PubMed Health⌕ Search

Biomedical subjects

E K Silbergeld

Publications and source records attributed to E K Silbergeld.

At least 19 recordsLinked to original sources
PubMed2005

Prenatal HgCl2 exposure in BALB/c mice: gender-specific effects on the ontogeny of the immune system.

Because mercury is highly toxic to developing organisms, we tested the hypothesis that prenatal exposure to HgCl(2) can induce persistent immune dysfunction. Pregnant BALB/c mice were administrated every other day, for 11 days with HgCl(2) (200 microg/kg). Their offspring were studied at PND10, 14, 21, and 60. Lymph nodes (LN), spleens, and thymus were harvested and proliferation and cytokine production were studied in vitro. We report that prenatal HgCl(2) exposure exerts organ-specific effects on cell number, proliferation, and cytokine production in pre-weaning pups. At adulthood (PND60), effects of prenatal HgCl(2) exposure were still observed, but expressed differently in females and males. In adult females, an inhibitory effect was observed on cytokine production by thymocytes, LN cells, and splenocytes. In males, a stimulatory effect was observed. Overall, we conclude that in vivo exposures to low doses of HgCl(2) can induce persistent sex-specific immunotoxic effects, observable in adulthood.

Animals↗
PubMed2005

In vitro HgCl2 exposure of immune cells at different stages of maturation: effects on phenotype and function.

This is the first study to investigate the hypothesis that the immunotoxic effects of inorganic mercury may be modulated by inherent differences in the responsiveness of immune cells related to the age of the donor. We exposed cells from lymph nodes, spleen, and thymus, collected from 7- and 10-day-old CD.1 pups, as well as from adult CD.1 mice, in terms of the effects of mercury in vitro on responses to Con-A stimulation with respect to proliferation, cytokine production, and cell phenotype. The effects of mercury on proliferation were age and organ dependent, while effects on cytokine production were only age dependent. Effects of mercury were observed only on splenocyte T-cell subpopulations and only in cells from 10-day-old pups and from adults. Mercury had no effect on IFN-gamma and IL-4 production by splenocytes from 7-day-old pups, but significantly decreased release of these cytokines by splenocytes from 10-day-old pups and adults. Hg did not affect IL-4 production by lymph node cells or thymocytes. In lymph node cells Hg affected IFN-gamma production only at 7 days. These data indicate that inherent properties of immune cells at different stages of development may influence the response to immunotoxicants.

Animals↗
PubMed2004

Altered brain activity in brevetoxin-exposed bluegill, Lepomis macrochirus, visualized using in vivo 14C 2-deoxyglucose labeling.

This study investigated the neurological effects of sublethal brevetoxin (PbTx-2) exposure in bluegill (Lepomis macrochirus) by measuring alterations in 2-deoxyglucose (2-DG) uptake in the brains of exposed fish. Changes in regional brain activity were quantified using digitized autoradiographs from exposed and control fish. Brains of brevetoxin-exposed fish had significantly higher labeling of 2-DG than brains of control fish. Regional increases in labeling were observed in the optic lobes, telencephalon, and cerebrum of PbTx-2 exposed fish. From these observations, we conclude that sublethal brevetoxin exposure in vivo in bluegill increases neurological stimulation, measured through quantification of [14C]2-DG uptake in the brain. Increases in the uptake of [14C]2-DG from this study may be indicative of differences in neural activity in the PbTx-exposed fish and are likely associated with the action of PbTx-2 on voltage-gated sodium channels (VGSC), as well as neurological alterations in calcium and neurotransmitter release downstream resulting from VGSC activation. These techniques quantify physiological alterations in fish brain activity resulting from exposure to brevetoxin and possibly other harmful algal bloom toxins.

Animals↗
PubMed2004

Evidence of histamine receptors in fish brain using an in vivo [14C]2-deoxyglucose autoradiographic method and an in vitro receptor-binding autoradiographic method.

It was hypothesized that fish possess functioning H1 histamine receptors that have the ability to bind agonists and antagonists specific to the H1 histamine receptor subtype. For these experiments, a combination of a novel, in vivo 2-deoxyglucose method and a standard in vitro autoradiography procedure was utilized. A regional, statistically significant dose response in neurological functioning was observed when fish were exposed to histaminergic agents (i.e., H1 agonists and antagonists), which created the first neurological profile for the H1 histamine receptor in fish brain. The H1 histamine receptor was chosen as a characterization receptor in fish because histamine has been linked to a variety of neurological functions such as the control of arousal, attention, sensory processing, and cognition. Histamine also plays a role in pituitary hormone secretion, appetite control, and, potentially, regulation of vestigular reactivity. In addition, the fish brain is well characterized structurally, and the existence of an H3-like receptor has been documented recently in zebrafish. However, to date there is little detailed information about specific localization and functioning of the H1 histamine receptor in fish.

Animals↗
PubMed2001

Association of transposition of the great arteries in infants with maternal exposures to herbicides and rodenticides.

The Baltimore-Washington Infant Study, a case-control study of congenital heart defects in liveborn infants conducted in 1981--1989, interviewed parents about a wide range of environmental exposures that occurred during and before the pregnancy. In the period 1987--1989, the questionnaire was expanded to include a detailed inquiry about exposures to pesticides. An analysis of these latter data revealed an association of maternal exposure to any pesticides during the first trimester with transposition of the great arteries in their infants (TGA; n = 66 infants), relative to 771 control infants, with an odds ratio of 2.0 (95% confidence interval (CI): 1.2, 3.3). No other heart defects were associated with pesticides. When analyzed by type of pesticide and adjusted for covariates, there were associations of TGA with maternal exposures to herbicides (odds ratio (OR) = 2.8; 95% CI: 1.3, 7.2) and to rodenticidal chemicals (OR = 4.7; 95% CI: 1.4, 12.1) but not to insecticides (OR = 1.5; 95% CI: 0.9, 2.6). No data were collected on specific chemicals or brand names. These results raise new questions about the possible epidemiologic association of TGA with some classes of pesticides and warrant new, carefully targeted investigations.

Adult↗
PubMed2001

Methylmercury-induced decrement in neuronal migration may involve cytokine-dependent mechanisms: a novel method to assess neuronal movement in vitro.

A major toxic effect associated with methylmercury (MeHg) exposure in developing humans is damage to the nervous system, which involves inhibition of cell migration, particularly in the cerebellum. The mechanisms by which MeHg impairs neural migration are not fully known, especially at low doses. In this paper we report on a novel method for observing and quantitating the movement of individual cells in primary cultures of murine neonatal cerebellar cells, which offers an opportunity to assess the role of endogenous and exogenous factors on neural migration. We have used this system to test the hypothesis that treatment with methylmercury would inhibit movement of granule cell neurons, possibly via a cytokine-mediated mechanism. We demonstrate that LPS (50 ng/ml) increases movement of neurons, concomitant with increased levels of TNF-alpha and IL-6 secreted protein, and IL-1alpha mRNA. Treatment with LPS did not increase the number of neurons that moved, but, of the cells that did move, exposure to LPS significantly increased the total distances moved. Treatment with methylmercury (0.1 microM) decreased the number of moving cells and inhibited overall distance traveled by granule cells.

Animals↗
PubMed2000

Lead as a carcinogen: experimental evidence and mechanisms of action.

Recent epidemiological and experimental work confirms that inorganic lead compounds are associated with increased risks of tumorigenesis. In animals, these risks can be induced at doses that are not associated with organ toxicity and in mice that do not produce alpha-2 urinary globulin in the kidney. Thus the mechanisms of lead carcinogenicity are unlikely to be fully explained as toxicity-related sequelae of high dose exposure or as a rat-specific response involving overexpression of a renal protein. Plausible mechanisms of lead carcinogenicity include direct DNA damage, clastogenicity, or inhibition of DNA synthesis or repair. Lead may also generate reactive oxygen species and cause oxidative damage to DNA. Recent data indicate that lead can substitute for zinc in several proteins that function as transcriptional regulators, including protamines. Lead further reduces the binding of these proteins to recognition elements in genomic DNA, which suggests an epigenetic involvement of lead in altered gene expression. These events may be of particular relevance in transplacental exposures and later cancer.

Animals↗
PubMed2000

Lead effects on protamine-DNA binding.

BACKGROUND: Lead impairs male fertility and may affect offspring of exposed males, but the mechanisms for this impairment are not completely clear. Protamine P1 and P2 families pack and protect mammalian sperm DNA. Human HP2 is a zinc-protein and may have an important role in fertility. As lead has affinity for zinc-containing proteins, we evaluated its ability in vitro to bind to HP2 and its effects on HP2-DNA binding. Methods and Results UV/VIS spectroscopic data indicated that HP2 binds both Pb(2+) and Zn(2+)(as chloride salts). They also provided evidence that thiol groups mainly participate for Zn(2+)-binding; however, HP2 has additional binding sites for Pb(2+). The mobility shift assay showed that lead interaction with HP2 caused a dose-dependent decrease on HP2 binding to DNA, suggesting that lead may alter chromatin stability. CONCLUSIONS: These in vitro results demonstrate that lead can interact with HP2 altering the DNA-protamine binding. This chemical interaction of lead with protamines may result in chromatin alterations, which in turn may lead to male fertility problems and eventually to DNA damage.

Chromatin↗
PubMed2000

Lead interaction with human protamine (HP2) as a mechanism of male reproductive toxicity.

During spermatogenesis, histones are replaced by protamines, which condense and protect sperm DNA. In humans, zinc contributes to sperm chromatin stability and binds to protamine P2 (HP2). Chemical interactions with nuclear protamines, which prevent normal sperm chromatin condensation, may induce changes in the sperm genome and thus affect fertility and offspring development. Since lead has a high affinity for zinc-containing proteins, we investigated lead interactions with HP2 as a novel mechanism of its toxicity to sperm. UV/vis and CD spectroscopy results indicated that HP2 binds Pb(2+) at two different sites, causing a conformational change in the protein. They also provided evidence that thiol groups are primarily involved in Zn(2+) and Pb(2+) binding to HP2 and that HP2 may have additional binding sites for Pb(2+) not related to Zn(2+). HP2 affinities for Pb(2+) and Zn(2+) were very similar, suggesting that Pb(2+) can compete with or replace Zn(2+) in HP2 in vivo. This interaction of lead with HP2 resulted in a dose-dependent decrease in the extent of HP2-DNA binding, although lead interaction with DNA also contributed to this effect. Therefore, the ability of lead to decrease the level of HP2-DNA interaction may result in alterations to sperm chromatin condensation, and thus in reduced fertility.

Animals↗
PubMed2000

Gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin induces developmental defects in the rat vagina.

At puberty, female rats exposed in utero to 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) exhibit a persistent thread of mesenchymal tissue surrounded by keratinized epithelium that partially occludes the vaginal opening. Our objective was to determine the earliest time during fetal development that morphological signs of this vaginal canal malformation could be detected and to obtain greater insight into mechanisms involved in this effect. Pregnant rats were administered a single dose of vehicle (control) or TCDD (1.0 microg/kg, po) on gestation day (GD) 15 and were sacrificed on GD 18, 19, 20, and 21 for histological evaluation of female. Gestational exposure to TCDD affected vaginal morphogenesis as early as GD 19, 4 days after exposure of pregnant dams. In exposed fetuses, the thickness of mesenchymal tissue between the caudal Mullerian ducts was increased, which resulted in a failure of the Mullerian ducts to fuse, a process normally completed prior to parturition. In addition, TCDD exposure appeared to inhibit the regression of Wolffian ducts. Thus, TCDD interferes with vaginal development by impairing regression of the Wolffian ducts, by increasing the size of interductal mesenchyme, and by preventing fusion of the Mullerian ducts. Taken together, these effects appear to cause the persistent vaginal thread defect observed in rats following in utero and lactational TCDD exposure.

Abnormalities, Drug-Induced↗
PubMed2000

Mercury exposure and murine response to Plasmodium yoelii infection and immunization.

Malaria has re-emerged in Amazonia over the past two decades. Many factors have been proposed for this, among them changes in population distribution, failures of vector control and pharmacologic management, and local as well as global environmental changes. Among the latter factors, we have studied the potential role of increasing exposures to the immunotoxic metal mercury, which is widely used in Amazonia for artisanal extraction of alluvial gold deposits. We report here that Hg impairs host resistance to malaria infection at exo-erythrocytic stages. Hg exposed mice have higher parasitemia following infection with sporozoites, but not after transfusion of infected red cells. In mice inoculated with irradiated sporozoites, Hg blocks acquisition of immunity. In addition Hg affects immunologic parameters that are known to be involved in host response to malaria infection. These results have potential implications for the incidence and prevalence of malaria among populations exposed to mercury from artisanal goldmining and consumption of contaminated fish regions with high rates of malaria and other infectious diseases.

Animals↗
PubMed1999

Lead: male-mediated effects on reproduction and development in the rat.

The present study was designed to determine the effect of relatively low levels of lead acetate (25 and 250 ppm) exposure on fertility and offspring viability in male Sprague-Dawley rats. Protein synthesis in 2-cell embryos was monitored by [35S] methionine labeling and two-dimensional SDS gel electrophoresis. Fertility was reduced in males with blood lead levels in the range 27-60 microg/dL. Lead was found to affect initial genomic expression in embryos fathered by male rats with blood lead levels as low as 15-23 microg/dL. Dose-dependent increases were seen in an unidentified set of proteins with a relative molecular weight of approximately 70 kDa (Mr). These results indicate that male-mediated effects of lead may be observed in the 2-cell embryo. The alteration observed in embryonic gene expression with paternal lead exposure may be useful for studying the role of the paternal contribution to the activation of the embryonic genome and protein synthesis in the early embryo.

Animals↗
PubMed1999

Chemicals and menopause: effects on age at menopause and on health status in the postmenopausal period.

Menopause, a natural stage in women's lives, signals the cessation of fertility and causes changes in health status for many women. Chemical exposures may induce early or premature menopause and increase the risks of morbidity and mortality in the postmenopausal period. Chemicals that are toxic to follicles can lower the age of menopause by depleting the ovary of oocytes. Women may be exposed to these chemicals in the workplace, at home, and through exposure to contaminated drinking water near hazardous waste sites, as well as by direct or indirect exposure to cigarette smoke.

Adult↗
PubMed1999

Neurotoxic effects of endocrine disruptors.

Endocrine disrupting chemicals are a newly defined category of environmental contaminants that may affect animal and human populations by interfering with normal hormone action. There is substantial concern that these agents could have a range of subtle and long-lasting effects. Because of the sensitivity of the developing central nervous system to low levels of endogenous gonadal hormones during development, the central nervous system may be a target for the action of endocrine disrupting chemicals.

Animals↗
PubMed1998

90-day feeding and one-generation reproduction study in Crl:CD BR rats with 17 beta-estradiol.

Over the past several years, there has been increasing concern that chemicals and pesticides found in the environment may mimic endogenous estrogens, potentially producing adverse effects in wildlife and human populations. Because estrogenicity is one of the primary concerns, a 90-day/one-generation reproduction study with 17 beta-estradiol was designed to set dose levels for future multigenerational reproduction and combined chronic toxicity/oncogenicity studies. The purpose of these studies is to evaluate the significance of a range of responses as well as to provide benchmark data for a risk assessment for chemicals with estrogen-like activities. This 90-day/one-generation reproduction study was conducted in male and female Crl:CD BR rats using dietary concentrations of 0, 0.05, 2.5, 10, and 50 ppm 17 beta-estradiol. Endpoints were chosen in order to evaluate both subchronic and reproductive toxicity. In addition, several mechanistic/biochemical endpoints were evaluated for their usefulness in follow-up studies. In the P1 generation, dietary administration of 2.5, 10, and 50 ppm 17 beta-estradiol produced dose-dependent decreases in body weight, body weight gain, food consumption, and food efficiency. At 10 and 50 ppm 17 beta-estradiol, minimal to mild nonregenerative anemia, lymphopenia, decreased serum cholesterol (50 ppm only), and altered splenic lymphocyte subtypes were also observed in the P1 generation. Additionally, at these concentrations, there were changes in the weights of several organs. Evidence of ovarian malfunction, characterized by reduced numbers of corpora lutea and large antral follicles, was observed at 2.5 ppm 17 beta-estradiol and above. Other pathologic changes in males and females fed 10 and 50 ppm 17 beta-estradiol included centrilobular hepatocellular hypertrophy; diffuse hyperplasia of the pituitary gland; feminization of the male mammary glands; mammary gland hyperplasia in females; increased number of cystic follicles in the ovary; hypertrophy of the endometrium and endometrial glands in the uterus; degeneration of seminiferous epithelium; and atrophy of the testes and the accessory sex glands. In the reproduction portion of this study, rats fed 10 or 50 ppm 17 beta-estradiol did not produce litters. While there was no evidence that the 50 ppm treated rats mated, 33.3% of the rats fed 10 ppm mated but did not produce litters. No effects on mating and fertility indices were observed in rats fed 0.05 and 2.5 ppm 17 beta-estradiol. Pup weights at birth were statistically decreased relative to control in the groups fed 0.05 and 2.5 ppm 17 beta-estradiol. Weights of the rats in the 0.05 ppm group recovered by postnatal day 4 and remained similar to control throughout the remainder of the study. The mean gestation length of the 0.05 ppm group was slightly, albeit not statistically significantly, shorter (0.5 days) than that of the control group, which may have contributed to the decrease in birth weight of the 0.05 ppm group. In contrast, the weights of the F1 generation rats fed 2.5 ppm 17 beta-estradiol remained decreased relative to the control group throughout the study. Parental administration of 17 beta-estradiol did not alter anogenital distance in male or female pups. The onset of sexual maturation, as measured by day of preputial separation in males and day of vaginal opening in females, was delayed in male rats fed 2.5 ppm (by 8.2 days) and was hastened in female rats fed 0.05 and 2.5 ppm (by 1.6 and 8.8 days, respectively). The age at vaginal opening ranged from 26 to 37, 26 to 35, and 21 to 25 days for rats fed 0, 0.05, and 2.5 ppm 17 beta-estradiol, respectively. Hence, the range of age at vaginal opening was similar between the control and 0.05 ppm group. The organ weight and pathologic alterations observed in the adult F1 generation rats were similar to those observed in the P1 generation rats. (ABSTRACT TRUNCATED)

Animals↗