1 cells.

Dichloroacetate (DCA) is used for different medical and industrial purposes and has been found to be a toxic by-product produced during the process of water chlorination. The DCA effects on superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) activities and glutathione (GSH) level were assessed and correlated with each other and also with cellular viabilities in J774A.1 macrophage cells. A concentration of 24 mm of DCA resulted in time-dependent decreases in cellular viability and glutathione level, and time-dependent increases in SOD activity when incubated with the cells for 24-48 h. DCA also resulted in significant increases in CAT and GSH-Px activities of the viable cells when incubated with the cells for 36 and 48 h. The changes in antioxidant enzyme activities and GSH levels were found to be strongly correlated with each other, and with cellular viabilities at different time points. While GSH did not result in any significant effects when added to the cells at concentrations ranging between 15 and 60 nmol ml(-1), it resulted in concentration-dependent increases in cellular viability when added to the DCA-treated cells, with maximal effects achieved at 45-60 nmol GSH ml(-1). However, cellular viability of the GSH + DCA treated cells remained below that of the control. Since viable cells from the DCA-treated cultures displayed significantly higher antioxidant enzyme activities compared with the control, it is concluded that those increases may have contributed to the cellular protection against DCA-induced cell death. Also, glutathione depletion has a major contribution to the observed cellular death induced by DCA.

Dichloroacetate- and trichloroacetate-induced phagocytic activation and production of oxidative stress in the hepatic tissues of mice after acute exposure.

Dichoroacetate (DCA) and trichloroacetate (TCA) are by-products formed during chlorination of the drinking water and were found to be hepatotoxic and hepatocarcinogenic in rodents. In this study, the abilities of the compounds to induce oxidative stress and phagocytic activation have been studied in B6C3F1 mice. Groups of mice were administered 300 mg/kg of either DCA or TCA, p.o, and were sacrificed after 6 or 12 h. Peritoneal lavage cells (PLCs) were isolated and assayed for superoxide anion (SA) production, and hepatic tissues were assayed for the production of SA, lipid peroxidation (LP), and DNA-single strand breaks (SSBs). TCA resulted in significant production of SA in the PLCs, and in the production of SA, LP, and DNA-SSBs in the hepatic tissues, 12 h after dosing, as compared with the control. DCA administration, on the other hand, resulted in significant increases in the productions of LP and DNA-SSBs in the hepatic tissues at both time points, and in SA production in PLCs and hepatic tissues, 6 h after dosing. However, DCA-induced increases in SA production in PLC and hepatic tissues declined at the 12-h time point, reaching control level in the hepatic tissues. These results may implicate the contribution of phagocytic activation to the induction of oxidative stress in the hepatic tissues and also the role of SA production in the induction of LP and/or DNA damage in those tissues, in response to the compounds. The results also suggest studying the involvement of these mechanisms in the long-term hepatotoxicity/hepatocarcinogencity of the compounds.

Association between the levels of biogenic amines and superoxide anion production in brain regions of rats after subchronic exposure to TCDD.

The effects of TCDD on the distribution of biogenic amines and production of superoxide anion (SA) in different brain regions of rats have been studied after subchronic exposure. Groups of females Sprague-Dawley rats were administered daily dose of 46ng TCDD/(kgday) (treated groups), or the vehicle used to dissolve TCDD (control group), for 90 days. The rats were sacrificed at the end of the exposure period and their brains were dissected into different regions including, hippocampus (H), cerebral cortex (Cc), cerebellum (C), and brain stem (Bs). The levels of different biogenic amines and some of their metabolites, including, norepinephrine (NE), dopamine (DA), 3,4-dihydroxy phenyl acetic acid (DOPAC), 4-hydroxy-3-methoxy-phenyl acetic acid (HVA), 5-hydroxy tryptamine (5-HT), and 5-hydroxy indole 3-acetic acid (5-HIAA), were determined in those brain regions, using a high performance liquid chromatography (HPLC) system with an electrochemical detector. SA production was also determined in those regions, using the cytochrome c reduction method. Results of analyses indicate significant increases in the levels of DA, NE and DOPAC in H, NE and HVA in Cc, NE and DA in Bs and NE in C. SA production was significantly increased in H and Cc, but not in Bs or C. The results also indicated strong correlations between DA and DOPAC, and SA and NE in all of the brain regions, and also between SA and 5-HT/HIAA in H and Cc. These results may indicate the contribution of biogenic amines, especially NE and 5-HT/HIAA to SA overproduction in some brain regions and may also indicate the potential of long term neurotoxic effects of those biogenic amines, in response to subchronic exposure to TCDD.

The effects of ellagic acid and vitamin E succinate on antioxidant enzymes activities and glutathione levels in different brain regions of rats after subchronic exposure to TCDD.

Ellagic acid (EA) and vitamin E succinate (VES) were previously shown to protect against 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD)-induced reactive oxygen species (ROS) overproduction in certain brain regions of rats after subchronic exposure. The current study was designed to assess the modulation of antioxidant enzyme activities and glutathione (GSH) levels as protective measures for VES and EA against TCDD-induced ROS overproduction in four regions of rat brain. TCDD was administered to groups of rats at a daily dose of 46 ng/kg for 90 d. EA and VES were administered to some other groups of rats either alone or simultaneously with TCDD, every other day for 90 d. At the end of the treatment period, animals were sacrificed and brain regions were dissected, including cerebral cortex (Cc), hippocampus (H), cerebellum (C), and brainstem (Bs), for assay of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities, as well as GSH levels. While treatment of rats with VES alone or in combination with TCDD resulted in significant increases in SOD and CAT activities in different brain regions, treatment with EA resulted in a significant rise in total GSH levels and GSH-Px activity in those regions. Results may suggest antioxidant modulation by VES and EA as a mechanism for the previously observed protection by these compounds against TCDD-induced ROS overproduction in brain. Data also indicate there are two different pathways in the protection provided by the two antioxidants.

The modulatory effects of ellagic acid and vitamin E succinate on TCDD-induced oxidative stress in different brain regions of rats after subchronic exposure.

The effects of ellagic acid (EA) and vitamin E succinate (VES) on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced oxidative stress in different brain regions of rats have been studied after subchronic exposure to the compounds. TCDD was administered to groups of rats at a dose of 46 ng/kg/day for 90 days. EA and VES were administered to groups of rats, either separately or simultaneously with TCDD, every other day for 90 days. At the end of the treatment period, animals were sacrificed and brains were dissected to cerebral cortex (Cc), hippocampus (H), cerebellum (C), and brain stem (Bs), and were assayed for production of superoxide anion (SA), lipid peroxidation (LP), and DNA single-strand breaks (SSBs). While TCDD administration to rats resulted in significant production of SA, LP, and DNA SSBs in Cc and H, simultaneous administration of VES or EA with the xenobiotics resulted in significant protection against those effects. The results also indicate that VES provided a better protyection against TCDD-induced effects in brains when compared with EA.

Protective effects of vitamin A and vitamin E succinate against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced body wasting, hepatomegaly, thymic atrophy, production of reactive oxygen species and DNA damage in C57BL/6J mice.

The protective effect of vitamin A and vitamin E succinate against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced acute toxicity and measures of oxidative stress was studied. Ten mice were treated with either vitamin A (50 mg/kg every other day for eight days) or vitamin E succiante (150 mg/kg/day followed by a dose of 40 mg/kg/day for five additional days). Half of each of the above groups of animals received TCDD on day 4. Five mice received corn oil or TCDD alone. After five days of TCDD treatment, antioxidant combination treatment with vitamin A and TCDD or vitamin E succinate and TCDD resulted in a significant reduction in indicators of acute toxicity including the decrease in total body and thymus weight as compared to TCDD alone (P<0.05). The combination treatment produced also a significant reduction in the increase in liver weight as compared to TCDD only (P<0.05). Following one day of treatment with 50 microg TCDD/kg, vitamin A and vitamin E succinate produced a significant decrease in the production of superoxide anion by peritoneal lavage cells (P<0.05) and in DNA-single strand breaks in the same cells (P<0.05) as assessed by the reduction of cytochrome c and the alkaline elution technique, respectively. A significant decrease in DNA-single strand breaks in peritoneal lavage cells was observed following 5 days treatment with 50 microg TCDD/kg (P<0.05). The results indicate a potential role for oxidative stress in the acute toxicity of TCDD and a protective effect for vitamin A and vitamin E succinate in the overall toxicity of TCDD including measures of oxidative stress.

Effects of superoxide dismutase and polyclonal tumor necrosis factor-alpha antibodies on chloroacetate-induced cellular death and superoxide anion production by J774.A1 macrophages.

Dichloroacetate (DCA) and trichloroacetate (TCA) are by-products that are formed during the process of water chlorination and have been previously shown to induce superoxide anion (SA) production and cellular death when added to J774.A1 macrophage cultures. In this study, the effects of superoxide dismutase (SOD) and polyclonal tumor necrosis factor-alpha (TNF-alpha) antibodies on DCA- and TCA-induced SA production and cellular death have been tested on the J774.A1 macrophage cultures. TCA and DCA were added to different cultures either alone, each at a concentration of 16 mM, or in combination with SOD (2-12 units/ml), or with TNF-alpha antibodies (10 and 25 units/ml). Cells were incubated for 48 h, after which cellular death/viability, lactate dehydrognase (LDH) leakage by the cells, and SA production by the cells were determined. While TCA and DCA caused significant cellular toxicity, indicated by reduction in cellular viability and increases in LDH leakage and SA production, SOD addition resulted in significant reduction of the effects induced by the compounds. On the other hand, addition of TNF-alpha antibodies to the DCA- and TCA-treated cultures resulted in significant reduction of DCA- but not TCA-induced cellular death and SA production by the cells. Although these results suggest a significant role for SA in DCA- and TCA-induced cellular death, they may also suggest two different mechanisms for the chloroacetate-induced SA production by the cells.

The role of antioxidant enzymes in TCDD-induced oxidative stress in various brain regions of rats after subchronic exposure.

The induction of oxidative stress by TCDD in various brain regions of rats has been investigated after subchronic exposure. TCDD was administered by gavage to female Sprague-Dawley rats at daily doses of 0, 10, 22, and 46 ng/kg for 13 weeks. The brains were dissected to cerebral cortex (Cc), hippocampus (H), cerebellum (C), and brain stem (Bs); the production of superoxide anion (SA) and lipid peroxides and the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px) were determined in those regions. TCDD caused dose-dependent increases in the production of SA and lipid peroxidation in Cc and H and those were associated with dose-dependent suppressions of SOD. While a TCDD dose of 10 ng/kg/d resulted in significant increases in catalase and GSH-Px activities in Cc and H, doses of 22 and 46 ng/kg/d resulted in dose-dependent suppressions of these two enzymes in the same regions. In the C and Bs, TCDD treatment did not result in significant production of SA and lipid peroxidation but it resulted in dose-dependent increases in the activities of various antioxidant enzymes. These results suggest that Cc and H are vulnerable to TCDD-induced oxidative stress after subchronic exposure, and that C and Bs are protected against that effect.

The induction of oxidative stress and cellular death by the drinking water disinfection by-products, dichloroacetate and trichloroacetate in J774.A1 cells.

The in vitro toxicity of the drinking water disinfection by products dichloroacetate (DCA) and trichloroacetate (TCA) were studied using the J774A.1 macrophage cell line. DCA and TCA were added to cell cultures at concentrations ranging between 8-32 mM and incubated for 24, 36 and 60 h. DCA and TCA effects on cellular viability, lactate dehydrogenase (LDH) release and superoxide anion (SA) production by the cells, as well as superoxide dismutase (SOD) activities of the cells were determined. DCA and TCA caused time- and concentration-dependent increases in cellular death, in LDH release and production of SA by the cells. The compounds also caused modulations in SOD activities of the cells, with increases observed at the lower concentrations and/or shorter periods of incubations and suppression with the higher concentrations and/or longer periods of incubation. The results of the study indicate that DCA and TCA induce macrophage activation and that the activation is associated with cellular toxicity. Also, DCA and TCA are found to be equitoxic to J774.A1 cells.

Induction of oxidative stress in the tissues of rats after chronic exposure to TCDD, 2,3,4,7,8-pentachlorodibenzofuran, and 3,3',4,4',5-pentachlorobiphenyl.

The abilities of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB126), and mixtures of these xenobiotics (toxic equivalents, TEQs) to induce oxidative stress in hepatic and brain tissues of rats have been investigated after chronic (30 wk) exposure to these congeners. TCDD, PeCDF, PCB126, and TEQs were administered daily to groups of rats at doses that corresponded to their toxic equivalency factors (TEFs), and the biomarkers of oxidative stress, including the production of superoxide anion, lipid peroxidation, and DNA single-strand breaks (SSBs), were determined in hepatic and brain tissues at the end of the exposure period. The three chemicals caused similar dose-dependent increases in the production of superoxide anion, lipid peroxidation, and DNA SSBs, which plateaued at certain dose ranges, followed by secondary increases at the higher dose levels. Similar effects were also produced by the TEQs; however, the dose-dependent increases in the biomarkers of oxidative stress were continuous and never achieved plateau levels. Except for PCB126, where statistical analyses revealed greater productions of superoxide anion and lipid peroxidation in brain tissues as compared with hepatic tissues, no significant differences were revealed between the two tissues in response to the other xenobiotics or the TEQs. Nonsignificant differences were also revealed when comparing the effects induced by the TEQs with those induced by the individual chemicals.