Cadmium exposure causes transcriptomic dysregulation in adipose tissue and associated shifts in serum metabolites.

Cadmium (Cd) is a toxic heavy metal found in natural and industrial environments. Exposure to Cd can lead to various metabolic disturbances, notably disrupting glucose and lipid homeostasis. Despite this recognition, the direct impact of Cd exposure on lipid metabolism within adipose tissue, and the mechanisms underlying these effects, have not been fully elucidated. In this study, we found that Cd accumulates in adipose tissues of mice subjected to Cd exposure. Intriguingly, Cd exposure in itself did not induce significant alterations in the adipose tissue under normal conditions. However, when subjected to cold stimulation, several notable changes were observed in the mice exposed to Cd, including a reduction in the drop of body temperature, a decrease in the size of inguinal white adipose tissue (WAT), and an increase in the expression of thermogenic genes UCP1 and PRDM16. These results indicate that Cd exposure might enhance the responsiveness of adipose tissue to external stimuli and increase the energy expenditure of the tissue. RNA-seq analysis further revealed that Cd exposure altered gene expression profiles, particularly affecting peroxisome proliferator-activated receptor (PPAR)-mediated metabolic pathways, promoting metabolic remodeling in adipose tissue and resulting in the depletion of lipids stored in adipose tissue for energy. Non-targeted metabolomic analysis of mouse serum showed that Cd exposure significantly disrupted metabolites and significantly increased serum fatty acid and triglyceride levels. Correspondingly, population-level data confirmed an association between Cd exposure and elevated levels of serum total cholesterol, total triglycerides, and low-density lipoprotein cholesterol. In summary, we provide substantial evidence of the molecular events induced by Cd that are relevant to the regulation of lipid metabolism in adipose tissue. Our findings suggest that the toxic effects of Cd can impact adipocyte functionality, positioning adipose tissue as a critical target for metabolic diseases resulting from Cd exposure.

Saturated fatty acids synergizes cadmium to induce macrophages M1 polarization and hepatic inflammation.

Exposure to the toxic metal cadmium (Cd) is a well-established risk factor for hepatic inflammation, but it remains unclear how metabolic components, such as different fatty acids (FAs), interact with Cd to influence this process. Understanding these interactions is essential for identifying potential preventative and therapeutic targets for this disorder. To address this question, we conducted in vitro and in vivo studies to investigate the combinatorial effect of Cd and saturated FAs on hepatic inflammation. Specifically, we assessed the cytotoxicity of Cd on macrophages and their polarization and inflammatory activation upon co-exposure to Cd and saturated FAs. Our results showed that while saturated FAs had minimal impact on the cytotoxicity of Cd on macrophages, they significantly collaborated with Cd in predisposing macrophages towards a pro-inflammatory M1 polarization, thereby promoting inflammatory activation. This joint effect of Cd and saturated FAs resulted in persistent inflammation and hepatic steatohepatitis in vivo. In summary, our study identified macrophage polarization as a novel mechanism by which co-exposure to Cd and saturated lipids induces hepatic inflammation. Our findings suggest that intervening in macrophage polarization may be a potential approach for mitigating the adverse hepatic effects of Cd.

Valproic acid counteracts polycyclic aromatic hydrocarbons (PAHs)-induced tumorigenic effects by regulating the polarization of macrophages.

Polycyclic aromatic hydrocarbons (PAHs) are common persistent organic pollutants that are carcinogenic, teratogenic and mutagenic, causing a variety of harm to human health. In this study, we investigated the mechanism of how valproic acid (VPA) interferes with the carcinogenesis of PAHs protect normal tissues via the regulation of macrophages' function. Using the established model of transformed malignant breast cancer by 7,12-dimethylbenz[a]anthracene (DMBA), a representative PAH carcinogen, we discovered VPA induces the polarization of macrophages toward the M1 phenotype in the tumor tissues, facilitates the expression of pro-inflammatory cytokines such as IFN-γ, IL-12 and TNF-α, activates CD8+ T cells to secret Granzyme B thus to promote the apoptosis of tumor cells and suppresses the viability of vascular endothelial cells in tissue stroma of tumor. Surprisingly, VPA selectively induces macrophages to polarize towards the M2 phenotype in normal tissues and promotes the expression of anti-inflammatory cytokines such as IL-10 to enhance cell proliferation. Additionally, at the cellular level, VPA can directly regulate the polarization of macrophages to affect the growth of vascular endothelial cells by simulating the living conditions of tumor and normal cells. Collectively, VPA exerts an interventional effect on tumor growth and a protective effect on normal tissues by regulation of selective macrophages' polarization in their microenvironment.

Valproic Acid-Like Compounds Enhance and Prolong the Radiotherapy Effect on Breast Cancer by Activating and Maintaining Anti-Tumor Immune Function.

Inadequate sustained immune activation and tumor recurrence are major limitations of radiotherapy (RT), sustained and targeted activation of the tumor microenvironment can overcome this obstacle. Here, by two models of a primary rat breast cancer and cell co-culture, we demonstrated that valproic acid (VPA) and its derivative (HPTA) are effective immune activators for RT to inhibit tumor growth by inducing myeloid-derived macrophages and polarizing them toward the M1 phenotype, thus elevate the expression of cytokines such as IL-12, IL-6, IFN-γ and TNF-α during the early stage of the combination treatment. Meanwhile, activated CD8+ T cells increased, angiogenesis of tumors is inhibited, and the vasculature becomes sparse. Furthermore, it was suggested that VPA/HPTA can enhance the effects of RT via macrophage-mediated and macrophage-CD8+ T cell-mediated anti-tumor immunity. The combination of VPA/HPTA and RT treatment slowed the growth of tumors and prolong the anti-tumor effect by continuously maintaining the activated immune response. These are promising findings for the development of new effective, low-cost concurrent cancer therapy.

The intervention of valproic acid on the tumorigenesis induced by an environmental carcinogen of PAHs.

This study investigated whether valproic acid (VPA, a histone deacetylase inhibitor) can interfere with the carcinogenicity of polycyclic aromatic hydrocarbons (PAHs). A typical representative compound of PAHs, 7,12-Dimethylbenz[a]anthracene (DMBA), was used to induce rat breast cancer. The results showed that therapeutic concentration of VPA (50 and 100 mg/kg) delayed the occurrence of tumors, reduced tumor formation rate and attenuated tumors growth, and have a protective effect on normal tissues. The macrophage-mediated inflammatory response was found to be associated with the observed effect of VPA. In addition, we screened and validated a possible gene, Sema3c, which was involved in DMBA-induced breast cancer development and can be inhibited by VPA.