The insecticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane (DDT) alters the membrane raft location of the TSH receptor stably expressed in Chinese hamster ovary cells

• Published in: Toxicology and applied pharmacology Vol. 253; no. 2; pp. 121 - 129
• Main Authors: De Gregorio, Francesca, Pellegrino, Mario, Picchietti, Simona, Belardinelli, Maria C., Taddei, Anna Rita, Fausto, Anna Maria, Rossi, Mario, Maggio, Roberto, Giorgi, Franco
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.06.2011; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; ALKANES; ANIMAL CELLS; Animals; AROMATICS; Biological and medical sciences; BODY; CELL CONSTITUENTS; CELL MEMBRANES; CHO CELLS; CHOLESTEROL; CONTROL; Cricetinae; Cricetulus; DDT; DDT - toxicity; ENDOCRINE GLANDS; ENVIRONMENTAL IMPACTS; ETHANE; GLANDS; HOMEOSTASIS; HORMONES; HYDROCARBONS; HYDROXY COMPOUNDS; INHIBITION; INSECTICIDES; Insecticides - toxicity; LIPIDS; Medical sciences; Membrane Microdomains - drug effects; MEMBRANE PROTEINS; Membrane rafts; MEMBRANES; ORGANIC CHLORINE COMPOUNDS; ORGANIC COMPOUNDS; ORGANIC HALOGEN COMPOUNDS; ORGANS; PEPTIDE HORMONES; PESTICIDES; Pesticides, fertilizers and other agrochemicals toxicology; PITUITARY HORMONES; PROTEINS; RECEPTORS; Receptors, Thyrotropin - drug effects; Receptors, Thyrotropin - genetics; Receptors, Thyrotropin - metabolism; SOMATIC CELLS; STEROIDS; STEROLS; THYROID; Thyroid disruptors; Toxicology; TSH; TSH receptor; DDT; Membrane rafts; TSH receptor; Thyroid disruptors; Lipid raft; Endocrine gland; Insecticide; Toxicity; Pesticides; Thyroid gland; In vitro; Ethane; CHO cell line; Organochlorine compounds
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2011.03.018

DDT is a highly lipophilic molecule known to deplete membrane rafts of their phosphoglycolipid and cholesterol contents. However, we have recently shown that DDT can also alter the thyroid homeostasis by inhibiting TSH receptor (TSHr) internalization. The present study was undertaken to verify whether DDT goitrogenic effects are due to the insecticide acting directly on TSHr or via alteration of the membrane rafts hosting the receptor itself. Our results demonstrate that, in CHO-TSHr transfected cells, TSHr is activated in the presence of TSH, while it is inhibited following DDT exposure. DDT can also reduce the endocytic vesicular traffic, alter the extension of multi-branched microvilli along their plasma membranes and induce TSHr shedding in vesicular forms. To verify whether TSHr displacement might depend on DDT altering the raft constitution of CHO-TSHr cell membranes the extent of TSHr and lipid raft co-localization was examined by confocal microscopy. Evidence shows that receptor/raft co-localization increased significantly upon exposure to TSH, while receptors and lipid rafts become dislodged on opposite cell poles in DDT-exposed CHO-TSHr cells. As a control, under similar culturing conditions, diphenylethylene, which is known to be a lipophilic substance that is structurally related to DDT, did not affect the extent of TSHr and lipid raft co-localization in CHO-TSHr cells treated with TSH. These findings corroborate and extend our view that, in CHO cells, the DDT disrupting action on TSHr is primarily due to the insecticide acting on membranes to deplete their raft cholesterol content, and that the resulting inhibition on TSHr internalization is due to receptor dislodgement from altered raft microdomains of the plasma membrane. ►DDT is a pesticide with a severe environmental impact ►Epidemiologic correlation exists between exposition to DDT and thyroid dysfunction ►DDT is a lipophilic molecule that has been shown to inhibit TSH receptor function ►DDT depletes membrane raft cholesterol content and by this way inhibits TSH receptor