Protective Effects of Moderate Ca Supplementation against Cd-Induced Bone Damage under Different Population-Relevant Doses in Young Female Rats

Abstract

Estimation of the skeleton-protective effects of Ca in Cd-induced bone damage is helpful in the assessment of Cd health risk. The aim of this study was to identify whether Ca supplementation during exposure to different population-relevant doses of Cd can prevent Cd-induced bone damage under the tolerable upper intake level of Ca supplementation. Young female Sprague-Dawley rats were given different population-relevant doses of Cd (1, 5, and 50 mg Cd/kg diet) and Ca supplementation (0.4% Ca supplementation) intervention. Ca supplementation significantly decreased Cd-induced bone microstructure damage, increased bone biomechanics (p < 0.05), serum bone formation marker level (p < 0.05) and expression of osteogenic gene markers exposure to the 5 and 50 mg Cd/kg diets. However, it had no impact on these indicators under the 1 mg Cd/kg diets, with the exception of expression of osteogenic marker genes. Ca supplementation significantly decreased serum Klotho level (p < 0.05), and fibroblast growth factor 23/Klotho-associated gene expression in the kidney and bone showed significant changes. In conclusion, Ca supplementation has a positive effect on bone formation and bone quality against the damaging impact of Cd, especially with exposure to the 5 mg and 50 mg Cd/kg diet, which may be related to its impact on the fibroblast growth factor 23/Klotho axis.

Vitamin D3 and calcium cosupplementation alleviates cadmium hepatotoxicity in the rat: Enhanced antioxidative and anti‐inflammatory actions by remodeling cellular calcium pathways

“…Previous reports have disclosed that Ca 2+ and VD 3 supplementations antagonized Cd-intestinal absorption and/or enhanced its excretion by the kidney. [31][32][33] Our study revealed that systemic, but not hepatic tissue, Cd levels were substantially lower in both monotherapy groups compared with the PC group, suggesting that the single protocols might have enhanced the renal excretion, whereas they had minimal effect on Cd-intestinal absorption. On the other hand, the VDC group disclosed the utmost corrective effects on serum and hepatic tissues Cd and Ca 2+ levels compared with the PC, VD, and Ca groups.…”

“…Herein, the different interventional protocols also exhibited significant inhibitions of Ca V 3.1, RyR1, ITPR1, CAM, CMAKIIα, and S100B with concomitant upregulations of Ca V 1.1 and S100A1 compared with the PC group. Prior studies have shown that Ca 2+ inhibited Cd influx into several cells, including hepatocyte . Furthermore, Ca 2+ supplementation ameliorated glucose metabolism by modulating many Ca 2+ ‐regulatory proteins, including RyRs and CAM‐CAMKII, and these effects were inhibited by Ca 2+ ‐channel blockers .…”

“…In this context, Cd‐intestinal absorption and toxic effects were more severe with VD 3 and Ca 2+ deficiency, and hepatic tissue Ca 2+ levels were diminished with chronic Cd toxicity . The trafficking of Cd across intestinal and renal cellular barriers also coincided with inhibitions of several VD‐dependent Ca 2+ ‐transporting proteins and it was suggested that Cd promoted its gathering by causing enterocytes absorption hindrance and excessive renal excretion of Ca 2+ . Moreover, VD 3 controls many cellular Ca 2+ ‐regulatory molecules including VDCCs, SOCs, and CAM‐CAMKII .…”

“…[35,45] The trafficking of Cd across intestinal and renal cellular barriers also coincided with inhibitions of several VDdependent Ca 2+ -transporting proteins and it was suggested that Cd promoted its gathering by causing enterocytes absorption hindrance and excessive renal excretion of Ca 2+ . [31][32][33] Moreover, VD 3 controls many cellular Ca 2+ -regulatory molecules including VDCCs, SOCs, and CAM-CAMKII. [50][51][52] VD 3 is also a potent anti-inflammatory and antioxidative hormone that has been shown to efficiently modulate many of the oxidative stress and the inflammatory pathways involved in Cd-induced cell damage.…”

“…Cd also deterred the activities of the Cyp27b1 enzyme and VDR, thus inhibiting the actions of VD 3 . While Ca 2+ and VD 3 replenishments inhibited Cd‐intestinal uptake and enhanced its renal excretion, higher Ca 2+ intake also counteracted Cd‐induced oxidative stress and inflammation . However, none of the previous studies either measured the effects of Cd on the hepatic expression of VD‐regulatory molecules or explored the protective antioxidative and anti‐inflammatory actions of the hormone.…”