Journal Article

Differential Estrogenic Effects of the Persistent Organochlorine Pesticides Dieldrin, Endosulfan, and Lindane in Primary Neuronal Cultures

Víctor Briz, José-Manuel Molina-Molina, Sara Sánchez-Redondo, Mariana F. Fernández, Joan O. Grimalt, Nicolás Olea, Eduard Rodríguez-Farré and Cristina Suñol

in Toxicological Sciences

Volume 120, issue 2, pages 413-427
Published in print April 2011 | ISSN: 1096-6080
Published online January 2011 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfr019
Differential Estrogenic Effects of the Persistent Organochlorine Pesticides Dieldrin, Endosulfan, and Lindane in Primary Neuronal Cultures

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The organochlorine chemicals endosulfan, dieldrin, and γ-hexachlorocyclohexane (lindane) are persistent pesticides to which people are exposed mainly via diet. Their antagonism of the γ-aminobutyric acid-A (GABAA) receptor makes them convulsants. They are also endocrine disruptors because of their interaction with the estrogen receptor (ER). Here, we study the effects of dieldrin, endosulfan, and lindane on ERs in primary cultures of cortical neurons (CN) and cerebellar granule cells (CGC). All the compounds tested inhibited the binding of [3H]-estradiol to the ER in both CN and CGC, with dieldrin in CGC showing the highest affinity. We also determined the effects of the pesticides on protein kinase B (Akt) and extracellular-regulated kinase 1 and 2 (ERK1/2) phosphorylation. Dieldrin and endosulfan increased Akt phosphorylation in CN, which was inhibited by the ERβ antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol. Instead, Akt and ERK1/2 phosphorylation induced by dieldrin in CGC was mediated by multiple activation of ERα, ERβ, and G protein–coupled receptor 30. Lindane did not activate these pathways, but it inhibited estradiol-mediated Akt and ERK1/2 activation. In CN, all the chemicals activated ERK1/2 through a mechanism involving GABAA and glutamate receptors. Long-term exposure to these pesticides reduced the levels of ERα, but not of ERβ. Moreover, extracts of CN treated with endosulfan, dieldrin, or lindane induced cell proliferation in MCF-7 human breast cancer–derived cells, whereas only extracts of CGC treated with dieldrin induced MCF-7 cell proliferation. Overall, the observed alterations on ER-mediated signaling and ER levels in neurons might contribute to the neurotoxicity of these organochlorine pesticides.

Keywords: pesticides; estrogen receptor; protein kinase B (Akt); extracellular-regulated kinase; GABAA receptor; neuronal cultures

Journal Article.  8619 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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