JAK3/STAT5b/PPARγ Pathway Mediates the Association between Di(2-ethylhexyl) Phthalate Exposure and Lipid Metabolic Disorder in Chinese Adolescent Students.

Our previous studies found that di (2-ethylhexyl) phthalate (DEHP) could disorder lipid metabolism in adolescents but the mechanisms underlying this association remained unclear. This study was undertaken to clarify the mediating effect of JAK3/STAT5/PPARγ on disorder lipid levels induced by DEHP in adolescents. We recruited 478 adolescent students (median age 18.1 years). The mRNA expression and DNA methylation levels of JAK3/STAT5/PPARγ were detected by real-time PCR and the MethylTarget, respectively. We used multiple linear regression to analyze the association between DEHP metabolites (MEHP, MEOHP, MEHHP, MECPP, MCMHP, and ΣDEHP) levels, mRNA expression, and DNA methylation levels. The mediating effect of JAK3/STAT5/PPARγ mRNA expression levels was examined by mediation analysis. We found that all DEHP metabolite levels were positively correlated with TC/HDL-C and LDL-C/HDL-C (P < 0.05). The MEOHP level was negatively associated with DNA methylation levels and positively associated with mRNA levels of PPARγ and STAT5b (P < 0.05). The MEHP level was negatively associated with the DNA methylation level and positively associated with the mRNA level of JAK3 (P < 0.05). Higher MEOHP was associated with a higher level of TC/HDL-C, the mediation analysis showed the mediation effect was 17.18% for the JAK3 level, 10.76% for the STAT5b level, and 11% for the PPARγ level. Higher MEHP was associated with a higher level of LDL-C/HDL-C, the mediation effect was 14.49% for the JAK3 level. In conclusion, DEHP metabolites decreased the DNA methylation levels, inducing the increase of the mRNA levels of JAK3/STAT5/PPARγ. In addition, the mRNA levels mediated the association between DEHP exposure and disorder lipid levels.

PM2.5 promoted lipid accumulation in macrophage via inhibiting JAK2/STAT3 signaling pathways and aggravating the inflammatory reaction.

BACKGROUND: Abnormal lipid accumulation in macrophages may lead to macrophages foaming, which is the most important pathological process of atherosclerosis. Atmospheric PM2.5 could enter the blood circulation and further affect the lipid metabolism of macrophages. But the underlying mechanism is not unclear. This study was undertaken to clarify the effect of PM2.5 on lipid metabolism in macrophages, and to explore the role of inflammatory reaction and JAK2/STAT3 signaling pathway in this process. METHOD: Macrophages derived from THP-1 cells were exposed to PM2.5 (0,100,200,400 µg/mL) for 6 h and 12 h. STAT3 agonist ColivelinTFA is used to specifically excite STAT3. The survival rate of macrophages was detected by CCK-8. The lipid levels in macrophages were detected by colorimetry. The levels of inflammatory factors secreted by macrophages were detected by ELISA. Q-PCR was used to detect the mRNA expression levels, and Western Blot was used to detect the protein expression levels of JAK2/STAT3 pathway genes. RESULT: The survival rate of macrophages was reduced by PM2.5, and the levels of TG, T-CHO and LDL-C of macrophages exposed to PM2.5 were increased. PM2.5 led to the increasing level of IL-6 and the decreasing level of IL-4, and the JAK2/STAT3 signaling pathway was inhibited by PM2.5. Colivelin TFA significantly decreased the increasing levels of TG, T-CHO and LDL-C levels, and increased the decreasing mRNA levels of IL-4, and LPL induced by PM2.5 (p < 0.05). DISCUSSION: PM2.5 could cause the lipid accumulation of macrophages by inhibiting the JAK2/STAT3 signaling pathway, and inflammatory responses may be involved in this process.

Role of Notch pathway in effect of mono-2-ethylhexyl phthalate on the proliferation and cell cycle of SH-SY5Y cell.

Neuroblastoma (NB) is an estrogen-dependent tumor. Mono-2-ethylhexyl phthalate (MEHP) has an estrogen-like effect. However, the effects of MEHP on the progression of NB are not well illustrated. This study was to clarify the effect of Notch pathway on proliferation and cell cycle of SH-SY5Y cell induced by MEHP. The viability of SH-SY5Y and BE2C cells were detected by CCK8; cell cycle and apoptosis were detected by flow cytometry; the protein expression levels of Notch pathway and cell cycle related proteins were detected by Western-blot. Results show that MEHP exposure can promote cell proliferation and altered the cell cycle. MEHP exposure can up-regulate the expression of C-MYC, Cyclin D1, Bcl-2 and affected the Notch pathway. In conclusion, MEHP exposure can promote NB cell proliferation and affect the cell cycle and apoptosis. Notch pathway plays a critical role in accelerating the cell cycle and inhibiting the apoptosis of SH-SY5Y cells caused by MEHP.