Sex-dependent effects of ambient PM2.5 pollution on insulin sensitivity and hepatic lipid metabolism in mice

Abstract

Background & aims: Emerging evidence supports ambient fine particulate matter (PM 2.5 ) exposure is associated with insulin resistance (IR) and hepatic lipid accumulation. In this study, we aimed to evaluate the sex-dependent vulnerability in response to PM 2.5 exposure and investigate the underlying mechanism by which PM 2.5 modulates hepatic lipid metabolism.Methods: Both male and female C57BL/6 mice were randomly assigned to ambient PM 2.5 or filtered air for 24 weeks via a whole body exposure system. High-coverage quantitative lipidomics approaches and liquid chromatographymass spectrometry techniques were performed to measure hepatic metabolites and hormones in plasma. Metabolic studies, histological analyses, as well as gene expression levels and molecular signal transduction analysis were applied to examine the effects and mechanisms by which PM 2.5 exposure-induced metabolic disorder.Results: Female mice were more susceptible than their male counterparts to ambient PM 2.5 exposure-induced IR and hepatic lipid accumulation. The hepatic lipid profile was changed in response to ambient PM 2.5 exposure. Levels of hepatic triacylglycerols (TAGs), free fatty acids (FFAs) and cholesterol were only increased in female mice from PM group compared to control group. Plasmalogens were dysregulated in the liver from PM 2.5 -exposed mice as well. In addition, exposure to PM 2.5 led to enhanced hepatic ApoB and microsomal triglyceride transport protein expression in female mice. Finally, PM 2.5 exposure inhibited hypothalamus-pituitary-adrenal (HPA) axis and decreased glucocorticoids levels, which may contribute to the vulnerability in PM 2.5 -induced metabolic dysfunction.Conclusions: Ambient PM 2.5 exposure inhibited HPA axis and demonstrated sex-associated differences in its effects on IR and disorder of hepatic lipid metabolism. These findings provide new mechanistic evidence of hormone regulation in air pollution-mediated metabolic abnormalities of lipids and more personalized care should be considered in terms of sex-specific risk factors.

Metabolomic Changes after Subacute Exposure to Polycyclic Aromatic Hydrocarbons: A Natural Experiment among Healthy Travelers from Los Angeles to Beijing

“…45 Similar exposure time-dependent change directions were observed in cortisol as well. The increase of cortisol after a 9-day exposure reflected the activation of the hypothalamic−pituitary−adrenal (HPA) axis, 45 while its decrease was indictive of feedback controls after a 6-month exposure 46 or impaired production via AhR activation. 41 The contrasted possible regulatory mechanisms are summarized in Figure 4.…”

The Physiological Effects of Air Pollution: Particulate Matter, Physiology and Disease

“…Effective insulin signaling is required for glucose homeostasis, and insulin resistance is closely associated with obesity and is a risk factor for the onset of type-2 diabetes ( 95 ). PM exposure is associated with insulin resistance and non-alcoholic fatty liver disease, driven by oxidative stress and dyslipidaemia ( 96 , 97 ). Together these studies highlight the link between air pollution and metabolic diseases including diabetes.…”

“…PM exposure to mice was found to induce hepatic oxidative stress, inflammation, negatively affect glucose tolerance and induce insulin resistance ( 96 , 120 ). Interestingly PM exposure has been found to increase hepatic triacylglycerols, free fatty acids and cholesterol levels in female but not in male mice ( 96 ). In addition to insulin resistance, PM exposure has been shown to exert toxic effects directly on the pancreas ( 121 ).…”

Impact of Sex and Age on the Mevalonate Pathway in the Brain: A Focus on Effects Induced by Maternal Exposure to Exogenous Compounds

“…Unfortunately, most of the studies analyzed the effects of exogenous compounds without addressing sex-dependency and thus missing a critical factor in understanding the impact of these compounds on the MVA pathway. Just to give an example, a recent study demonstrates that female mice are more susceptible than their male counterparts to ambient PM2.5 exposure, with cholesterol levels increased only in exposed female mice compared to control group [ 84 ]. Furthermore, evaluating the toxicity of the fungicide myclobutanil (MYC) in zebrafish, Pang and colleagues demonstrated a marked sex-specific modulation of liver cholesterol metabolism.…”