30 research outputs found
Estrogen-Like Effects of Cadmium in Vivo Do Not Appear to be Mediated via the Classical Estrogen Receptor Transcriptional Pathway
Cadmium is a toxic metal classified as human carcinogen and ubiquitously found in our
environment mainly from anthropogenic activities. Exposure to cadmium has been
associated with increased risk of certain hormone-dependent cancers in humans, and the
metal has been proposed to possess endocrine disruptive properties by mimicking the
physiological actions of estrogens. However, the mechanisms behind these effects are
unclear.
The overall aim of this thesis was to provide mechanistic insights into the
estrogenicity of cadmium that may have implications for the human health. To achieve
this aim, investigations on the estrogen-like effects of cadmium as well as possible
involvement of classical/non-classical estrogen receptor signaling was studied in mice,
and these mechanisms were further scrutinized in cell-based models. Furthermore,
associations of biomarker of cadmium exposure with endogenous circulating sex
hormones were evaluated in a population-based study of women.
Results presented here indicate that exposure to cadmium does not affect the genomic
estrogen response in vivo in mice, suggesting that classical estrogen signaling is not
targeted by cadmium. However, some estrogen-like effects were observed in cadmium
exposed mice, i.e. significant thickening of uterine epithelia, in the absence of uterine
weight increase, and activation of ERK1/2 MAPKs in the liver. This suggests the
existence of alternative signaling pathways modulated by cadmium. In addition,
exposure to a wide dose range of cadmium, dose-dependently increased the expression
of the endogenous genes Mt1, Mt2, p53, c-fos, and Mdm2 in mouse liver, with p53 being
the most sensitive gene. However, phosphorylation of ERK1/2 was already induced at
the lowest exposure level (0.5”g/kg body weight), rendering ERK1/2 a more sensitive
marker of exposure than any change in gene expression. Furthermore, in vivo findings
suggest that cadmium-induced effects are markedly concentration dependent: low-level
exposure activates protein-kinases whereas high-level exposure turns on cellular stress
responses. The data from in vitro studies indicate that cadmium at regular human
exposure levels activates protein-kinase signaling through Raf-MEK-ERK/MAPKs, and
we identified EGFR and GPR30 as the mediating receptors. This cadmium-induced
activation of protein-kinases further leads to a disturbance in Mdm2/p53 balance, with a
significant increase in the Mdm2/p53 ratio in the presence of genotoxic compounds,
which in turn suggest that cadmium may disrupt stress response to genotoxins. In 438
postmenopausal women, a positive association was observed between the concentrations
of cadmium in blood and testosterone in serum, while an inverse association was
observed with estradiol. This may suggest that cadmium affects steroidogenesis.
In conclusion, data presented in this thesis collectively suggests that cadmium-induced
estrogen-like effects do not involve classical estrogen receptor signaling but rather
appear to be mediated via membrane-associated signaling. The activation/
transactivation of GPR30/EGFR-Raf-MEK-ERK/MAPKs and Mdm2 represent a general
mechanism by which cadmium may exert its effects. Since EGFR, ERK and Mdm2 are
all known key players in cancer promotion, cadmium-induced activation of these and
disturbance in the estradiol/testosterone balance in women may have implications for the
promotion/development of hormone-related cancers
Endocrine, metabolic and apical effects of in utero and lactational exposure to non-dioxin-like 2,2 ',3,4,4 ',5,5 '-heptachlorobiphenyl (PCB 180): A postnatal follow-up study in rats
PCB 180 is a persistent and abundant non-dioxin-like PCB (NDL-PCB). We determined the developmental toxicity profile of ultrapure PCB 180 in developing offspring following in utero and lactational exposure with the focus on endocrine, metabolic and retinoid system alterations. Pregnant rats were given total doses of 0, 10, 30, 100, 300 or 1000 mg PCB 180/kg bw on gestational days 7-10 by oral gavage, and the offspring were sampled on postnatal days (PND) 7, 35 and 84. Decreased serum testosterone and triiodothyronine concentrations on PND 84, altered liver retinoid levels, increased liver weights and induced 7-pentoxyresorufin O-dealkylase (PROD) activity were the sensitive effects used for margin of exposure (MoE) calculations. Liver weights were increased together with induction of the metabolizing enzymes cytochrome P450 (CYP) 2B1, CYP3A1, and CYP1A1. Less sensitive effects included decreased serum estradiol and increased luteinizing hormone levels in females, decreased prostate and seminal vesicle weight and increased pituitary weight in males, increased cortical bone area and thickness of tibial diaphysis in females and decreased cortical bone mineral density in males. Developmental toxicity profiles were partly different in male and female offspring, males being more sensitive to increased liver weight, PROD induction and decreased thyroxine concentrations. MoE assessment indicated that the 95th percentile of current maternal PCB 180 concentrations do not exceed the estimated tolerable human lipid-based PCB 180 concentration. Although PCB 180 is much less potent than dioxin-like compounds, it shares several toxicological targets suggesting a potential for interactions
Toxicological Profile of Ultrapure 2,2 ',3,4,4 ',5,5 '-Heptachlorbiphenyl (PCB 180) in Adult Rats
Peer reviewe
Sex-dependent gene expression in early brain development of chicken embryos
Abstract Background Differentiation of the brain during development leads to sexually dimorphic adult reproductive behavior and other neural sex dimorphisms. Genetic mechanisms independent of steroid hormones produced by the gonads have recently been suggested to partly explain these dimorphisms. Results Using cDNA microarrays and real-time PCR we found gene expression differences between the male and female embryonic brain (or whole head) that may be independent of morphological differentiation of the gonads. Genes located on the sex chromosomes (ZZ in males and ZW in females) were common among the differentially expressed genes, several of which (WPKCI-8, HINT, MHM non-coding RNA) have previously been implicated in avian sex determination. A majority of the identified genes were more highly expressed in males. Three of these genes (CDK7, CCNH and BTF2-P44) encode subunits of the transcription factor IIH complex, indicating a role for this complex in neuronal differentiation. Conclusion In conclusion, this study provides novel insights into sexually dimorphic gene expression in the embryonic chicken brain and its possible involvement in sex differentiation of the nervous system in birds.</p
Associations between cadmium exposure and circulating levels of sex hormones in postmenopausal women.
Recent epidemiological as well as in vivo and in vitro studies collectively suggest that the metalloestrogen cadmium (Cd) could be a potential risk factor for hormone-related cancers in particularly breast cancer. Assessment of the association between Cd exposure and levels of endogenous sex hormones is of pivotal importance, as increased levels of such have been associated with a higher risk of breast cancer in postmenopausal women. The present study investigated the perceived relationship (multivariable-adjusted linear regression analyses) between Cd exposure [blood Cd (B-Cd) and urinary Cd (U-Cd)], and serum levels of androstenedione, testosterone, estradiol, and sex-hormone binding globulin (SHBG), in 438 postmenopausal Swedish women without hormone replacement therapy (HRT). A significant positive association between B-Cd (median 3.4nmol/L) and serum testosterone levels, as well as a significant inverse association between B-Cd and serum estradiol levels and with the estradiol/testosterone ratio were encountered. However, U-Cd (median 0.69nmol/mmol creatinine) was inversely associated with serum estradiol levels only. Our data may suggest that Cd interferes with the levels of testosterone and estradiol in postmenopausal women, which might have implications for breast cancer risk
Biological and chemical determination of dioxin-like compounds in sediments by means of a sediment triad approach in the catchment area of the river Neckar
To evaluate the sediment quality of selected sites in the catchment area of the River Neckar, an integrative assessment approach was used to assess the ecological hazard potential of dioxin-like sediment compounds. The approach is based on 7-ethoxyresorufin-O-deethylase (EROD) induction in embryonic chicken liver culture and comprehensive chemical analyses of polycyclic aromatic hydrocarbons (priority PAHs according to the US Environmental Protection Agency). The majority of the sediment extracts exhibited high potencies as EROD-inducers. In one sediment sample, which was influenced by a sewage treatment plant, a very high concentration of 930 ng bioassay 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalents (bio-TEQs )/g organic carbon could be determined. However, in none of the samples, more than 6% of the EROD-inducing potency could be explained by the PAHs analyzed chemically. Thus, non-analyzed compounds with EROD-inducing potency were present in the extracts. A fractionation of sediment samples according to pH allowed to localize the major part of EROD-inducing compounds in the neutral fractions. However, a significant portion of the EROD induction could also be explained by the acidic fractions. Following the concept of the Sediment Quality Triad according to Chapman, in situ alterations of macrozoobenthos were examined. A comparison of the results predicted by the EROD assay and chemical analyses with alterations in situ, as measured by means of the saprobic index and the ecotoxicological index according to Carmargo, revealed a high ecological relevance of the results of bioassays and chemical analyses for major site