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.

Combined action of estrogen receptor agonists and antagonists in two-hybrid recombinant yeast in vitro

“…Here, the former two showed similar strong antiestrogenicity with an EC 50 of 4.71 Â 10 À 7 and 4.03 Â 10 À 7 mol/L, respectively, which is consistent with the report that they had similar treatment efficacies in breast cancer (Howell et al, 2004). HCH performed as a weak ER antagonist in the recombinant yeast (EC 50 ¼4.60 Â 10 À 5 mol/L), although both its estrogenic and antiestrogenic activities have been observed in other organisms (Briz et al, 2011;Chadwick et al, 1988;Huang et al, 2006;Raizada et al, 1980). Because the binding of an antiestrogen to ER cannot initiate the expression of the reporter gene lac-Z, the inhibition effect test had to be executed by simultaneously exposing the yeast cells to E2 and the tested antagonist.…”

Interactions of Endosulfan and Methoxychlor Involving CYP3A4 and CYP2B6 in Human HepaRG Cells

“…Endosulfan has been reported to affect a variety of organ systems and physiologic functions (Moon and Chun, 2009). Animal studies have shown its toxicity to the liver, kidney, blood, immune, reproductive, and nervous systems (Choudhary and Joshi, 2003;Singh et al, 2008;Briz et al, 2011). Methoxychlor induces follicular atresia, reduces ovulation rate, and decreases embryo implantation in rats and mice (Tiemann, 2008).…”

Assessment of organochlorine pesticides and plasticisers in the Selangor River basin and possible pollution sources

“…Organochlorine pesticides such as DDTs and its metabolites have a detrimental effect on the endocrine and reproductive systems in both wildlife and humans due to their ability to interact with hormone receptors especially estrogen receptor (Frigo et al, 2002;Guillette et al 1994;Jian Li et al 2008;Scippo et al 2004;Uchida et al 2010). HCB was found to stimulate estrogendependent cell proliferation in MCF-7 cells (Garcia et al 2010) while lindane and dieldrin is suggested to contribute to their neurotoxicity by altering the levels of estrogen receptor and its mediated signalling in neurons (Briz et al 2011).…”