The effect of exposure to a commercial 2,4-D formulation during gestation on the immune response in CD-1 mice.

Pregnant CD-1 mice were administered a commercial 2,4-dichlorophenoxyacetic acid (2,4-D) formulation on days 6-16 days of gestation, in drinking water at concentrations ranging from 0 to 1.0% of the formulated product, equivalent to approximately 0-650 mg/kg per day expressed as the amine derivative. The effect of 2,4-D on immune function was evaluated in offspring 7 weeks after birth. The dams tolerated repeated 2,4-D exposure in drinking water without difficulty. The offspring exhibited decreased body weight with minor reductions in the kidney weights in the 0.1 and 1.0% 2,4-D treatment groups. A generalized suppression of lymphocyte stimulation by concanavalin A (Con A) was observed at high dose of commercial 2,4-D formulation (1.0%). Cytometric studies of the lymphocyte subpopulations demonstrated an increased relative count of B cells and reduced T cytotoxic or suppressor cells in the 1.0% formulation. The humoral immune response, antibody production against sheep red blood cells and peritoneal macrophage phagocytic function, were not altered by 2,4-D. Since the immune alterations in the offspring were observed many weeks after exposure, it appears as though 2,4-D exposure during gestation causes permanent changes in cell types associated with immune function. Since 2,4-D is not considered a persistent chemical, it is unlikely that 2,4-D residues are contributing significantly to the observed immune alterations. The immune alterations were observed only in the higher treatment groups. Therefore, the impact on human and animal health from an immune perspective, which would be encountered following normal application in the environment, would be minimal.

The effect of exposure to a commercial 2,4-D herbicide formulation during gestation on urethan-induced lung adenoma formation in CD-1 mice.

Female CD-1 mice were exposed to a commercial amine formulation of 2,4-dichlorophenoxyacetic acid (2,4-D) on days 6-16 of gestation in drinking water at concentrations ranging from 0 to 1.0% of the formulated product, equivalent to approximately 0-650 mg/kg/d expressed as the amine derivative. The effect of 2,4-D on urethan-induced pulmonary adenoma formation was evaluated in female offspring 19 w after birth. Urethan-induced sleeping times observed following ip injection of 1.5 mg urethan/g bw 7 w after birth were not altered by 2,4-D (p = 0.10), indicating that 2,4-D did not affect the rate of urethan elimination. 2,4-D exposure did not affect the number of tumors produced (p = 0.58), but did reduce the mean tumor diameter in the highest dose group (p < 0.01). This minor antineoplastic activity of 2,4-D may be related, in part, to inhibitory effects of 2,4-D on various enzymatic or metabolic pathways, essential for cellular growth and tissue development. Since exposure to 2,4-D during pregnancy had little impact of tumor production, it is unlikely that persistent alteration to developing immune cells involved in the cell-mediated immunosurveillance mechanisms occurred. The subtle alteration in tumor size and the mild impairment of growth in the offspring were observed almost exclusively in the highest treatment group. Since this level of exposure is well in excess of those associated with normal application of 2,4-D, the hazard to non-target mammalian populations appears minimal.

Trace mineral and vitamin concentrations in the liver and serum of wild muskoxen from Victoria Island.

Selected trace minerals and vitamins were assayed in the liver and serum of 25 wild muskoxen (Ovibos moschatus) from Victoria Island, (Nunavut, Canada) in November, 1995. Mean +/- SE liver concentrations in micromol/kg wet weight were 260+/-16 for copper; 1.04+/-0.06 for selenium; 11.5+/-0.7 for molybdenum and 62.8+/-3.3 for vitamin E. Mean +/- SE serum concentrations in micromol/L were 14.2+/-0.3 for copper; 0.75+/-0.04 for selenium, 1.53+/-0.07 for vitamin A and 5.80+/-0.55 for vitamin E. Comparison of liver and serum concentrations of copper, selenium and vitamin E showed that the concentration in one tissue was a relatively poor indicator of the concentration in the other. The copper-molybdenum interaction often seen in domestic species was not observed. In general, the concentrations of metals and vitamins found in muskoxen were comparable to those in other ungulates although serum vitamin E concentrations were about one-fourth of those expected.

Suppression of rat and mouse lymphocyte function by urban air particulates (Ottawa dust) is reversed by N-acetylcysteine.

Epidemiology studies have demonstrated increased pulmonary morbidity such as allergy and infection with episodes of high particulate air pollution (size range 0.1-10 microm diameter, PM10), but the mechanism(s) for this association is not yet well defined. The present study was undertaken to evaluate the effects of EHC-93 urban particles (Ottawa dust) on immune functions of peripheral blood mononuclear cells (PBMCs) and splenocytes from male Fischer 344 rats and C57Bl/6 mice. Immune function endpoints evaluated included cell viability, lymphocyte blastogenesis stimulated by T-cell mitogen (concanavalin A, Con A) or B-cell mitogens [lipopolysaccharide (LPS) or LPS/dextran sulfate], intracellular Ca2+ concentration, interleukin 2 (IL-2) production, and expression of receptors for transferrin (TfR) and IL-2 (IL-2R). In addition, the effect of N-acetylcysteine (NAC), an antioxidant, on the toxicity of EHC-93 particles was evaluated. Total EHC-93 particles, water leachate of EHC-93, and washed EHC-93 suppressed proliferation of PBMCs and splenocytes to T- and B-cell mitogens. Treatment of splenocytes with EHC-93 particles did not alter intracellular Ca2+ concentration or mitogen-induced expression of TfR and IL-2R expression, but increased IL-2 production assayed by enzyme-linked immunosorbent assay (ELISA). In spite of an increase in IL-2 production, exogenous IL-2 when added to cultures was able to reverse the suppression of Con A-induced lymphocyte proliferation by EHC-93 particles. Furthermore, the suppressive effect of EHC-93 particles on mitogen-induced lymphocyte proliferation was completely abolished by addition of the antioxidant NAC to cultures, suggesting a possible role of oxidative factors for the toxicity of EHC-93 particles.

Effect of chlorpyrifos on immune function in rats.

A commercial formulation of chlorpyrifos was evaluated for effects on selected immune system functions in male Fisher 344 rats. Chlorpyrifos in an olive oil vehicle was administered by oral gavage twice weekly for 28 d at a dose of 5.0 mg/kg for each treatment. Body weight and organ/body weight ratios were unaffected by the chlorpyrifos. In contrast, chlorpyrifos impaired T-lymphocyte blastogenesis induced by concanavalin A (P = 0.03) and phytohemagglutinin (P = 0.023), but did not alter B-lymphocyte blastogenesis induced by lipopolysaccharide/dextran (P = 0.082. Humoral immunity (anti-sheep red blood cell), a T-lymphocyte macrophage-dependent response, was also reduced (P = 0.019) when the antibody response was expressed/10(6) spleen cells, although the response expressed/spleen was unaffected (P = 0.32), reflecting increased lymphocyte production. The total splenic lymphocyte counts in the chlorpyrifos-treated rats increased by 91% (P < 0.0001), therefore reducing the antibody response when expressed/10(6) spleen cells. Chlorpyrifos had no effect on macrophage phagocytosis (P = 0.27), but increased the relative percentage expression of CD5+ (P = 0.028) and CD8+ (P = 0.003). The presence of normal antibody and phagocytic responses in association with reduced T-lymphocyte blastogenesis and enhanced expression of specific cell surface antigens indicated that chlorpyrifos induced immune alterations associated with lymphocyte subpopulations.

Effect of pentachlorophenol on immune function.

The organochlorine compound, pentachlorophenol, was evaluated for effects on immune system function in male Fisher 344 rats. Pentachlorophenol was prepared in an olive oil vehicle and was administered by oral gavage twice weekly for 28 days at a dose of 2.0 mg/kg per treatment. Exposure to pentachlorophenol increased body weight gains (P=0.024) during the treatment period. Liver (P=0.034) and kidney (P=0.012) body weight ratios were also increased. Pentachlorophenol exposure enhanced T-lymphocyte blastogenesis induced by concanavalin A (Con A)(P=0.0001) and phytohemagglutinin (PHA)(P=0.048) evaluated using stimulation indices. Corresponding B-lymphocyte blastogenesis induced by lipopolysaccharide/dextran (LPS/dex)(P=0.0034) was also enhanced by pentachlorophenol exposure. Pentachlorophenol suppressed the antibody response against sheep red blood cells (SRBCs) by 39% when the response was expressed per viable spleen cell (P=0.006). This suppression was not evident when the response was expressed per spleen (P=0.22), suggesting that a compensatory mechanism or extramedullary splenic hemopoiesis was occurring minimizing the overall impact on humoral immunity. The enhanced B- and T-lymphocyte blastogenesis may also reflect compensatory or hemopoietic activity. Pentachlorophenol exposure had no effect on peritoneal macrophage phagocytosis (P=0.31) or lymphocyte cell surface antigen expression. The observed alterations in lymphocyte blastogenesis and humoral immunity subsequent to pentachlorophenol exposure do not appear to be associated with phagocytosis or lymphocyte cell surface antigen expression.

Copper deficiency in a herd of captive muskoxen.

At necropsy, a mature muskox cow was found to have exceedingly low serum and liver copper concentrations of 4.8 = mumol/L and 0.02 mmol/kg, respectively. Serum copper levels were also low in remaining members of the herd but returned to normal after parenteral treatment with calcium copper edetate.

Effect of 2,4-dicholorophenoxyacetic acid, trifluralin and triallate herbicides on immune function.

The commercial formulations of 3 commonly used herbicides (the amine salt of 2,4-dichlorophenoxyacetic acid, trifluralin and triallate) were evaluated for effects on immune function in male Fisher 344 rats. The herbicides were prepared in an olive oil vehicle and administered by oral gavage twice weekly for 28 d at the following doses: 10.0 mg 2,4-D/kg; 17.5 mg trifluralin/kg; 5.0 mg triallate/kg/treatment. Normal body weight and organ/body weight ratios indicated the rats tolerated the herbicide treatments without difficulty. Exposure to 2,4-D did not alter lymphocyte blastogenesis, 1 gm antibody production (anti-sheep red blood cell), lymphocyte cell surface marker expression or phagocytic function of peritoneal macrophages. Trifluralin acted as a weak mitogen, but impaired T-lymphocyte blastogenesis induced by phytohemagglutinin and concanavalin A. Other immunological measurements were unaffected by trifluralin exposure. Triallate exposure reduced peritoneal macrophage phagocytosis by 33%, showed weak mitogenic properties and impaired T-lymphocyte blastogenesis in the presence of phytohemagglutin. Triallate also increased the anti-sheep red blood cell response expressed/spleen by 43%, a phenomenon suggestive of a compensatory response to minimize the impact on overall immune function. The changes in lymphocyte or macrophage function due to the herbicide treatments were not associated with changes in lymphocyte cell surface antigen expression.

Effect of roundup and tordon 202C herbicides on antibody production in mice.

Female CD-1 mice were exposed to Tordon 202C (2,4-dichlorophenoxyacetic acid [2,4-D] and picloram) or Roundup (glyphosate) in drinking water for 26 d at concentrations ranging from 0 to 0.42% or from 0 to 1.05%, respectively. The mice were inoculated with sheep red blood cells to produce a T-lymphocyte, macrophage dependent antibody response on day 21 of the herbicide exposure period. Tordon 202C dosing reduced weight gain and water consumption at the 0.42% level of exposure. Roundup exposure did not alter weight gain or water consumption. Antibody production was unaffected by Roundup dosing, suggesting that Roundup is unlikely to cause immune dysfunction under normal application conditions. In contrast, all levels of Tordon 202C exposure reduced antibody production by as much as 45%. The immunosuppressive activity of Tordon 202C was associated with levels more than 12 x the normal application level, although it was not determined which component of the formulation was responsible for the immunosuppression effect. The presence of immune alteration subsequent to exposure to Tordon 202C at levels marginally above the normal application levels suggests that chronic exposure to Tordon 202C in the environment has the potential to alter immune function.

Investigation of the selenium status of aborted calves with cardiac failure and myocardial necrosis.

Lesions of heart failure, specifically cardiac dilation or hypertrophy along with a nodular liver (chronic passive congestion) and ascites, have been found in 4-5% of aborted bovine fetuses. In this study, a group of 22 such fetuses was compared with groups of aborted fetuses without lesions of heart failure and with nonaborted fetuses obtained from a slaughterhouse. The fetuses were necropsied, tissues were taken for histopathology, and samples were collected for routine bacteriologic and virologic examinations. Liver and kidney tissue was saved for selenium analysis. Histopathologic examinations of myocardium of fetuses with cardiac failure revealed myocardial necrosis and mineralization in 7 fetuses, lymphocytic myocarditis in 5 fetuses, myocardial fibrosis in 5 fetuses, or no microscopic lesions in 5 fetuses. Mean liver selenium levels were 5.5 mumol/kg in the fetuses with heart lesions, 6.5 mumol/kg in the fetuses without heart lesions and 7.5 mumol/kg in fetuses from the slaughterhouse; these differences were statistically significant. The results suggest that selenium deficiency in bovine fetuses may cause myocardial necrosis and heart failure. This study also provides data on normal liver and kidney selenium levels in bovine fetuses from the analyses of 19 nonaborted fetuses.

Immunomodulatory and protective effects of N-acetylcysteine in mitogen-activated murine splenocytes in vitro.

N-Acetylcysteine (NAC) is a pro-glutathione drug used to treat chronic lung disorders and because of its anti-AIDS virus activity in vitro, has been proposed for AIDS therapy. The effect of NAC on mitogen-activated-lymphocyte blastogenesis in C57B1/6 mouse splenocytes and ability of NAC to protect lymphocytes against mitogen-induced cytotoxicity was examined in vitro. NAC increased splenocyte proliferation in the presence of optimal and suboptimal concentrations of concanavalin A (Con A) and lipopolysaccharide (LPS). Stimulatory and costimulatory effects of NAC on mitogen-induced responses were also evident. The dose-response relationship describing the effects of NAC on lymphocyte proliferation with Con A-induced responses were enhanced in a dose-dependent manner, whereas the corresponding LPS-induced responses increased to a maximum level followed by decline in responses at higher concentrations of NAC. When splenocytes were incubated with inhibitory supraoptimal concentrations of Con A (10 microg/ml) or LPS (150 microg/ml), NAC partially enhanced the Con A-induced response but completely prevented the inhibitory effect of supraoptimal concentrations of LPS on splenocyte blastogenesis. Optimal and supraoptimal concentrations of Con A caused activation-induced cell death in the splenocytes whereas comparable concentrations of LPS did not produce a similar effect. Splenocyte cell death produced by the optimal mitogenic concentrations of Con A was completely blocked by the addition of NAC to cultures. Immunomodulation and protective effects of NAC were observed in mitogen-activated lymphocytes in vitro.

Immunotoxicity studies in mink (Mustela vison) chronically exposed to dietary bleached kraft pulp mill effluent.

The immunotoxic potential of bleached kraft pulp mill effluent (BKME) to cell-mediated immunity in mink (Mustela vison) was investigated October 1993 through May 1994. For 26 weeks, 20 mink were fed a diet based upon fish caught within 6 km downstream of a bleached kraft mill in Saskatchewan, Canada. Water for this group contained 25% softwood-run BKME. Twenty control mink were fed nutritionally matched diets based upon fish from lakes receiving no municipal or industrial effluent and tap water. Using in vitro and in vivo immunotoxicity assays, the proliferative response of mink peripheral blood mononuclear cells (PBMC) to mitogens was optimal, at 72 hr with 10 micrograms/ml Concanavalin A, 1/80 dilution pokeweed mitogen, and 1/80 dilution phytohemagglutinin. Bacterial cell wall Escherichia coli lipopolysaccharide did not stimulate mitosis of the mink PBMC. No difference (P < 0.05) in PBMC proliferation was seen between the control and BKME-exposed mink with any of the mitogens used. Delayed type hypersensitivity (DTH), a cell mediated response, was assessed in mink vaccinated with live bacille Calmette-Guérin (BCG) and then challenged by intradermal toe web injection with 200 micrograms of sonicated BCG approximately 6 weeks later. The DTH response in the BKME-exposed mink was impaired based upon assessment using skin thickness measurements, histopathological assessment and image analyzer technology. This decreased response is evidence for suboptimal immune function associated with BKME exposure, which could affect the competitive fitness of piscivorous mammals naturally exposed to BKME.

The effects of iron deficiency and iron overload on cell-mediated immunity in the mouse.

The influence of Fe status on cell-mediated immunity was studied in weanling mice fed on Fe-deficient (7 mg Fe/kg), Fe-sufficient (120 mg Fe/kg) and high-Fe (3000 or 5000 mg Fe/kg) diets for 7 weeks. The contact sensitivity (CS) response to dinitrofluorobenzene (DNFB), the in vivo delayed-type hypersensitivity (DTH) response to sheep erythrocytes (SRBC) and the ability of primed spleen cells to transfer DTH response to naive normal mice were suppressed in mice consuming the Fe-deficient diet. High-Fe diets (3000 or 5000 mg Fe/kg) selectively suppressed the CS response to DNFB, but the DTH response to SRBC or the transfer of DTH response by primed spleen cells to naive normal mice remained normal. Spleen cell functions associated with the expression of class II major histocompatibility (MHC) surface antigens, concanavalin A-induced interleukin-2 (IL-2) secretion or the antigen-presenting cell (APC) ability to stimulate antigen-dependent proliferation of an SRBC-specific helper T-lymphocyte clone were not altered by Fe status. However, consistent with the suppressed DTH response in the Fe-deficient mice was the suppressed concanavalin A-induced T-lymphocyte blastogenesis and the interferon-gamma (INF-gamma) production by spleen cells from mice fed on the Fe-deficient diet. Spleen cells from mice fed on excess levels of Fe in the diet secreted less INF-gamma than the control mice, although T-lymphocyte proliferation remained unaffected. Suppression of the cellular immune response associated with Fe deficiency may be related in part to impaired T-lymphocyte proliferation and INF-gamma secretion rather than to deficits in IL-2 secretion or APC function.

Effect of iron status on endotoxin-induced mortality, phagocytosis and interleukin-1 alpha and tumor necrosis factor-alpha production.

The host susceptibility to endotoxin (lipopolysaccharide, LPS), production of interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF-alpha) or phagocytosis in resident peritoneal macrophages were examined in iron-deficient and iron-loaded mice. Four groups of weanling male CD-1 mice were fed diet containing 7, 120, 5000 or 8000 ppm iron for 7 w. Body weight gain or hematocrit was not affected by iron consumption except for a lower weight gain in mice fed the 8000f1p4 iron diet. Iron-deficient and loaded diets produced a marked decrease and increase in liver iron concentration, respectively (P < 0.05). When challenged with an ip lethal dose of LPS, mortality was enhanced in iron-deficient and loaded mice (P = 0.035). The production of TNF-alpha and IL-1 alpha was assessed in the peritoneal macrophages stimulated by LPS in vitro. The production of IL-1 alpha and TNF-alpha was not altered in macrophages from iron-deficient mice. In contrast, macrophages from the 2 iron-loaded groups of mice produced more TNF-alpha (150% of control) without altering IL-1 alpha production. However, the total peritoneal leukocyte cell yield was not different among the treatment groups. Phagocytosis in the peritoneal macrophages determined by in vitro uptake of yeast cells was lower in the iron-deficient or loaded mice. This study indicates that iron deficiency and overload enhance LPS toxicity and impair phagocytosis, whereas excess iron also increases TNF-alpha production by macrophages.

The IgM and IgG antibody responses in iron-deficient and iron-loaded mice.

The humoral immune response was evaluated in male CD-1 mice fed the iron deficient (7 ppm Fe), iron sufficient (120 ppm Fe), and high-iron diets (3000 or 5000 ppm Fe) for 54 d. The IgM and IgG antibody responses against sheep erythrocytes (SRBC) determined by hemolytic plaque assay were suppressed by 65.4 and 51.2%, respectively, in the iron deficient mice. Subclinical iron deficiency was manifested by a marked reduction in hepatic iron concentration without any changes in hematocrit or body weight gain. In contrast, consumption of high-iron diets caused a marked accumulation of iron in the liver and a twofold reduction in the IgM antibody response without alteration in the IgG response. The suppression of the IgG antibody response in the iron deficient mice, however, did not result in a compensatory increase in delayed type hypersensitivity response.

The vitamin A and vitamin E status of horses raised in Alberta and Saskatchewan.

The purpose of the study was to determine normal baseline levels of vitamin A and vitamin E in clinically normal horses under typical field conditions in Saskatchewan and Alberta. Heparinized blood samples were collected from approximately 400 clinically healthy horses selected from 24 locations in Alberta and Saskatchewan during a two-year period. For each horse, historical information including feed type, vitamin supplementation, time of year, sex, and age were recorded. From each blood sample, the plasma vitamin A (all-transretinol) and vitamin E (alpha-tocopherol) levels were measured using high pressure liquid chromatography. Normal baseline plasma vitamin A and vitamin E concentrations recorded during the study were 0.70 mumol/L and 7.65 mumol/L, respectively. The plasma vitamin concentrations were lower in the younger horses. The plasma vitamin levels were higher from May to August, as compared to other times of the year. Horses grazing fresh pasture exclusively during the summer months had plasma vitamin A and vitamin E concentrations that were 27% and 63% greater than horses fed harvested or stored feeds during the same time period. Sex-related differences were not evident in the study. A number of factors may influence the baseline plasma vitamin A and vitamin E levels in horses. Consequently, it is unadvisable to use a single evaluation to assess vitamin status. Multiple sampling from individual horses or sampling from many horses within a herd may reduce the variability and improve the ability to monitor vitamin status from plasma submissions.

Effect of postnatal ethanol exposure on expression of differentiation antigens of murine splenic lymphocytes.

Ethanol is a recognized immunosuppressive agent in the chronic alcoholic. However, the effects of ethanol exposure on the developing immune system have not been extensively investigated. This study evaluated the effects of early postnatal ethanol exposure, via breast milk, on splenic lymphocyte differentiation antigen expression in offspring reared by ethanol-fed mice. Maternal mice were fed a liquid diet containing 20% ethanol-derived calories during pregnancy (E-P), pregnancy and lactation (E-PL), or lactation (E-L). Ad libitum-fed (C) and pair-fed (PF) control groups, fed a control liquid diet, were included. Expression of differentiation antigens on splenic lymphocytes from 21-day-old offspring reared by females in 1 of the 3 ethanol exposure conditions was evaluated by flow cytometry. Offspring reared by E-P females had similar numbers of splenic lymphocytes as offspring reared by C and pair-fed during pregnancy (PF-P) females. In contrast, offspring reared by E-PL and E-L females had fewer splenic lymphocytes than both PF-PL and PF-L (respectively), and C offspring. The number of Thy 1.2+, CD4+, CD8+, and IgG+ (B-cell) splenic lymphocytes was reduced in E-PL and E-L offspring compared with PF and C offspring. E-P offspring had fewer CD4+ and IgG+ splenic lymphocytes than C, but not PF-P, offspring. The percentage of Thy 1.2+ splenic lymphocytes was significantly reduced among E-PL and E-L offspring compared with PF-PL and PF-L (respectively), and C offspring.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatotoxicity associated with dietary iron overload in mice.

1. Weanling male CD-1 mice were fed 120 (control), 5000 and 8000 mg of iron kg-1 for seven weeks. The haematocrit (P = 0.265), water consumption (P = 0.170) and percentage body weight ratios of kidney, spleen and heart were not affected by iron supplementation. 2. Iron supplementation reduced weight gain (P = 0.023), increased weight of liver (P = 0.0001), the iron deposition index and concentration of iron in the liver (P < 0.01). A strong correlation between liver iron concentration and level of iron in the diet (r = 0.989) was observed. Histologically, the deposition of iron was restricted to the hepatocytes, Kupffer cells and splenic macrophages. 3. Consumption of 5000 and 8000 mg of iron kg-1 resulted in hepatic damage, as judged by elevated serum alkaline phosphatase and alanine aminotransferase activities (P < 0.05). 4. This study indicates that prolonged feeding of excess dietary iron has the potential to cause hepatic accumulation of iron with resultant liver toxicity, and that mice may be a suitable model to study the mechanisms of dietary iron overload.

Vitamin E is protective against iron toxicity and iron-induced hepatic vitamin E depletion in mice.

This study examined the effect of excess dietary iron on liver function, iron and vitamin E status and the protective activity of vitamin E. Consumption of excess dietary iron (3000, 5000, 8000 mg iron/kg/diet) compared with consumption of the control diet (120 mg iron/kg diet) by weanling male CD-1 mice for 7 wk resulted in accumulation of iron in liver, increased relative liver weights and a reduction in hepatic vitamin E stores. The concentration of vitamin E in the liver was negatively correlated with dietary iron concentration (r = 0.998). Weekly administration of vitamin E (20 mg/kg, subcutaneously) prevented iron-induced liver damage without altering hepatic iron stores. Pretreatment of adult male CD-1 mice with a single subcutaneous dose of vitamin E (20 mg/kg body wt) 24 h prior to a lethal dose of iron (60 mg/kg, intraperitoneally) resulted in 100% protection. A similar dose of vitamin E given 5, 30 or 60 min (intravenously) after iron intoxication enhanced survival to 90, 70 and 80%, respectively, compared with the untreated control group. Vitamin E treatment 30 min after iron intoxication reduced mortality by 75% compared with intravenous treatment with 10 mg/kg of deferoxamine (Desferal). Data in this study indicate that vitamin E may be a useful antidote for iron toxicoses and that iron-induced depletion of vitamin E may play a role in the pathogenesis of iron toxicity.

Influence of low dietary iron and iron overload on urethan-induced lung tumors in mice.

Weanling male CD-1 mice were fed low iron (7 ppm), control (120 ppm) and iron loaded diets (3000 or 5000 ppm) for 19 weeks. After seven weeks, the mice received 1.5 mg urethan/g ip, and tumor development was evaluated 12 weeks later. The low iron diet increased the incidence of lung adenomas by 86%. The iron loaded diets did not influence adenoma development. Tumor size was unaffected by iron status (p = 0.297). These results indicate that low iron body status promotes tumor development and are inconsistent with the hypothesis that excess iron promotes cancer growth and that low iron protects against tumor growth.