Exposure to dithiocarbamate fungicide Ziram results in hepatic and renal toxicity in Long Evan rats.

Ziram is a dimethyldithiocarbamate fungicide that is complexed to the metal zinc. The focus of this study is to examine the effects of dimethyldithiocarbamate exposure on metal homeostasis, glutathione levels, and the physiological parameters of the kidney and liver in Long-Evan rats. Our results indicate significant accumulation of copper or zinc, and changes in total GSH or GSH/GSSG ratio in the liver and kidneys of animals treated with Ziram only. Histopathological examination of liver and kidney sections indicate the presence of infiltrates in the liver of animals treated with Ziram only, whereas protein aggregates, sloughing of cells and increased KIM-1 positive cells, an indicator of tubule deterioration, are seen in the kidneys of animals treated with Ziram and sodium-dimethyldithiocarbamate, the salt form of the dimethyldithiocarbmate backbone. These findings suggest that the overall toxicological effect of Ziram is mediated by an intrinsic property rather than to dimethyldithiocarbamate backbone or metal moiety.

Toxicity of the biocide polycarbamate, used for aquaculture nets, to some marine fish species.

We investigated toxic effects of the antifouling biocide polycarbamate (PC) on marine fish by conducting acute, early-life stage toxicity (ELS), and embryo toxicity tests. Mummichog (Fundulus heteroclitus) 96-h LC50 values for hatched larvae (body weight about 2.0 mg) and juveniles (660 ±â€¯36 mg) were about 12 and 630 µg/L, respectively. The ELS test using mummichog embryos yielded a lowest-observed-effect concentration of 3.9 µg/L and a no-observed-effect concentration of 2.1 µg/L with growth as the most sensitive endpoint. The embryo toxicity test for spotted halibut (Verasper variegatus) revealed a 10-d EC50 of 8.1 µg/L with abnormality as an endpoint. During the ELS and embryo toxicity tests, morphological abnormalities (notochord undulation) were induced in the embryos. Biochemical and gene-expression analysis suggest that PC-induced morphological abnormalities involve disruption of lysyl oxidase-mediated collagen fiber organization, essential for notochord formation, and inhibition of gene expression related to notochord formation.

Intranasal administration of sodium dimethyldithiocarbamate induces motor deficits and dopaminergic dysfunction in mice.

The primary etiology of Parkinson's disease (PD) remains unclear, but likely reflects a combination of genetic and environmental factors. Exposure to some pesticides, including ziram (zinc dimethyldithiocarbamate), is a relevant risk factor for PD. Like some other environmental neurotoxicants, we hypothesized that ziram can enter the central nervous system from the nasal mucosa via the olfactory nerves. To address this issue, we evaluated the effects of 1, 2 or 4 days of intranasal (i.n., 1 mg/nostril/day) infusions of sodium dimethyldithiocarbamate (NaDMDC), a dimethyldithiocarbamate more soluble than ziram, on locomotor activity in the open field, neurological severity score and rotarod performance. We also addressed the effects of four daily i.n. NaDMDC infusions on olfactory bulb (OB) and striatal measures of cell death, reactive oxygen species (ROS), tyrosine hydroxylase, and the levels of dopamine, noradrenaline, serotonin, and their metabolites. A single i.n. administration of NaDMDC did not significantly alter the behavioral measures. Two consecutive days of i.n. NaDMDC administrations led to a transient neurological deficit that spontaneously resolved within a week. However, the i.n. infusions of NaDMDC for 4 consecutive days induced motor and neurological deficits for up to 7 days after the last NaDMDC administration and increased striatal TH immunocontent and dopamine degradation within a day of the last infusion. Pharmacological treatment with the anti-parkinsonian drugs l-DOPA and apomorphine improved the NaDMDC-induced locomotor deficits. NaDMDC increased serotonin levels and noradrenaline metabolism in the OB 24 h after the last NaDMDC infusion, ROS levels in the OB 2 h after the last infusion, and striatum 2 and 24 h after the last infusion. These results demonstrate, for the first time, that i.n. NaDMDC administration induces neurobehavioral and neurochemical impairments in mice. This accords with evidence that dimethyldithio-carbamate exposure increases the risk of PD and highlights the possibility that olfactory system could be a major route for NaDMDC entry to central nervous system.

Carbamate pesticide-induced apoptosis in human T lymphocytes.

We previously found that carbamate pesticides induced significant apoptosis in human natural killer cells. To investigate whether carbamate pesticides also induce apoptosis in human T lymphocytes, in the present study Jurkat human T cells were treated in vitro with thiram, maneb, carbaryl or ziram. Apoptosis was determined by FITC-Annexin-V/PI staining. To explore the mechanism of apoptosis, intracellular levels of active caspase 3 and mitochondrial cytochrome-c release were determined by flow cytometry. We found that thiram, ziram, maneb and carbaryl also induced apoptosis in a time- and dose-dependent manner in the human T cells. However, the strength of the apoptosis-inducing effect differed among the pesticides, with the: thiram > ziram > maneb > carbaryl. Moreover, thiram significantly increased the intracellular level of active caspase 3 and caspase inhibitors significantly inhibited apoptosis. Thiram also significantly caused mitochondrial cytochrome-c release. These findings indicate that carbamate pesticides can induce apoptosis in human T cells, and the apoptosis is mediated by the activation of caspases and the release of mitochondrial cytochrome-c.

Ziram and sodium N,N-dimethyldithiocarbamate inhibit ubiquitin activation through intracellular metal transport and increased oxidative stress in HEK293 cells.

Ubiquitin activating enzyme E1 plays a pivotal role in ubiquitin based protein signaling through regulating the initiating step of the cascade. Previous studies demonstrated that E1 is inhibited by covalent modification of reactive cysteines contained within the ubiquitin-binding groove and by conditions that increase oxidative stress and deplete cellular antioxidants. In this study, we determined the relative contribution of covalent adduction and oxidative stress to E1 inhibition produced by ziram and sodium N,N-dimethyldithiocarbamate (DMDC) in HEK293 cells. Although no dithiocarbamate-derived E1 adducts were identified on E1 using shotgun LC/MS/MS for either ziram or DMDC, both dithiocarbamates significantly decreased E1 activity, with ziram demonstrating greater potency. Ziram increased intracellular levels of zinc and copper, DMDC increased intracellular levels of only copper, and both dithiocarbamates enhanced oxidative injury evidenced by elevated levels of protein carbonyls and expression of heme oxygenase-1. To assess the contribution of intracellular copper transport to E1 inhibition, coincubations were performed with the copper chelator triethylenetetramine hydrochloride (TET). TET significantly protected E1 activity for both of the dithiocarbamates and decreased the associated oxidative injury in HEK293 cells as well as prevented dithiocarbamate-mediated lipid peroxidation assayed using an ethyl aracidonate micelle system. Because TET did not completely ameliorate intracellular transport of copper or zinc for ziram, TET apparently maintained E1 activity through its ability to diminish dithiocarbamate-mediated oxidative stress. Experiments to determine the relative contribution of elevated intracellular zinc and copper were performed using a metal free incubation system and showed that increases in either metal were sufficient to inhibit E1. To evaluate the utility of the HEK293 in vitro system for screening environmental agents, a series of additional pesticides and metals was assayed, and eight agents that produced a significant decrease and five that produced a significant increase in activated E1 were identified. These studies suggest that E1 is a sensitive redox sensor that can be modulated by exposure to environmental agents and can regulate downstream cellular processes.

Toxicity and bioaccumulation of the wood preservative copper dimethyldithiocarbamate in tissues of Long-Evans rats.

This study examined the toxicity and accumulation of copper in the livers and kidneys of Long-Evans rats after a subacute exposure to copper dimethyldithiocarbamate (CDCC) wood preservative. CDDC was recently introduced as an alternative to chromated copper arsenate (CCA) preserved wood. Female rats (220-270 g) were treated with 0, 25, 50, or 75 mg/kg CDDC by oral gavage for 3 wk. Light microscopy revealed that higher doses of CDDC induced diffuse necrosis and a loss of sinusoids in the livers of Long-Evans rats with vacuolization in the highest dose. Rats treated with 25 mg/kg CDDC displayed a thickening of the basement membrane of Bowman's capsule and the mesangium. Exposure to higher CDDC concentrations (50 and 75 mg/kg) showed moderate to marked expansion of the mesangial matrix and glomerular necrosis with an overall loss of glomerular structure seen in the highest dose. The concentration of copper was significantly increased in the tissues of animals exposed to CDDC in a dose-dependent manner. Western blot analysis revealed the induction of the stress protein Hsp70 and the formation of 4-hydroxy-2-nonenal (4HNE) adducts in liver and renal tissues, indicating peroxidative damage. CDDC was shown to be toxic to the livers and kidneys, at all doses used, and this toxicity is related to peroxidative insult.

Suppression of the steroid-primed luteinizing hormone surge in the female rat by sodium dimethyldithiocarbamate: relationship to hypothalamic catecholamines and GnRH neuronal activation.

In female rodents, hypothalamic norepinephrine (NE) has a role in stimulating the secretion of gonadotropin-releasing hormone (GnRH) that triggers the ovulatory surge of luteinizing hormone (LH). NE synthesis from dopamine (DA) is catalyzed by dopamine-beta-hydroxylase (DbetaH) which contains a copper cofactor. Sodium dimethyldithiocarbamate (DMDC) is a pesticide with metal chelating properties that has been found to reduce DbetaH activity. The resultant decrease in NE causes a suppression of both the LH surge and ovulation. The present study examined the dose-related impact of DMDC on hypothalamic GnRH neuronal activation indicated by the nuclear presence of the early gene product c-fos. It represents an essential link between effects on NE and suppression of the surge. Ovariectomized (OVX), estradiol-, and progesterone-primed Sprague-Dawley rats were given a single ip injection of 0, 3.6, 7.1, 14.2, or 28.4 mg/kg DMDC in separate groups of females to assess tissue GnRH/c-fos immunostaining, hypothalamic catecholamines, and serial blood samplings for LH. A dose-related decline in hypothalamic NE and increase in DA at 2 h after DMDC administration were consistent with a decrease in c-fos-positive GnRH neurons, with an almost complete absence of c-fos at the two highest doses. The effects correlated well with a suppression of the surge, although the percentage decrease in c-fos neurons at 7.1 mg/kg only attenuated the surge peak, not the overall amount of circulating LH. The present data offer further evidence that the impact of DMDC on the LH surge is central in origin and in doing so defines the toxic pathway for this effect on ovulation.

The effects of the wood preservative copper dimethyldithiocarbamate in the hippocampus of maternal and newborn Long-Evans rats.

The potential toxic effects on human health and deleterious effects to the environment by copper dimethyldithiocarbamate (CDDC), an alternative wood preservative to chromated copper arsenate (CCA) have not been investigated. This study describes the neurotoxicity and accumulation of copper in the hippocampus of maternal and newborn Long-Evans rats following a subacute exposure to CDDC. Pregnant rats (220-270g) were treated daily with 0mg/kg, 25mg/kg, 50mg/kg, or 75mg/kg CDDC by oral gavage starting from day 6 of gestation and continuing to parturition. Following parturition, maternal and newborn rats were euthanized and brain tissues were removed, processed, and stored for analysis. Electron microscopy revealed demyelination and by-products of peroxidative damage in treated maternal hippocampi. Treated newborn hippocampi exhibited numerous degenerating mitochondria, membrane bound inclusion bodies, and vacuoles containing degraded structures. Graphite furnace atomic absorption spectrophotometry (GFAAS) demonstrated a significant increase in copper concentration in the tissues of treated animals as compared to controls. Western blot analysis revealed an induction of stress proteins HO-1 and Hsp70 and the formation of 4-hydroxy-2-nonenal (4HNE) adducts. CDDC was shown to be toxic to the brains, at all doses used and this toxicity is attributable to copper-induced lipid peroxidation.

Moderating influence of the drinking water disinfection by-product dibromoacetic acid on a dithiocarbamate-induced suppression of the luteinizing hormone surge in female rats.

The disinfection by-product dibromoacetic acid (DBA) has been found in female rats to increase circulating concentrations of both estradiol (E2) and estrone (E1). This effect is apparently due, at least in part, to a suppression in hepatic catabolism. The present study investigated whether DBA, by increasing sex steroid levels, is able either to augment the hypothalamic up-regulation involved in triggering a luteinizing hormone (LH) surge, or to affect the ability of the neurotoxicant sodium dimethyldithiocarbamate (DMDC) to block the surge. Sprague-Dawley rats were gavaged for 14 days with DBA (0-150mg/kg) and ovariectomized on dosing day 11, and at the same time implanted with an estradiol capsule to generate daily LH surges. An injection of 0.1mM/kg DMDC was administered at 13:00h on day 14 and blood was sampled over the afternoon. DBA induced a dose-related increase in total estrogens. For identified surges, areas under the LH curve partitioned into two groups, comprising the two lower (0 and 37.5mg/kg DBA) and the two higher (75 and 150mg/kg) treatment groups. Consequently, low and high DBA groups were compared and found to be significantly different. At 150mg DBA/0.1mM DMDC, the timing of an identifiable LH peak was comparable to non-DMDC females, unlike the 37.5mg DBA/0.1mM DMDC group in which the appearance of peak concentrations was delayed. A significant effect with DBA treatment alone was not present. Results indicated that this exposure to DBA induced a dose-related increase in total estrogen concentrations that paralleled a diminished DMDC blockade of the LH surge. The effect appeared to be attributable to an augmentation in the estrogen-associated up-regulation in brain mechanisms stimulating the surge.

Dithiocarbamates have a common toxic effect on zebrafish body axis formation.

We previously determined that the dithiocarbamate pesticide sodium metam (NaM) and its active ingredient methylisothiocyanate (MITC) were developmentally toxic causing notochord distortions in the zebrafish. In this study, developing zebrafish were exposed to isothiocyanates (ITCs), dithiocarbamates (DTCs) and several degradation products to determine the teratogenic relationship of these chemical classes at the molecular level. All dithiocarbamates tested elicited notochord distortions with notochord NOELs from <4 to 40 ppb, while none of the ITCs caused notochord distortions with the exception of MITC. Carbon disulfide (CS(2)), a common DTC degradate, also caused distortions at concentrations >200 times the DTCs. Whole mount in situ hybridization of developmental markers for collagen (collagen2a1), muscle (myoD), and body axis formation (no tail) was perturbed well after cessation of treatment with pyrolidine-DTC (PDTC), dimethyl-DTC (DMDTC), NaM, MITC, and CS(2). Therefore, distinct albeit related chemical classes share a common toxic effect on zebrafish notochord development. To test the responsiveness of the distortion to metal perturbation, five metal chelators and 2 metals were studied. The membrane permeable copper chelator neocuproine (NCu) was found to cause notochord distortions similar to DTC-related molecules. DMDTC and NCu treated animals were protected with copper, and collagen 2a1 and no tail gene expression patterns were identical to controls in these animals. PDTC, NaM, MITC, and CS(2) were not responsive to copper indicating that the chelation of metals is not the primary means by which these molecules elicit their developmental toxicity. Embryos treated with DMDTC, NaM, and NCu were rescued by adding triciaine (MS-222) which abolishes the spontaneous muscle contractions that begin at 18 hpf. In these animals, only collagen 2a1 expression showed a similar pattern to the other notochord distorting molecules. This indicates that the perturbation of no tail expression is in response to the muscle contractions distorting the notochord, while collagen 2a1 is associated with the impact of these molecules on much earlier developmental processes.

In vivo and in vitro hepatotoxicity and glutathione interactions of N-methyldithiocarbamate and N,N-dimethyldithiocarbamate in the rat.

The ability of N-methyldithiocarbamate (NMDC) to generate methylisothiocyanate and HS(-) together with its greater acid stability suggest that NMDC may exert greater acute toxicity following oral exposure than its dialkyl analog,N,N-dimethyldithiocarbamate (DMDC). To assess this possibility, cell culture, perfused liver, and in vivo studies were performed to delineate differences in the hepatotoxicity and thiol interactions of NMDC and DMDC in the rat. The role of methylisothiocyanate and HS(-) in NMDC-induced hepatotoxicity was evaluated and glutathione interactions characterized through analysis of reduced glutathione (GSH), glutathione disulfide (GSSG), and S-methylthiocarbamoylglutathione (GSMITC) using HPLC and liquid chromatography tandem mass spectrometry (LC/MS/MS). Following oral administration, centrilobular hepatocyte necrosis and enzyme leakage was observed for NMDC but not for DMDC. Dose dependent decreases of intracellular GSH were produced by both dithiocarbamates in primary hepatocytes but DMDC appeared to deplete GSH through the generation of GSSG whereas NMDC produced GSMITC consistent with the generation of a methylisothiocyanate intermediate. In primary hepatocytes, both NMDC and DMDC cytotoxicity was increased by prior depletion of intracellular GSH and diminished by prior supplementation of GSH. The results obtained using perfused livers were similar for NMDC in that elevated levels of GSMITC were detected in the bile; however, DMDC produced only a modest increase of GSSG over controls that was not significantly different to that produced by NMDC. Results obtained from isolated liver mitochondria and primary hepatocytes were not consistent with NMDC producing HS(-)-mediated inhibition of mitochondrial respiration. These data support a greater potential for hepatotoxicity to result following oral exposure to NMDC relative to DMDC and that glutathione may play a role in cytoprotection for NMDC, presumably through detoxification of a methylisothiocyanate metabolite.

Evaluation of the aneugenic potential of the fungicide Ferbam in mice.

Ferbam, a potent dithiocarbamate fungicide is used as a protectant against a wide variety of fungal diseases in fruits, vegetables, and ornamental plants. The wide-spread use of this chemical is likely to pollute the environment. Hence, it was planned to test the possible genotoxicity of Ferbam through its aneugenic potential in the in vivo mouse (Mus musculus) test system. Four different doses of Ferbam, namely, 7.5, 15.0, 30.0, 60.0 mg/kg body weight were administered orally to mice Mus musculus suspended in gum tragacanth representing, respectively, 1/16, 1/8, 1/4;, 1/2 th of the LD50 value. They were sacrificed at 6-, 12-, 24-, and 48-h intervals along with a distilled water negative control at 2 mg/kg body weight. Colchicine treated animals were used as positive controls. Bone marrow preparations were made following the standard Hypotonic flame dry Giemsa staining technique to study the dose and time yield effect of Ferbam. The aneugenic potential was evaluated for C-mitotic effects by scoring the mitotic index, c-mitoses frequency, anaphase reduction, and hyper/hypodiploidy induction. Ferbam showed a significant increase in the mitotic index and C-mitoses effects and anaphase decreased at the highest doses of 30 and 60 mg/kg at 12- and 24-h intervals. Colchicine induced significant effects in all the aneugenic parameters observed at all the time intervals. There was no significant induction of either hyperdiploidy or hypodiploidy by Ferbam, unlike colchicine, indicating that the fungicide Ferbam is not aneugenic in the mouse test system.

Leukemia and exposure to 1,3-butadiene, styrene and dimethyldithiocarbamate among workers in the synthetic rubber industry.

This study evaluated relations between exposure to 1,3-butadiene (BD), styrene (STY) and dimethyldithiocarbamate (DMDTC) and mortality from leukemia among synthetic rubber industry workers. Subjects were 13130 men employed for at least 1 year during 1943-1991 at any of six plants that manufactured synthetic rubber. Death certificates and medical records identified workers with leukemia. Cumulative exposure estimates were based on plant- and time period-specific process and task characteristics, linked to subjects' work histories. Poisson regression estimated relative rates (RRs) for workers exposed to each agent compared to unexposed workers. Leukemia (N=59) was positively associated with BD ppm-years (RRs of 1.0, 1.2, 2.0 and 3.8, for exposures of 0, >0-<86.3, 86.3-<362.2 and 362.2+ ppm-years; only the RR for the highest exposure category was statistically significant), STY ppm-years (RRs of 1.0, 1.2, 2.3 and 3.2, for exposures of 0, >0-<20.6, 20.6-<60.4 and 60.4+ ppm-years; only the RR for the highest exposure category was statistically significant) and DMDTC mg-years/cm (RRs of 1.0, 2.3, 4.9 and 2.9, for 0, >0-<566.6, 566.6-<1395.1 and 1395.1+ mg-years/cm; the RR for each non-zero exposure category was statistically significant) after adjusting for age and years since hire. After further adjusting each agent-specific set of RRs for the other two agents, a positive but imprecise relation remained for BD and DMDTC but not for STY. The association with BD was stronger for ppm-years due to exposure intensities >100 ppm than for ppm-years due to lower concentrations. BD and DMDTC, but not STY, were positively associated with leukemia in multivariable analyses. The independent effect of each agent was difficult to evaluate because of correlations with other agents and imprecision.

Application of process chemistry and SAR modelling to the evaluation of health findings of lower olefins.

Epidemiology studies show increased leukemia mortality among styrene butadiene rubber (SBR) workers but not among butadiene monomer production employees. A detailed review of the SBR manufacturing process indicates that sodium dimethyldithiocarbamate (DMDTC) introduced into the SBR manufacturing process for a period in the 1950s coincides with increased leukemia mortality. Using the Computer-Optimized Molecular Parametric Analysis of Chemical Toxicity (COMPACT), we assessed the enzyme (cytochrome P450) substrate specificity of an olefin series including 1,3-butadiene (BD) and also modeled its interaction with DMDTC. These analyses showed correlation of a structural/electronic parameter--the COMPACT radius--with the presence or absence of cytogenetic activity and also found that DMDTC would inhibit the oxidative metabolism of BD at least at high concentrations. Both DMDTC and its diethyl analog (DEDTC) bind with CYP 2E1 and CYP 2A6. Both of these isoforms are important in the initial oxidative metabolism of butadiene and other olefins. In co-exposure studies in mice of DMDTC with BD or with epoxybutene (EB), we found that there was a reduced increase in genotoxic activity based on micronuclei induction compared with BD or EB exposure alone. Treatment with DMDTC significantly increased the protein carbonyl contents of hepatic microsomes compared with that of controls, a finding that may be related to DMDTC's activity as a prooxidant. Co-exposure with DMDTC and EB increased hepatic microsomal carbonyls to levels significantly greater than those of DMDTC-treated mice, while EB administration in the absence of DMDTC did not change protein carbonyls relative to those of controls. The increase in hepatic microsomal protein carbonyls suggests that DMDTC may modulate EB metabolism towards the formation of reactive intermediates that react with proteins. The present molecular modeling and mechanistic studies suggest that co-exposure of BD and DMDTC is a plausible biological hypothesis regarding increased leukemia risk among SBR workers.

The influence of co-exposure to dimethyldithiocarbamate on butadiene metabolism.

Treatment of rats and mice with a single oral dose of dimethyldithiocarbamate (DMDTC; 250 mg/kg) had a marked effect on hepatic CYP2E1 and aldehyde dehydrogenase activities, measured in vitro, for up to 24 h after dosing. The same treatment did not affect CYP2A6, glutathione S-transferase, epoxide hydrolase, alcohol dehydrogenase activities or hepatic glutathione levels. As a consequence of the loss of CYP2E1 activity, butadiene metabolism in liver fractions from DMDTC treated rats and mice was markedly reduced, as was the metabolism of the mono-epoxide to the di-epoxide in mouse liver. The conversion of the mono-epoxide to the diol by epoxide hydrolases was not affected by DMDTC treatment. Urinary excretion of radioactivity, following dosing with DMDTC and exposure to 200 ppm C-14 butadiene for 6 h, was markedly reduced in rats, but increased in mice. The profiles of urinary metabolites were qualitatively similar from mice exposed to butadiene to those exposed after dosing with DMDTC. In the rat, pre-dosing with DMDTC resulted in the formation of three additional urinary metabolites following exposure to butadiene. Overall, DMDTC appears to impact qualitatively and quantitatively on the metabolism of butadiene. The nature and full significance of these changes has yet to be characterised.

Dimethyldithiocarbamate inhibits in vitro activation of primary human CD4+ T lymphocytes.

Dithiocarbamates (DTC), a diverse group of industrial and therapeutic chemicals, have been reported to inhibit, enhance or have no effect on the immune system. These apparent inconsistencies reflect the complexity of the DTCs biological activities and are probably due in part to differences in dose, route of exposure, animal species used and/or specific compound tested. The studies described herein were undertaken to investigate the immunotoxicity of one member of this family, dimethyldithiocarbamate (DMDTC). We demonstrate that 0.1-0.5 microM DMDTC inhibits TNF-alpha-induced activation of NF-kappaB in primary human CD4+ T cells. This inhibition is not accompanied by a loss in viability, and DMDTC-treated T cells retain other active signaling pathways throughout the exposure duration. The inhibition of NF-kappaB is apparently permanent as DMDTC-treated T cells did not regain normal TNF-alpha activation, even after 72 h in culture. DMDTC does not appear to alter NF-kappaB directly as pre-incubation of nuclear extracts with DMDTC does not diminish binding activity of this protein. We further demonstrate that 0.1-0.5 microM DMDTC inhibits intracellular IL-2 production and decreases surface expression of CD25 (the alpha subunit of the IL-2 receptor) in T cells stimulated with phorbol ester. These data demonstrate that DMDTC is a potent immunosuppressive compound in vitro.

Blockade of ovulation in the rat by systemic and ovarian intrabursal administration of the fungicide sodium dimethyldithiocarbamate.

Dithiocarbamates, acting as inhibitors of catecholamine synthesis, have been reported to block ovulation in female rats following systemic administration by suppressing the neural noradrenergic signaling involved in triggering the ovulatory surge of luteinizing hormone. The ovaries also synthesize norepinephrine and receive noradrenergic input via sympathetic innervation, and it has been suggested that such input may play a role in follicular maturation and ovulation. The current experiments investigated whether the dithiocarbamate fungicide dimethyldithiocarbamate (DMDTC) would block oocyte release in normally cycling rats when administered systemically during the proestrous presurge period, and if so, would the compound also have a comparable direct ovarian effect on ovulation in response to a local intrabursal exposure of one ovary late on the day of vaginal proestrus. The results showed that a dose-related suppression of oocyte release was present in response to both intraperitoneal and intrabursal (IB) injections. But these effects appear to be mediated through different mechanisms. The unilateral IB injections were effective only on the exposed side for each ovarian pair, while no alterations were seen in ovarian norepinephrine. IB administration 24 h earlier blocked ovulation on both sides, while hCG injections were able to restore ovulation on the noninjected side only, implying that diestrous DMDTC was inhibiting the LH surge. The data indicate that while an effect on hypothalamic catecholamine synthesis may underlie the ovulatory blockade following intraperitoneal DMDTC administration, it does not appear to be involved in the response to local ovarian exposure. Moreover, the blockade in response to the diestrous IB exposure likely involves two separate mechanisms, one attributable to an alteration in ovarian hormonal feedback to the brain (or pituitary), inhibiting the LH surge, and the other associated with a direct, as yet undetermined, effect on local preovulatory events within the ovary.

Study of the interactions between copper, cadmium, and ferbam using the protozoan Colpidium campylum bioassay.

The toxicity of a copper-cadmium-ferbam mixture has been studied using the protozoan Colpidium campylum bioassay. The assays were designed according to the factorial experiments method, associated with multiple regression analysis. The results show that, at the concentrations tested, a synergy occurs between cadmium and ferbam, whereas the copper is only oligodynamic.

Effect of DNOC, Ferbam and Imidan exposure on mouse sperm morphology.

DNOC, Ferbam and Imidan were tested in (C3H X C57BL/6) F1 mice to assess their potential testicular toxicity. Chemicals were administered i.p. and per os at different doses for 5 consecutive days. After 35 days the testicular was toxicity was evaluated by measuring the testicular weights, the sperm counts and the percentage of abnormal sperm. DNOC and Imidan failed to induce teratospermia in mice treated by both routes of administration. Conversely Ferbam induced a statistically significant increase in teratospermia only following per os administration to mice at a dose of 1000 mg/kg b.w./day. These data indicate that per os administration of Ferbam succeeded in producing active metabolites able to interfere with the differentiation process of spermatogenic cells.