Arsenite and cadmium promote the development of mammary tumors.

Previous studies demonstrate that the heavy metal cadmium and the metalloid arsenite activate estrogen receptor-alpha in breast cancer cells by forming a high-affinity complex with the ligand-binding domain of the receptor and that environmentally relevant doses of cadmium have estrogen-like activity in vivo. The present study showed that in estrogen-receptor positive cells, arsenite and cadmium increased the global expression of estrogen-responsive genes and that an environmentally relevant dose of arsenite also had estrogen-like activity in vivo. Similar to estrogens, exposure of ovariectomized animals to arsenite induced the expression of the progesterone receptor, GREB1, and c-fos in the mammary gland and the expression of complement C3, c-fos, and cyclin D1 in the uterus and the increase was blocked by the antiestrogen ICI-182,780. When virgin female animals were fed a diet, that mimics exposure to either arsenite or cadmium, and challenged with the chemical carcinogen dimethylbenzanthracene, there was an increase in the incidence of mammary tumors and a decrease in the time to tumor onset, but no difference in the total number of tumors, tumor multiplicity, or total tumor volume. Together with published results, these data showed that environmentally relevant amounts of arsenite and cadmium had estrogen-like activity in vivo and promoted mammary tumorigenesis.

Alteration of Mammary Gland Development and Gene Expression by In Utero Exposure to Cadmium.

Environmental exposure to estrogens and estrogen like contaminants during early development is thought to contribute to the risk of developing breast cancer primarily due to an early onset of puberty; however, exposure during key developing windows may also influence the risk of developing the disease. The goal of this study was to ask whether in utero exposure to the metalloestrogen cadmium alters mammary gland development due to acceleration of puberty onset or to an effect on early development of the mammary gland. The results show that, in addition to advancing the onset of puberty, in utero exposure to the metalloestrogen cadmium altered mammary gland development prior to its effect on puberty onset. In utero exposure resulted in an expansion of the number of mammosphere-forming cells in the neonatal mammary gland and an increase in branching, epithelial cells, and density in the prepubertal mammary gland. In the postpubertal mammary gland, there was a further expansion of the mammary stem/progenitor cell population and overexpression of estrogen receptor-alpha (ERα) that was due to the overexpression and altered regulation of the ERα transcripts derived from exons O and OT in response to estradiol. These results suggest that in utero exposure to cadmium increases stem/progenitor cells, cell density, and expression of estrogen receptor-alpha that may contribute to the risk of developing breast cancer.

Reproductive toxicity and meiotic dysfunction following exposure to the pesticides Maneb, Diazinon and Fenarimol.

The comprehensive identification and mechanistic analysis of reproductive toxicants constitutes one of the major hurdles in the toxicological assessment of chemicals originating from the large number of chemicals to be tested and the difficulty in examining germ cells at various stages of their development. We previously described the development of an assay in the roundworm Caenorhabditis elegans that allows the detection of chemicals bearing aneugenic activity and that could be used for the detection of germline toxicity. We present here new evidence for the reproductive toxicity of three pesticides identified in our germline toxicity assay: Maneb, Diazinon and Fenarimol. We show that all three pesticides cause an acute germline nuclear loss in exposed nematodes in a dose-dependent fashion. The loss of germline nuclei coincides with the meiotic stage of pachytene during Prophase I and is dependent on the germline apoptotic machinery suggesting activation of a meiotic checkpoint. Further investigation revealed a profound dysregulation of the meiotic program revealed by (1) an alteration of the kinetics of double strand repair, (2) the disruption of the process of chromosome morphogenesis at the end of Prophase I and (3) the reorganization of the meiotic differentiation gradient inherent to the C. elegans germline following exposure to Maneb and Diazinon. These defects correlate with a significant increase in embryonic lethality and a corresponding decrease in the number of progeny. These results therefore provide strong evidence for the reproductive toxicity of Maneb, Diazinon and Fenarimol rooted in the alteration of early steps of germ cell differentiation.

[Assessment of the impact over one year of a workplace health promotion programme in the province of Bergamo]. / Stima dell's effecto ad un anno di un programma di promozione della salute nei luoghi di lavoro in provincia di Bergamo.

OBJECTIVES: To estimate short-term effects of integrated health promotion in the workplace within the framework of the Bergamo WHP (Workplace Health Promotion) network, which involves 94 companies and about 21,000 workers. METHODS: A controlled non-randomized, before-after evaluation was carried out. Data were collected through anonymous questionnaires before (t0) and after participation in a 12-month health promotion programme (t1). The "control" group consisted of workers of companies participating in the programme who had not yet undertaken any interventions in the theme areas covered by the assessment. RESULTS: In the workers participating in the programme, positive early effects (after 12 months) were related to intake of food providing protection (fruit and vegetables) and increased rates of smoking cessation. The effects were more evident in males and in white collars. The physical activity and alcohol consumption trends went in the desired direction and with more effects than in the non-participating group, but without statistical significance. In the short term, no evident changes in events of road injury risk or in the quality of personal relationships were seen, probably due to the small size of the sample involved in these study areas. CONCLUSIONS: The results, although within the methodological limitations of the study, showed that after 12 months there was a reduction in some important risk factors for chronic diseases in workers participating in the programme, particularly for fruit and vegetable intake and smoking cessation. It will be important to monitor the effects of the programme on other risk factors in the medium and long term, and also the impact of employment status and gender so as to adjust the programme interventions accordingly. Cooperation with occupational/authorized physicians with use of their data collected from health surveillance, together with a limited set of general risk factor indicators, would be a desirable development for further studies.

Alteration of mammary gland development and gene expression by in utero exposure to arsenic.

Early life exposure to estrogens and estrogen like contaminants in the environment is thought to contribute to the early onset of puberty and consequently increases the risk of developing breast cancer in the exposed female. The results of this study show that in utero exposure to the metalloestrogen arsenite altered mammary gland development prior to its effect on puberty onset. In the prepubertal gland, in utero exposure resulted in an increase in the number of mammosphere-forming cells and an increase in branching, epithelial cells, and density. In the postpubertal gland, in utero exposure resulted in the overexpression of estrogen receptor-alpha (ERα) that was due to the increased and altered response of the ERα transcripts derived from exons O and OT to estradiol. These results suggest that, in addition to advancing puberty onset, in utero exposure to arsenite alters the pre- and postpubertal development of the mammary gland and possibly, the risk of developing breast cancer.

Metals and breast cancer.

Metalloestrogens are metals that activate the estrogen receptor in the absence of estradiol. The metalloestrogens fall into two subclasses: metal/metalloid anions and bivalent cationic metals. The metal/metalloid anions include compounds such as arsenite, nitrite, selenite, and vanadate while the bivalent cations include metals such as cadmium, calcium, cobalt, copper, nickel, chromium, lead, mercury, and tin. The best studied metalloestrogen is cadmium. It is a heavy metal and a prevalent environmental contaminant with no known physiological function. This review addresses our current understanding of the mechanism by which cadmium and the bivalent cationic metals activate estrogen receptor-α. The review also summarizes the in vitro and in vivo evidence that cadmium functions as an estrogen and the potential role of cadmium in breast cancer.

Cadmium--a metallohormone?

Cadmium is a heavy metal that is often referred to as the metal of the 20th century. It is widely used in industry principally in galvanizing and electroplating, in batteries, in electrical conductors, in the manufacture of alloys, pigments, and plastics, and in the stabilization of phosphate fertilizers. As a byproduct of smelters, cadmium is a prevalent environmental contaminant. In the general population, exposure to cadmium occurs primarily through dietary sources, cigarette smoking, and, to a lesser degree, drinking water. Although the metal has no known physiological function, there is evidence to suggest that the cadmium is a potent metallohormone. This review summarizes the increasing evidence that cadmium mimics the function of steroid hormones, addresses our current understanding of the mechanism by which cadmium functions as a hormone, and discusses its potential role in development of the hormone dependent cancers.

AZFc partial deletions in Chilean men with severe spermatogenic failure.

OBJECTIVE: To determine the prevalence of AZFc subdeletions in infertile Chilean men with severe spermatogenic impairment. DESIGN: Prospective analysis. SETTING: University infertility clinic. PATIENT(S): Ninety-five secretory azo/oligozoospermic men without AZFc Y chromosome microdeletions: 71 whose testicular histology showed severe spermatogenic impairment and 24 who exhibited reduced testicular volume and elevated serum FSH levels. As controls, we studied 77 men (50 fertile and/or normozoospermic, and 27 with azoospermia and normal spermatogenesis). INTERVENTION(S): Peripheral blood was drawn to obtain genomic DNA for polymerase chain reaction (PCR) digestion assays of DAZ-sequence nucleotide variants and for AZFc-STS PCR after a complete testicular characterization (biopsy, hormonal, and physical evaluation). MAIN OUTCOME MEASURE(S): DAZ genes and AZFc subdeletion types. RESULT(S): In cases we observed two "gr/gr" subdeletions (2.1%), one with absence of DAZ1/DAZ2 (g1/g2 subtype), and the other with absence of DAZ3/DAZ4 (r2/r4 subtype). Additionally, we found a g1/g3 subdeletion in a patient with Sertoli-cell-only syndrome. In controls, we observed two gr/gr subdeletions with absence of DAZ1/DAZ2 (2.6%) in a fertile/normozoospermic and in an obstructive azoospermic man. CONCLUSION(S): AZFc subdeletions do not seem to cause severe impairment of spermatogenesis. Moreover, gr/gr-DAZ1/DAZ2 subdeletions do not appear to affect fertility in Chilean men.

Absence of Fas protein detection by flow cytometry in human spermatozoa.

OBJECTIVE: To investigate the expression of Fas protein on the surface of ejaculated spermatozoa of normozoospermic and nonnormozoospermic men. DESIGN: Prospective study. SETTING: University infertility clinic. PATIENT(S): Twenty-three volunteer normozoospermic men (controls) and 43 men undergoing infertility evaluation (cases). INTERVENTION(S): Analysis of ejaculated spermatozoa by indirect immunofluorescence of Fas protein by flow cytometry. MAIN OUTCOME MEASURE(S): Comparison of flow cytometric analysis of autofluorescence, control tests (secondary antibody and isotype control), and experimental tests (anti-Fas monoclonal antibody) in the spermatozoa of ejaculated samples. RESULT(S): No expression of Fas protein was found on the surface of ejaculated spermatozoa of controls and cases. CONCLUSION(S): The Fas molecules are not present in substantial amounts in the ejaculated spermatozoa of normozoospermic and nonnormozoospermic men. Therefore, our results do not support the "abortive apoptosis" theory.