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.

Long-term fine particular exposure and incidence of frailty in older adults: findings from the Chinese Longitudinal Healthy Longevity Survey.

BACKGROUND: The association between fine particular matter (PM2.5) and frailty is less studied, and the national burden of PM2.5-related frailty in China is unknown. OBJECTIVE: To explore the association between PM2.5 exposure and incident frailty in older adults, and estimate the corresponding disease burden. DESIGN: Chinese Longitudinal Healthy Longevity Survey from 1998 to 2014. SETTING: Twenty-three provinces in China. SUBJECTS: A total of 25,047 participants aged ≥65-year-old. METHODS: Cox proportional hazards models were performed to evaluate the association between PM2.5 and frailty in older adults. A method adapted from the Global Burden of Disease Study was used to calculate the PM2.5-related frailty disease burden. RESULTS: A total of 5,733 incidents of frailty were observed during 107,814.8 person-years follow-up. A 10 µg/m3 increment of PM2.5 was associated with a 5.0% increase in the risk of frailty (Hazard Ratio = 1.05, 95% confidence interval = [1.03-1.07]). Monotonic, but non-linear exposure-response, relationships of PM2.5 with risk of frailty were observed, and slopes were steeper at concentrations >50 µg/m³. Considering the interaction between population ageing and mitigation of PM2.5, the PM2.5-related frailty cases were almost unchanged in 2010, 2020 and 2030, with estimations of 664,097, 730,858 and 665,169, respectively. CONCLUSIONS: This nation-wide prospective cohort study showed a positive association between long-term PM2.5 exposure and frailty incidence. The estimated disease burden indicated that implementing clean air actions may prevent frailty and substantially offset the burden of population ageing worldwide.

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.

Human biomonitoring of toxic and essential metals in younger elderly, octogenarians, nonagenarians and centenarians: Analysis of the Healthy Ageing and Biomarkers Cohort Study (HABCS) in China.

BACKGROUND: Metals can be either toxic or essential to health, as they play different role in oxidative stress and metabolic homeostasis during the ageing process. Population-based biomonitoring have documented levels and ranges in concentrations among general population of 0-79 years of age. In people aged 80 and above, toxic metals and essential metals may have different risk profiles, and thus need to be better studied. OBJECTIVE: Our aim is to investigate concentrations of toxic metals (arsenic, cadmium, lead and mercury) and essential metals (chromium, cobalt, molybdenum, manganese, nickel and selenium) and their role in diseases, nutritional status among younger elderly, octogenarians, nonagenarians and centenarians. METHODS: A total of 932 younger elderly, 643 octogenarians, 540 nonagenarians, 386 centenarians were included from the cross-sectional Healthy Aging and Biomarkers Cohort Study in 2017-2018. Blood or urine biological substrates were collected from each participant to determine the concentrations of toxic metals and essential metals by inductively coupled plasma mass spectrometry. Random forest was constructed to rank the importance of toxic metals and essential metals in longevity. LASSO penalized regressions were performed to select the most significant metals associated with diseases and nutritional status, of which simultaneously included all metals and adjusted for the confounding factors. RESULTS: Compared to women, we found higher biomarker concentrations in men for toxic metals (41.2 µg/L vs 34.4 µg/L for blood lead, 1.56 µg/L vs 1.19 µg/L for blood mercury) and lower concentration of essential metals (0.48 µg/L vs 0.58 µg/L for blood molybdenum, 10.0 µg/L vs 11.1 µg/L for blood manganese). These factors may contribute to gender difference observed in longevity, that women live longer than men. Blood lead and urine cadmium tended to increase with age (P <0.001); blood cobalt, molybdenum, manganese increased with age, blood selenium decreased with age while the prevalence of selenium deficiency was extremely low in centenarians. Among toxic metals and essential metals, LASSO penalized regression identified the most significant metals associated with chronic kidney disease was cadmium and arsenic; and it was manganese, cobalt, and selenium for diabetes; it was selenium, molybdenum, lead for anemia; it was mercury for underweight. In random forest model, the top four important metals in longevity were selenium, arsenic, lead and manganese both in men and women. CONCLUSIONS: Generally, toxic metals levels were significantly higher while essential metals were relatively sufficient in Chinese centenarians. Toxic metals and essential metals played different role in diseases, nutritional status and longevity in the process of aging. Our research provided real world evidence of biomonitoring reference values to be used for the ongoing population health surveillance in longevity.