Chronic lead exposure exacerbates hepatic glucolipid metabolism disorder and gut microbiota dysbiosis in high-fat-diet mice.

Lead (Pb) and obesity are co-occurring risk factors for metabolic disorders. However, there is still a lack of study on the combined effects of both stressors on metabolism. C57BL/6J mice were exposed to 200 mg/L Pb or/and HFD for 24 weeks and were used to investigate the effects and underlying mechanisms of chronic Pb exposure on obese mice. The results showed that Pb significantly increased body weight, visceral obesity, fasting blood glucose levels, and insulin resistance, and aggravated liver damage, hepatic lipid accumulation and steatosis in HFD-fed mice. Further analysis showed that Pb significantly inhibited insulin signaling pathway PI3K/AKT and fatty acid ß-oxidation, and accelerated fatty acid synthesis. Moreover, Pb exacerbated HFD-induced disruption of gut microbiota homeostasis, manifested by increased proportions of pathogenic genera such as Desulfovibrio, Alistipes and Helicobacter, and decreased proportions of beneficial microbes Akkermansia and Barnesiella, which were negatively associated with obesity. These results indicated that Pb exposure exacerbated the disruption of liver glucolipid metabolism in HFD mice possibly by disrupting gut microbiota.

Cadmium exposure decreases fasting blood glucose levels and exacerbates type-2 diabetes in a mouse model.

PURPOSE: Although the effects of cadmium (Cd) on the development of diabetes have been extensively investigated, the relationship between Cd exposure and the severity of established diabetes is unclear. Herein, we investigate the effects of long-term exposure to Cd in a streptozotocin-induced mouse model of type-2 diabetes mellitus (T2DM) and the underlying mechanism. METHODS: C57BL/6 Mice were divided into the following four groups: (1) control group; (2) Cd-exposed group; (3) diabetic group; (4) Cd-exposed diabetic group. Cd exposure was established by the administration of 155 ppm CdCl2 in drinking water. After 25 weeks of treatment, serum fasting glucose and insulin were measured. Meanwhile, the liver and pancreas specimens were sectioned and stained with Hematoxylin and eosin. Gluconeogenesis, glycolysis, lactate concentration, and fibrosis in liver were evaluated. RESULTS: Clinical signs attributable to diabetes were more apparent in Cd-exposed diabetic mice, while no effects of Cd exposure were found on non-diabetic mice. Cd exposure significantly decreased fasting blood glucose (FBG) levels in diabetic group. We further demonstrated that the glycolysis related hepatic enzymes, pyruvate kinase M2 (PKM-2) and lactic dehydrogenase A (LDHA) were both increased, while the gluconeogenesis related hepatic enzymes, phosphoenolpyruvate-1 (PCK-1) and glucose-6-phosphatase (G6Pase) were both decreased in Cd exposed diabetic mice, indicating that Cd increased glycolysis and inhibited gluconeogenesis in diabetic model. Moreover, lactate accumulation was noted accompanied by the increased inflammation and fibrosis in the livers of diabetic mice following Cd exposure. CONCLUSIONS: Cd exposure disturbed glucose metabolism and exacerbated diabetes, providing a biological relevance that DM patients are at greater risk when exposed to Cd.

Effects of Combined Exposure to Cadmium and High-Fat Diet on Bone Quality in Male Mice.

This study investigated the effects of combined exposure to low-dose cadmium and high-fat diet on femoral bone quality in male mice. Eight-week-old male SPF C57BL/6J mice were randomly divided into four groups: normal control group (Con), low-cadmium group (Cd), high-fat diet group (HFD), and high-fat diet plus low-dose cadmium group (HFD + Cd); the second and fourth groups were treated intraperitoneally with CdCl2 (1.0 mg/kg body weight) twice weekly for 20 weeks. Assays related to bone quality were performed. Body weight of HFD plus Cd mice was significantly lower than HFD mice. Femoral length was not different among groups, but femoral weight was decreased in the HFD plus Cd group compared with other three groups. Level of Cd in bone was significantly increased in HFD plus Cd group. There was no difference in cortical BMD among groups; however, cortical bone quality parameters were decreased in HFD plus Cd group. Cd and HFD each reduced trabecular bone quality and together had further detrimental effects on these bone parameters. Based on biomechanical analysis, femoral bone strength was decreased, being more brittle and less resistant to biomechanical forces in the HFD plus Cd mice. HFD plus Cd mice had lower OPG mRNA expression and higher RANKL mRNA expression than others. HFD or Cd can cause adverse effects on bone and together had further detrimental effects associated with RANKL/OPG signaling.

Long-Term Exposure to Low-Dose Lead Induced Deterioration in Bone Microstructure of Male Mice.

The aim of this study was to investigate the long-term effects of low-dose lead exposure on bone microstructure in mice. Ten SPF 12-week-old male C57BL/6J mice were randomly divided into two groups: control (deionized water) and lead exposure (150 ppm of lead acetate in drinking water). After 24 weeks treatment, mice were weighed and the left femurs were collected and stored at - 80 °C. The right femurs of the mice were scanned by Micro-CT for three-dimensional reconstruction, and bone mineral density, bone volume fraction, trabeculae thickness, trabeculae number, and trabeculae separation were measured. The right tibia was collected to investigate histopathological changes in H&E-stained sections. The gene expression of osteoprotegerin (OPG), RANKL, and runt-related transcription factor 2 (Runx2) was determined using real-time PCR. The bone density of femoral cancellous bone and the number of cancellous bone trabeculae in the lead exposure group were both significantly decreased compared with the control group. Bone marrow stromal cell numbers were decreased following lead administration, and lipid droplet vacuoles were observed in the lead group. Levels of OPG were significantly decreased in the lead group, and lead also inhibited the expression of Runx2 compared with the control group. Long-term exposure to low doses of lead can cause bone damage without inducing other obvious symptoms through decreasing bone density and the number of cancellous bone trabeculae, further suppressing bone formation. It suggests that lead may exacerbate bone loss and osteoporosis, especially in the elderly.