title: Differential estrogenic effects of the persistent organochlorine pesticides dieldrin, endosulfan, and lindane in primary neuronal cultures.
abstract: 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 (GABA(A)) 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 [(3)H]-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 GABA(A) 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.
authors.affiliation: Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas, Institut d'investigacions Biomèdiques August Pi i Sunyer, E-08036 Barcelona, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Briz
authors.forename: José-Manuel
authors.initials: JM
authors.lastname: Molina-Molina
authors.forename: Sara
authors.initials: S
authors.lastname: Sánchez-Redondo
authors.forename: Mariana F
authors.initials: MF
authors.lastname: Fernández
authors.forename: Joan O
authors.initials: JO
authors.lastname: Grimalt
authors.forename: Nicolás
authors.initials: N
authors.lastname: Olea
authors.forename: Eduard
authors.initials: E
authors.lastname: Rodríguez-Farré
authors.forename: Cristina
authors.initials: C
authors.lastname: Suñol
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D004026:Dieldrin / Q000737:chemistry / Q000633:toxicity; D052244:Endocrine Disruptors / Q000737:chemistry / Q000633:toxicity*; D004726:Endosulfan / Q000737:chemistry / Q000633:toxicity; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D001556:Hexachlorocyclohexane / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000737:chemistry / Q000633:toxicity*; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010575:Pesticides / Q000737:chemistry / Q000633:toxicity*; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism
chemical_list: D052244:Endocrine Disruptors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D006843:Hydrocarbons, Chlorinated; D010575:Pesticides; D011963:Receptors, GABA-A; D001556:Hexachlorocyclohexane; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D004026:Dieldrin; D004726:Endosulfan