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Author Silva, Elisabete ♦ Kabil, Alena ♦ Kortenkamp, Andreas
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ CELL PROLIFERATION ♦ ESTRADIOL ♦ GENES ♦ GROWTH FACTORS ♦ RECEPTORS ♦ ESTRANES ♦ ESTROGENS ♦ HORMONES ♦ HYDROXY COMPOUNDS ♦ MEMBRANE PROTEINS ♦ MITOGENS ♦ ORGANIC COMPOUNDS ♦ PROTEINS ♦ STEROID HORMONES ♦ STEROIDS
Abstract Estrogen receptor (ER) transcriptional cross-talk after activation by 17{beta}-estradiol (E2) has been studied in considerable detail, but comparatively little is known about the ways in which synthetic estrogen-like chemicals, so-called xenoestrogens, interfere with these signalling pathways. E2 can stimulate rapid, non-genomic signalling events, such as activation of the Src/Ras/Erk signalling pathway. We investigated how activation of this pathway by E2, the estrogenic environmental contaminants o,p'-DDT, {beta}-HCH and p,p'-DDE, and epidermal growth factor (EGF) influences the expression of ER target genes, such as TFF1, ER, PR, BRCA1 and CCND1, and the proliferation of breast cancer cells. Despite commonalities in their estrogenicity as judged by cell proliferation assays, the environmental contaminants exhibited striking differences in their non-genomic and genomic signalling. The gene expression profiles of o,p'-DDT and {beta}-HCH resembled the effects observed with E2. In the case of {beta}-HCH this is surprising, considering its reported lack of affinity to the 'classical' ER. The expression profiles seen with p,p'-DDE showed some similarities with E2, but overall, p,p'-DDE was a fairly weak transcriptional inducer of TFF1, ER, PR, BRCA1 and CCND1. We observed distinct differences in the non-genomic signalling of the tested compounds. p,p'-DDE was unable to stimulate Src and Erk1/Erk2 activations. The effects of E2 on Src and Erk1/Erk2 phosphorylation were transient and weak when compared to EGF, but {beta}-HCH induced strong and sustained activation of all tested kinases. Transcription of TFF1, ER, PR and BRCA1 by E2, o,p'-DDT and {beta}-HCH could be suppressed partially by inhibiting the Src/Ras/Erk pathway with PD 98059. However, this was not seen with p,p'-DDE. Our investigations show that the cellular activities of estrogens and xenoestrogens are the result of a combination of extranuclear (non-genomic) and nuclear (genomic) events and highlight the need to take non-genomic effects and signalling cross-talk into consideration, when screening for environmental estrogens. Otherwise, chemicals devoid of ER affinity, such as {beta}-HCH, but with an effect profile otherwise similar to estrogens might be overlooked in safety testing.
ISSN 0041008X
Educational Use Research
Learning Resource Type Article
Publisher Date 2010-06-01
Publisher Place United States
Journal Toxicology and Applied Pharmacology
Volume Number 245
Issue Number 2


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