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.
Toxicol Sci. 2011 Apr;120(2):413-27. doi: 10.1093/toxsci/kfr019. Epub 2011 Jan 27.
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.
有机氯化学品硫丹、狄氏剂和γ-六氯环己烷（林丹）是人们主要通过饮食接触到的持久性农药。它们拮抗γ-氨基丁酸-A（GABA(A)）受体，使它们具有惊厥作用。由于它们与雌激素受体（ER）相互作用，它们也是内分泌干扰物。在这里，我们研究了狄氏剂、硫丹和林丹对皮质神经元（CN）和小脑颗粒细胞（CGC）原代培养物中 ER 的影响。所有测试的化合物都抑制了 [(3)H]-雌二醇与 CN 和 CGC 中 ER 的结合，其中 CGC 中的狄氏剂表现出最高的亲和力。我们还确定了这些农药对蛋白激酶 B（Akt）和细胞外调节激酶 1 和 2（ERK1/2）磷酸化的影响。狄氏剂和硫丹增加了 CN 中 Akt 的磷酸化，而 ERβ拮抗剂 4-[2-苯基-5,7-双（三氟甲基）吡唑并[1,5-a]嘧啶-3-基]苯酚则抑制了这种磷酸化。相反，狄氏剂在 CGC 中诱导的 Akt 和 ERK1/2 磷酸化是通过 ERα、ERβ和 G 蛋白偶联受体 30 的多种激活介导的。林丹没有激活这些途径，但它抑制了雌二醇介导的 Akt 和 ERK1/2 激活。在 CN 中，所有化学物质通过涉及 GABA(A)和谷氨酸受体的机制激活 ERK1/2。长期接触这些农药会降低 ERα的水平，但不会降低 ERβ的水平。此外，用硫丹、狄氏剂或林丹处理的 CN 提取物可诱导 MCF-7 人乳腺癌衍生细胞的增殖，而只有用狄氏剂处理的 CGC 提取物可诱导 MCF-7 细胞的增殖。总的来说，观察到的神经元中 ER 介导的信号转导和 ER 水平的改变可能导致这些有机氯农药的神经毒性。
