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• Orally administered polystyrene nanoparticles (PS-NPs) translocate into the circulatory system. • PS-NPs cause glycolipid and irreversible damage to organs in mice. • PS-NPs increase ROS levels and induce the inflammatory response. • Resveratrol mitigates insulin resistance and gluconeogenesis induced by PS-NPs in mice. Nanoplastics-induced developmental and reproductive toxicity, neurotoxicity and immunotoxicity are a focus of widespread attention. However, the effects of nanoplastics (NPs) on glycolipid metabolism and the precise underlying mechanisms are unclear at present. Here, we showed that oral administration of polystyrene nanoparticles (PS-NPs) disrupts glycolipid metabolism, with reactive oxygen species (ROS) identified as a potential key signaling molecule. After PS-NPs treatment, excessive production of ROS induced the inflammatory response and activated the antioxidant pathway through nuclear factor-erythroid factor 2-related factor 2. The activation of nuclear factor-κB (NFκB) signaling pathway induced the phosphorylation of the mitogen-activated protein kinases (MAPK) signaling pathway, which induced the activation of extracellular regulated kinases (ERK) and p38. Constitutive activation of the MAPK signaling proteins induced high continued phosphorylation of insulin receptor substrate-1, in turn, leading to decreased protein kinase B (Akt) activity, which weakened the sensitivity of liver cells to insulin signals and induced insulin resistance. In parallel, phosphorylation of Akt led to loss of control of FoXO1, a key gene of gluconeogenesis, activating transcription of glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase (PEPCK) in a manner dependent on PGC1α. Moreover, the activated ERK promoted lipid accumulation through ERK-PPARγ cascades. Therefore, sterol regulatory element-binding protein-1 and levels of its downstream lipogenic enzymes, ACC-1, were up-regulated. Upon treatment with the antioxidant resveratrol, PS-NPs-induced glucose and lipid metabolic disorders were improved by inhibiting ROS-induced activation of NFκB and MAPK signaling pathway in mice. Based on above, PS-NPs exposure disrupts glycolipid metabolism in mice, with ROS identified as a potential key signaling molecule. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Methylparaben (MP, 25 mg/kg) induces glycolipid metabolism disorders in mice. • MP induces metabolic disorder via the X-box binding protein 1 pathway. • Toyocamycin alleviates the glycolipid metabolic disorder induced by MP. Methylparaben (MP), a preservative widely used in daily supplies, exists in both the environment and the human body. However, the potential health risks posed by MP remain unclear. This study aimed to unravel the mechanisms by which MP disrupts glucose and lipid homeostasis. For this, we administered MP to mice and observed changes in glucose and lipid metabolism. MP exposure led to hyperglycemia, hyperlipidemia, visceral organ injury, and hepatic lipid accumulation. RNA sequencing results from mice livers indicated a close association between MP exposure and endoplasmic reticulum (ER) stress, inflammatory response, and glucose and lipid homeostasis. Western blotting and quantitative reverse transcription–polymerase chain reaction revealed that MP activated ER stress, particularly the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) pathway, which further promoted the activation of the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. The activation of these pathways phosphorylated insulin receptor substrate-1 (IRS1) (ser 307), resulting in decreased phosphorylation of protein kinase B (Akt) (ser 473), leading to insulin resistance. Additionally, MP exposure promoted lipogenesis through ER stress. To explore potential remedies, we administered the ER stress inhibitor 4-phenylbutyric acid (4-PBA) and the IRE1α-XBP1 pathway inhibitor toyocamycin to mice, both of which protected against metabolic disorders and organ injury caused by MP. These findings suggest that MP induces disruptions in glucose and lipid metabolism through ER stress, primarily through the IRE1α-XBP1 pathway. [ABSTRACT FROM AUTHOR]

Lambda-cyhalothrin (LCT) is a critical synthetic Type II pyrethroid insecticide widely applied. Several studies suggest pyrethroids could induce fat accumulation, promote adipogenesis, and impair liver function. Now, the influences of LCT on the hepatic lipid metabolism and the cellular mechanism is still unknown. AMPK has important function in regulating cellular energy balance. To indicate the potential pathogenesis of liver injury caused by LCT exposure, ICR mice were orally administrated with LCT at a dose of 0.4 mg/kg and 2 mg/kg. The results suggest that LCT induced obesity, dyslipidemia and hepatic steatosis. In addition, LCT also induced oxidative stress, liver function injury, and disorganized structure of the liver. Furthermore, upregulation of PPARγ, FASN, and SREBP1c expression, as well as reduction of PPARα and FGF21 expression, bringing with decreases of phosphorylated ratios of AMPK and ACC were found in LCT-L group. These results indicate that LCT at 0.4 mg/kg could result in dyslipidemia and hepatic steatosis in mice. In addition, activation of AMPK in hepatocytes effectively attenuated the effects of LCT. The detailed mechanism of LCT-induced hepatic steatosis is associated with AMPK and its downsteam genes. Activation of AMPK might be a novel protection against the progression of hepatic steatosis induced by LCT. [ABSTRACT FROM AUTHOR]

Tris (2-chloroethyl) phosphate (TCEP), the most widely useful and most frequently detective organophosphate flame retardants in environment, has been shown potential relationship with adolescent weight. Probiotics is an effective therapy for metabolic diseases such as obesity and NAFLD with gut microbiota dysregulation. This study aims to explore the protective effects of probiotics against lipid metabolic disorder induced by chronic TCEP exposure and demonstrate the mechanism of this event. The data showed that dietary complex probiotics supplement attenuated TCEP-induced obesity, hyperlipidemia, liver dysfunction, and hepatic steatosis. In addition, dietary complex probiotics suppressed TCEP-promoted ileal FXR signaling, and upregulated hepatic FXR/SHP pathway inhibited by TCEP. Moreover, dietary complex probiotics stimulated PPARα-mediated lipid oxidation and suppressed SREBP1c/PPARγ-mediated lipid synthesis via regulation of FXR signaling. Therefore, this study indicates that dietary complex probiotics could protect against hepatic steatosis via FXR-mediated signaling pathway in TCEP-induced metabolism disorder in mice, resulting in attenuation of systemic lipid accumulation. [Display omitted] [ABSTRACT FROM AUTHOR]

Microplastic (MP) and nanoplastic (NP) induce neurotoxicity, cytotoxicity, and reproductive system toxicity in mammals. However, the impacts of NPs on the endocrine system are obscure. Here, monodisperse polystyrene nanoplastics (PS-NPs) were prepared by emulsion polymerization and the accumulation of fluorescent PS-NPs in various organs, including the liver, kidney, spleen, and pancreas, was examined. The oral administration of PS-NPs induced visceral organ injury, and the main toxicities were damage to hepatic function and the abnormity of lipid metabolism. Global transcriptome sequencing (RNA-Seq) revealed the impact of PS-NPs on the genes involved in reactive oxygen species (ROS) generation and the PI3K/Akt signaling pathway, which is associated with glucose metabolism in mice. Chronic exposure to PS-NPs significantly increased plasma glucose levels and ROS levels, but did not affect plasma insulin secretion. The phosphorylation of insulin receptor substrate (IRS)-1 at Ser307 was raised, which decreased the phosphorylation of Akt (at Ser473) in the PI3K/Akt pathway. Collectively, these findings suggested that the oral administration of PS-NPs significantly increased ROS, hepatic triglycerides, and cholesterol accumulation. The high levels of ROS disturbed the PI3K/Akt pathway, causing insulin resistance and increased plasma glucose in the mouse liver. [Display omitted] • Orally administered polystyrene nanoparticles (PS-NPs) were studied. • These accumulate in viscera & tissues. • PS-NPs affect plasma glucose metabolism in mice. • They increase ROS and hepatic triglyceride content, and fatty droplet accumulation. • PS-NPs induce hyperglycemia via the PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]