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New mechanistic insights on the metabolic-disruptor role of chlorpyrifos in apoE mice: a focus on insulin- and leptin-signalling pathways

Artikel i vetenskaplig tidskrift
Författare Fiona Peris-Sampedro
J. Blanco
M. Cabre
P. Basaure
L. Guardia-Escote
J. L. Domingo
D. J. Sanchez
M. T. Colomina
Publicerad i Archives of Toxicology
Volym 92
Nummer/häfte 5
Sidor 1717-1728
ISSN 0340-5761
Publiceringsår 2018
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi
Sidor 1717-1728
Språk en
Länkar dx.doi.org/10.1007/s00204-018-2174-...
Ämnesord Apolipoprotein E, Insulin, Leptin, Paraoxonase, Chlorpyrifos, Pesticide, Diabetes, persistent organic pollutants, decabromodiphenyl ether bde-209, oxidative stress, transgenic mice, developmental exposure, diabetic-nephropathy, targeted replacement, agricultural health, pesticide-residues, lipid-peroxidation, Toxicology
Ämneskategorier Endokrinologi och diabetes

Sammanfattning

Recently, we have provided evidence, suggesting that mice expressing the human apolipoprotein E3 (apoE3) are more prone to develop an obesity-like phenotype and a diabetic profile when subchronically fed a chlorpyrifos (CPF)-supplemented diet. The aim of the current study was to examine the underlying mechanisms through which CPF alters both insulin- and leptin-signalling pathways in an APOE-dependent manner. Both adult apoE3- and E4-targeted replacement and C57BL/6 mice were exposed to CPF at 0 or 2 mg/kg body weight/day through the diet for 8 consecutive weeks. We determined the expression of JAK2, p-JAK2, STAT3, p-STAT3, SOCS3, IRS-1, p-IRS-1, AKT, p-AKT, GSK3 beta, p-GSK3 beta, and apoE in the liver, as well as hepatic mRNA levels of pon1, pon2, and pon3. CPF markedly disrupted both leptin and insulin homeostasis, particularly in apoE3 mice. Indeed, only CPF-fed apoE3 mice exhibited an increased phosphorylation ratio of STAT3, as well as increased total SOCS3 protein levels. Similarly, the exposure to CPF drastically reduced the phosphorylation ratio of both AKT and GSK3 beta, especially in apoE3 mice. Overall, CPF reduced the expression of the three pon genes, principally in C57BL/6 and apoE3 mice. These results provide notable mechanistic insights on the metabolic effects of the pesticide CPF, and attest the increased vulnerability of apoE3 carriers to its metabolic-disruptor role.

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