Age-related changes in toxicity and biotransformation of potassium cyanide in male C57BL/6N mice

Age-related changes in toxicity and biotransformation of KCN, an ubiquitous environmental toxicant, have not been previously examined. Male C57BL/6N mice aged 2-3 (young), 10-12 (middle-aged), and 25-30 (old) months were administered KCN at 1, 2, 4, and 6 mg/kg po, and toxic manifestations were monitored for up to 2 hr. The toxic response to KCN (prostration and labored breathing) was significantly greater in 10-12 and 25-30 month vs that in 2-3 month mice at 4 and 6 mg/kg KCN. The basis for this age-related difference in in vivo toxicity was examined by studying biotransformation of KCN to thiocyanate by liver and brain rhodanese (RHO), as well as activity of liver and brain cytochrome oxidase (C-OX), inhibition of C-OX by KCN, and activity of beta-mercaptopyruvate transsulfurase (MT). Tissue and blood levels of CN- following a toxic dose of 6 mg/kg KCN were also measured. No age-related differences were observed in the specific activity of liver and brain RHO, MT, or C-OX. In addition, no differences were observed in the percentage inhibition of C-OX by KCN, or in the Ki for inhibition of brain and liver C-OX. However, activity of brain RHO on a per gram tissue basis was significantly lower in 10-12 and 25-30 months vs that in 2-3 month mice. Liver and blood concentrations of CN- were not significantly different in 2-3 vs 10-12 month mice following treatment with 6 mg/kg KCN; however, significantly greater concentrations of CN- were observed at 4 and 25 min in brains of 10-12 month mice compared to that in 2-3 month mice. These results indicate that increased sensitivity to KCN in older mice may be due in part to a decrease in the amount of brain RHO and altered tissue kinetics of CN- following a toxic dose in older mice.     

Immunotoxicity in C57BL/6 mice exposed to benzene and Aroclor 1254

Benzene-induced hematotoxicity is believed to result from the reaction of benzene metabolites with hemopoietic cells. The effect of acute benzene exposure on splenic lymphocyte function in mice was examined before and after induction of hepatic metabolism with Aroclor 1254. Mice were given single, ip injections of benzene (44–660 mg/kg) for 3 consecutive days. Spleen cells were harvested on the fourth day and evaluated for their ability to proliferate after mitogen stimulation and to mature into antibody-producing cells. Mice also were pretreated 4 days prior to benzene administration with 550 mg/kg Aroclor 1254 to induce hepatic metabolism. The results showed that benzene inhibited T- and B-lymphocyte mitogenesis and inhibited the ability of antigen-reactive precursors to produce plaque-forming cells (PFC) against sheep red cells. Aroclor pretreatment ameliorated benzene-induced leukopenia and suppression of mitogenesis, but did not prevent the reduction in PFC. Aroclor alone caused a dose-dependent reduction in PFC frequency. These results indicate that Aroclor 1254 can preferentially inhibit the generation of antibody-producing cells and also suggest that hepatic metabolism of benzene results in toxicity to lymphocyte function.     

Comparative metabolism of benzene and trans,trans-muconaldehyde to trans,trans-muconic acid in DBA/2N and C57BL/6 mice

Our laboratory recently identified trans,trans-muconaldehyde (MUC), a six-carbon diene dialdehyde, as a hematotoxic microsomal metabolite of benzene (Latriano et al., Proc Natl Acad Sci USA 83: 8356-8360, 1986). We also showed that MUC is metabolized in vitro to trans,trans-muconic acid (MA), a six-carbon diene dicarboxylic acid and known urinary metabolite of benzene. To elucidate further the role of ring-opened metabolites in benzene toxicity, the metabolism of benzene and MUC was examined in the benzene sensitive DBA/2N mouse strain and the less benzene sensitive C57BL/6 strain. A sensitive assay for urinary MA analysis was developed. The percent of benzene dose excreted as urinary MA within the first 24 hr after treatment decreased with an increase in benzene dose, i.e. from 9.8 to 0.4% in DBA/2N mice and from 17.6 to 0.2% in C57BL/6 mice treated with 0.5 to 880 mg/kg benzene. DBA/2N mice excreted significantly (P less than or equal to 0.05) more MA compared with C57BL/6 mice after treatment with hematotoxic benzene doses (220-880 mg/kg). At low benzene doses (0.5 to 2.5 mg/kg), C57BL/6 mice excreted significantly (P less than or equal to 0.05) more MA compared with DBA/2N mice. There were no significant differences in the metabolism of MUC to MA between the two strains after treatment with 0.5 to 3.0 mg/kg. Furthermore, mice from both strains excreted similar amounts of muconic acid when treated with 0.7 to 7.1 mg/kg MA. These results are consistent with the hypothesis that reactive ring-opened metabolites such as trans,trans-muconaldehyde play a role in benzene hematotoxicity. Sensitivity towards benzene may be due, in part, to increased metabolism to ring-opened compounds.     

Ethanol vapor self-administration in adult C57BL/6J male mice

To determine if ethanol vapor is reinforcing, chambers with two nose-poke devices were used. First, C57BL/6J mice were trained to nose-poke at one (FR port) and then to hold a nose-poke for at least 1 s at the second (reward port) for 10% sucrose reinforcement. When mice held reward port nose-pokes for > or = 1 s on 95% of session trials, ethanol vapor (0.05%, w/v) or clean air replaced sucrose. In experiment 1, the FR requirement at the FR port was incremented from 1 to 8. Ethanol vapor (n=3) or clean air (n=3) was delivered for 1 s following a single nose-poke at the reward port after completing response requirements at the FR port. Nose-pokes at the FR port increased with increasing FR to maintain ethanol vapor intake, while clean air intake and its associated responding extinguished. In experiment 2, mice (n=4) controlled the duration of ethanol vapor delivery by providing vapor for as long as the mouse held a single poke in the reward port after completing response requirements at the FR port. Nose-pokes at the FR port increased with increasing FR to maintain ethanol vapor intake at the reward port. These findings indicate that ethanol vapor is reinforcing in adult C57BL/6J male mice.     

Teratogenicity of three polychlorinated dibenzofurans in C57BL/6N mice

Polychlorinated dibenzofurans (PCDFs) are widespread environmental contaminants which have been detected in human tissues and implicated in several poisoning incidents. Their toxic effects are similar to those observed with other related halogenated aromatic hydrocarbons such as TCDD. The teratogenic effects of three PCDFs, 1,2,3,7,8-pentachlorodibenzofuran (1-PeCDF), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF), were assessed in C57BL/6N mice. Pregnant mice were exposed on Gestation Days 10-13 to 10 ml corn oil/kg containing PCDFs. The dams were killed on Gestation Day 18 and maternal and fetal toxicity were assessed. All three compounds were highly teratogenic, with very steep and parallel dose-response curves for the two diagnostic indicators of dioxin-like teratogenicity, hydronephrosis, and cleft palate. 4-PeCDF was the most teratogenic with an ED50 of 36 micrograms/kg for cleft palate and 7 micrograms/kg for hydronephrosis. 4-PeCDF was approximately 4 times as potent as 1-PeCDF and 10 times as potent as HCDF. The teratogenic responses occurred at a dose below that where any obvious maternal or fetal toxicity was detected. Thus, these three compounds cause teratogenic responses similar to those seen with TCDD but are only 1/10 to 1/100 as potent.     

Immunotoxic effects of short-term atrazine exposure in young male C57BL/6 mice.

The herbicide atrazine (ATR) is a very widely used pesticide; yet the immunotoxicological potential of ATR has not been studied extensively. Our objective was to examine the effect of ATR on selected immune parameters in juvenile mice. ATR (up to 250 mg/kg) was administered by oral gavage for 14 days to one-month-old male C57BL/6 mice. One day, one week, and seven weeks after the last ATR dose, mice were sacrificed, and blood, spleens, and thymuses were collected and processed for cell counting and flow cytometry. Thymus and spleen weights were decreased by ATR, with the thymus being more sensitive than the spleen; this effect was still present at seven days, but not at seven weeks after the last ATR dose. Similarly, organ cellularity was persistently decreased in the thymus and in the spleen, with the splenic, but not thymic cellularity still being depressed at seven weeks post ATR. Peripheral blood leukocyte counts were not affected by ATR. There were also alterations in the cell phenotypes in that ATR exposure decreased all phenotypes in the thymus, with the number of CD4(+)/CD8(+) being affected the least. At the higher doses, the decreases in the thymic T-cell populations were still present one week after the last ATR dose. In the spleen, the CD8(+) were increased and MHC-II(+) and CD19(+) cells were decreased one day after the last ATR dose. Also, ATR treatment decreased the number of splenic na?ve T helper and T cytotoxic cells, whereas it increased the percentage of highly activated cytotoxic/memory T cells. Interestingly, the proportion of mature splenic dendritic cells (DC; CD11c(high)), was also decreased and it persisted for at least one week, suggesting that ATR inhibited DC maturation. In the circulation, ATR exposure decreased CD4(+) lymphocytes at one day, whereas at seven days after the last ATR dose, in addition to the decrease in CD4(+) lymphocytes, the MHC-II(+) cells were also decreased at the 250 mg/kg dose. Thus, ATR exposure appears to be detrimental to the immune system of juvenile mice by decreasing cellularity and affecting lymphocyte distribution, with certain effects persisting long after exposure has been terminated.     

Age-related differential sensitivity to MK-801-induced locomotion and stereotypy in C57BL/6 mice

Psychomotor effects elicited by systemic administration of the noncompetitive NMDA (N-methyl-D-aspartate) receptor antagonist MK-801 (dizocilpine maleate) represent perturbation of glutamatergic pathways, providing an animal model for psychotic symptoms of schizophrenia. Hyperlocomotion and stereotypy are the two main psychomotor behaviors induced by MK-801. This study compared MK-801-induced hyperlocomotion and stereotypy in young (1-month old) and aged mice (12-month old), in order to determine how the aging process may influence these behaviors. The tested MK-801 doses ranged from 0.015 to 1 mg/kg. The data indicated that MK-801 impacted the aged mice more pronouncedly than the young mice, as both hyperlocomotion and stereotypy were increased significantly more in the aged mice relative to the young mice. These results suggest an age-related increase in MK-801 sensitivity in mice.     

Teratogenic effects of polychlorinated dibenzofurans in combination in C57BL/6N mice

Polychlorinated dibenzofurans (PCDFs) are highly toxic environmental contaminants which have been involved in several incidents of human poisoning. Two congeners, 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF), have been shown to persist in the tissues of victims of accidental ingestion from Japan and Taiwan. The teratogenicity of these compounds, both alone and in combination, was assessed in C57BL/6N mice. Pregnant mice were treated with 10 ml/kg corn oil containing no PCDFs, 4-PeCDF (0-30 micrograms/kg), HCDF (0-300 micrograms/kg), or a combination of the two on gestation Days 10-13, followed by necropsy on gestation Day 18. Maternal and fetal toxicity were assessed and selected soft tissues were examined for abnormalities. Both chemicals caused hydronephrosis and cleft palate in the absence of any overt toxicity. Hydronephrosis occurred at doses approximately fivefold lower than those causing cleft palate. The combination of 4-PeCDF and HCDF was additive for terata based on responses predicted by probit analysis. In addition, the combination of 2,3,4,5,3',4'-hexachlorobiphenyl (0-60 mg/kg), a structurally related compound also present in PCDF poisoning victims, and 4-PeCDF appears additive. Thus, these chemicals, which cause toxic effects similar to those of 2,3,7,8-tetrachlorodibenzo-p-dioxin, are additive in the induction of fetal anomalies in the mouse.     

Cis‐bifenthrin induces immunotoxicity in adolescent male C57BL/6 mice

Bifenthrin (BF) is an important synthetic pyrethroid. Previous studies have demonstrated that cis‐BF exhibits toxic effects on development, the neurological, reproductive and endocrine system. In this study, we evaluated the immunotoxicity caused by cis‐BF in adolescent male C57BL/6 mice. Mice were exposed orally to 0, 5, 10, and 20 mg/kg/d for 3 weeks. The results showed that body weight, spleen weight, and splenic cellularity decreased in mice exposed to 20 mg/kg/d cis‐BF. Additionally, we found that the mRNA levels of the pro‐inflammatory factors IL‐1β, IL‐6, CXCL‐1, and TNF‐α, in peritoneal macrophages, the spleen, and the thymus were inhibited in the cis‐BF‐treated groups. Moreover, MTT assays demonstrated that cis‐BF inhibited splenocyte proliferation stimulated by LPS or Con A, as well as the secretion of IFN‐γ on Con A stimulation. Collectively, the results of this study suggest that exposure to cis‐BF has the potential to induce immunotoxicity in adolescent male C57BL/6 mice.     

Subchronic effects of perfluorooctanesulfonate exposure on inflammation in adult male C57BL/6 mice

Previous studies indicate that exposure to perfluorooctanesulfonate (PFOS), a ubiquitous and highly persistent environmental contaminant, induces immunotoxicity in mice. However, few studies have specifically assessed the effects of PFOS on inflammation. This study utilized a standard 60‐day oral exposure period to assess the effects of PFOS on the response of inflammatory cytokines [tumor necrosis factor α (TNF‐α), interleukin‐1 β (IL‐1β), and interleukin‐6 (IL‐6)]. Adult male C57BL/6 mice were dosed daily by oral gavage with PFOS at 0, 0.0083, 0.0167, 0.0833, 0.4167, 0.8333 or 2.0833 mg/kg/day to yield a targeted Total Administered Dose (TAD) over 60 days of 0, 0.5, 1, 5, 25, 50, or 125 mg PFOS/kg, respectively. The percentage of peritoneal macrophages (CD11b⁺ cells) was significantly increased at concentrations ≥1 mg PFOS/kg TAD in a dose‐dependent manner. Ex vivo IL‐1β production by peritoneal macrophages was elevated substantially at concentrations of ≥5 mg PFOS/kg TAD. Moreover, PFOS exposure markedly enhanced the ex vivo production of TNF‐α, IL‐1β and IL‐6 by peritoneal and splenic macrophages when stimulated either in vitro or in vivo with lipopolysaccharide (LPS). The serum levels of these inflammatory cytokines observed in response to in vivo stimulation with LPS were elevated substantially by exposure to PFOS. PFOS exposure elevated the expression of pro‐inflammatory cytokines TNF‐α, IL‐1β, IL‐6, and proto‐oncogene, c‐myc, in the spleen. These data suggest that exposure to PFOS modulates the inflammatory response, and further research is needed to determine the mechanism of action. © 2010 Wiley Periodicals, Inc. Environ Toxicol, 2012.     

Stimulatory effects of ethanol in C57BL/6 mice

Although ethanol stimulation is well documented in several species including humans, there is some controversy about whether the stimulation occurs in the highly inbred mouse strain, C57BL/6. Since inbred mouse strains are frequently used to elucidate mechanisms for individual differences in reaction to alcohol, the present study was undertaken to more completely characterize the behavioral effects of ethanol and to help resolve some of the controversy regarding the drug's stimulatory effect on C57 mice. Activity of female C57BL/6cr mice was assessed in either a lighted or dark environment for 20 min after injections of water or ethanol at doses of 0.5, 1.0, 2.0, 4.0 g/kg. Elevated activity (stimulation) was observed in mice injected with relatively low ethanol doses and tested in the light. The 2.0 g/kg dose produced a transient elevation in activity which declined rapidly across time. Animals tested under the dark condition were not stimulated by the drug but had activity reductions to high doses of ethanol. The detection of ethanol-induced stimulation appears to be related to the performance of control mice rather than a light-related difference in ethanol sensitivity.     

Retinoic acid and 2,3,7,8-tetrachlorodibenzo-p-dioxin selectively enhance teratogenesis in C57BL/6N mice

TCDD is one of the most toxic man-made compounds and an extremely potent teratogen in mice. Many of its toxic symptoms resemble those seen during vitamin A deficiency. Vitamin A and its derivatives, such as alltrans-retinoic acid (RA), are also teratogenic in mice, as well as many other species. Both TCDD and RA produce cleft palate in susceptible strains of mice. However, while TCDD produces hydronephrosis, RA does not, and TCDD does not produce limb bud defects while RA does. To determine whether TCDD and RA would enhance or antagonize the teratogenic effects of the other compound, C57BL/6N dams were treated po on Gestation Day (gd) 10 or 12 with 10 ml corn oil/kg containing TCDD (0-18 micrograms/kg), RA (0-200 mg/kg), or combinations of the two chemicals. Dams were killed on gd 18 and toxicity and teratogenicity assessed. Coadministration of TCDD and RA had no effect on maternal or fetal toxicity beyond what would be expected by either compound alone. Cleft palate was induced by RA at lower doses on gd 10 than on gd 12, but by TCDD at lower doses on gd 12 than on gd 10. Sensitivity to TCDD-induced hydronephrosis was similar on both gd 10 and 12. The limb bud defects were only observed when RA was administered on gd 10, not when given on gd 12. No other soft tissue or skeletal malformations were related to administration of TCDD or RA. No effect of TCDD was observed on the incidence or severity of limb bud defects induced by RA, nor did RA influence the incidence or severity of hydronephrosis induced by TCDD. However, the incidence of cleft palate was dramatically enhanced by coadministration of the xenobiotic and vitamin. On both gd 10 and 12, the dose-response curves for cleft palate induction were parallel, suggesting some similarities in mechanism between the two compounds. However, combination treatment resulted in a synergistic response that varied with the stage of development and was tissue specific.     

Pharmacological modulation of stress-induced behavioral changes in the light/dark exploration test in male C57BL/6J mice

Psychological stress is a major risk factor for mood and anxiety disorders. However, the phenotypic manifestation of stress effects varies across individuals, likely due, in part, to genetic variation. Modeling the behavioral and neural consequences of stress across genetically diverse inbred mouse strains is a valuable approach to studying gene × stress interactions. Recent work has shown that C57BL/6J mice exposed to ten daily sessions of restraint stress exhibited increased exploration of the aversive light compartment in the light/dark exploration (LDE) test. Here we sought to clarify the nature of this stress-induced phenotype by testing the ability of treatment with various clinically efficacious drugs of different therapeutic classes to rescue it. Ten days of restraint increased light compartment exploration, reduced body weight and sensitized the corticosterone response to swim stress. Subchronic administration (during stress and LDE testing) of fluoxetine, and to a lesser extent, lithium chloride, rescued stress-induced LDE behavior. Chronic fluoxetine treatment prior to (plus during stress and testing) failed to block the LDE stress effect. Acute administration of antipsychotic haloperidol, anti-ADHD medication methylphenidate or anxiolytic drug chlordiazepoxide, prior to LDE testing, was also unable to normalize the LDE stress effect. Collectively, these data demonstrate a treatment-selective prophylactic rescue of a restraint stress-induced behavioral abnormality in the C57BL/6J inbred strain. Further work with this novel model could help elucidate genetic and neural mechanisms mediating stress-induced changes in mouse 'emotion-relevant' behaviors and, ultimately, further understanding of the pathophysiology of stress-related neuropsychiatric disorders. This article is part of a Special Issue entitled 'Anxiety and Depression'.     

Chronic effects of perfluorooctanesulfonate exposure on immunotoxicity in adult male C57BL/6 mice

A paucity of data exists to corroborate the few studies that report immune suppression after exposure to perfluorooctanesulfonate (PFOS). In this study, adult male C57BL/6 mice were exposed to PFOS daily via gavage for 60 days [0, 0.5, 5, 25, 50, or 125 mg/kg total administered dose (TAD)]. The results showed that liver mass was significantly increased at ≥5 mg PFOS/kg TAD and in a dose-dependent manner. Lymphocyte proliferation and natural killer cell activity were altered in male mice. Plaque forming cell (PFC) response was suppressed beginning at 5 mg/kg TAD. Based on the liver mass and PFC response, the no observed adverse effect level and lowest observed adverse effect level for male mice exposed PFOS for 60 days was 0.5 and 5 mg/kg TAD, respectively. Measured PFOS serum concentrations at these dose levels were 0.674 ± 0.166 and 7.132 ± 1.039 mg/l, respectively. These results indicate that PFOS exposure can affect the immunity function in mice at levels approximately 50-fold for highly exposed human populations.     

Ethanol disrupts fear conditioning in C57BL/6 mice

Ethanol has been demonstrated to disrupt numerous forms of learning. For example, ethanol disrupts fear conditioning in rats. Surprisingly, the opposite result was reported for mice. Because of the importance of mouse models in ethanol research and the predominance of transgenic mice generated on a C57BL/6 background, the present study examined the effects of acute ethanol administration on fear conditioning in C57BL/6 mice. Fear conditioning was chosen because of the apparent contradiction in results between mice and rats, because of its popularity in assessing forebrain-dependent learning and because the task examines two types of learning: (i) the hippocampus-dependent contextual learning and (ii) the hippocampus-independent conditioned stimulus-unconditioned stimulus learning. Dose-response curves were generated for ethanol (0.5, 1.0 and 1.5 g/kg) given on either training day, testing day, or both days. Ethanol, in a dose-dependent manner, disrupted fear conditioning when given on training day or given on both training and testing days. Ethanol given on testing day only did not disrupt fear conditioning. The present results demonstrate that ethanol disrupts fear conditioning in C57BL/6 mice.     

Intravenous cocaine self-administration: individual differences in male and female C57BL/6J mice

This study examined individual differences in male and female C57BL/6J (C57) mice responding for intravenous cocaine reinforcement. The experiment used 4 groups of mice, distinguished by sex and cocaine unit dose (0.3 or 1 mg/kg/infusion). Mice trained to lever respond for IV cocaine were given the drug initially on an FR2 schedule and then on a Progressive Ratio 2(PR2) schedule. Hierarchical linear modeling (HLM) techniques were used to examine data generated across four FR2 and four PR2 sessions, as well as within session data when cocaine was delivered on the PR2 schedule. HLM techniques, although uncommon in the animal literature, characterize individual differences in human studies and are likely to be useful in more complex preclinical studies. Analysis established distinct patterns of self-administration both across and within sessions. Responses for cocaine delivered on the FR2 schedule was dose-dependent, but did not differ according to sex. Response output was greater when either dose of cocaine was delivered on the PR2 than the FR2 schedule. Although response output for the more rewarding 1 mg/kg unit dose was similar for the two sexes, males responded more and had greater cocaine intake than females when the less reinforcing 0.3 mg/kg dose was delivered at the more behaviorally challenging PR2 schedule. HLM analysis of response patterns and cocaine intake within the PR2 sessions corroborated this sex difference and also indicated that trajectories differed for individual mice after accounting for the sex and dose factors. The reduced response output by females for cocaine in the present experiment is consistent with previous reports that sex differences in the rewarding effects of either alcohol or food reinforcement were revealed for C57 mice only when delivered on more behaviorally demanding schedules (e.g. PR2 or FR100).     

Teratogenic effects of 2,3,7,8-tetrabromodibenzo-p-dioxin and three polybrominated dibenzofurans in C57BL/6N mice

Brominated flame retardants involved in many industrial uses contain polybrominated dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs) as contaminants. The levels of these contaminants can be dramatically increased by combustion. These chemicals are closely related in structure to the polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), of which 2,3,7,8-tetrachloridibenzo-p-dioxin (TCDD) is the most toxic isomer. TCDD and related PCDFs are potent mouse teratogens inducing cleft palate and hydronephrosis at doses below those at which overt maternal and embryo/fetal toxicity occurs. This study examines the teratogenic effects of 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD), 2,3,7,8-tetrabromodibenzofuran (TBDF), 1,2,3,7,8-pentabromodibenzofuran (1PeBDF), and 2,3,4,7,8-pentabromodibenzofuran (4PeBDF) in C57BL/6N mice treated on gestation day (gd) 10 and examined on gd 18. Pregnant dams were treated with 0-4000 micrograms of each congener per kilogram body weight in 10 ml corn oil/kg. Dose selection was based on the relative toxicity of the chlorinated isomers. Maternal toxicity and developmental toxicity were assessed, and the hard palate and kidney, the target organs for the teratogenic effects of TCDD and related compounds, were examined for structural abnormalities. While the maternal liver weight increased at all dose levels examined for all four compounds, there was no evidence of any maternal toxicity. Embryo/fetal mortality was increased only at greater than or equal to 500 microgram TBDF/kg, while fetal weight increased in a dose-related manner following exposure to TBDD and TBDF. All compounds produced hydronephrosis (HN) at doses below that at which cleft palate (CP) occurred. The incidence of HN was significantly increased above background levels at the following doses (micrograms/kg): TBDD, 3; TBDF, 25; 1PeBDF, 500; 4PeBDF, 400. The LOELs (micrograms/kg) for CP were: TBDD, 48; TBDF, 200; 1PeBDF, 4000; 4PeBDF, 2400. The cleft palate incidence for all four brominated compounds and TCDD could be fit to a common slope, compatible with the concept that these chemicals all exert their teratogenic effects through a common mechanism. The potency of these chemicals, relative to TCDD as 1 for the induction of cleft palate, is TBDD, 0.24; TBDF, 0.10; 1PeBDF, 0.004; and 4PeBDF, 0.005. Previous studies from our laboratory had determined that the chlorinated dibenzofuran isomers had relative potencies of 0.05 (TCDF), 0.03 (1PeCDF), and 0.09 (4PeCDF). Thus, bromination decreases the teratogenic activity of TBDD relative to TCDD and of both 1- and 4PeBDF relative to the chlorinated isomers. However, substitution of bromines for chlorines increases the potency of TBDF relative to TCDF.(ABSTRACT TRUNCATED AT 400 WORDS)     

Teratogenic potency of TCDD, TCDF and TCDD-TCDF combinations in C57BL/6N mice

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,7,8-tetrachlorodibenzofuran (TCDF) cause the same spectrum of fetal anomalies in C57BL/6N mice. Pregnant dams were treated with TCDD, TCDF and combinations of the 2 compounds on gestation day 10, and examined for maternal and fetal effects on day 18. The fetal kidneys were the most sensitive target for teratogenicity. The dose response for cleft palate induction fit the probit model for both compounds, suggesting that TCDD was approximately 30 times more potent than TCDF. The interaction between these 2 compounds was consistent with a model for additive toxicity.     

Biotransformation of mexidol in inbred BALB/C and C57BL/6 mice

The pharmacokinetics and biotransformation of mexidol was studied in BALB/C and C57BL/6 mice. The blood plasma contains dealkylated metabolites, and the urine contains glucuronoconjugated derivatives of the drug. The process of glucuronoconjugation more intensively proceeds in C57BL/6 mice than in BALB/C mice.