Association Of Environmental Cadmium Exposure With Osteoporosis And Bone Remodeling

Cadmium is a heavy metal of considerable toxicity with destructive impact on bone and kidney.There were few studies on population with high Cd(due to high dietary Cd intake)exposure.Studies suggested that Cd might have direct toxic effects on bone.This study aimed to assess the association between osteoporosis and long-term environmental Cd exposure through diet in southern China,and calculated the values of benchmark dose using the Benchmark Dose Software.Multiple regression and logistic regression were used to analysis the relationship between Cd and osteoporosis.We also investigated the bone turnover markers,and intended to uncover potential mechanisms of Cd-induced effects on bone.We used rat model of chronic exposure to Cd to study the Cd's effect on MSCs and kidney.We intended to develop AOPs for toxic effects of Cd.A total of 1116 subjects from a Cd-polluted area and a non-Cd-polluted area were investigated.Urinary Cd concentrations of all studied subjects ranged from 0.21 to 87.31 ?g/g creatinine,with a median of 3.97 pg/g creatinine.In all subjects,the benchmark dose and benchmark dose lower bound were 1.14(0.61)and 2.73(1.83)?g/g creatinine,with benchmark response set at 5%and 10%,respectively.The benchmark dose of urinary Cd was lower in women than in men.Multivariate linear regression models indicated a significant negative association of urinary Cd concentrations with bone mineral density.The results did not change significantly after additional adjustment for urinary levels of NAG,?1-microglobulin,?2-microglobulin,and U-Alb.In logistic regression models,both categorical and continuous urinary Cd concentrations were positively correlated with osteoporosis.Subjects in the second,third,and fourth quartiles of urinary Cd concentration had increased osteoporosis in multivariable-adjusted analyses compared with subjects in the first quartile[odds ratio(OR)= 3.13,95%confidence interval(CI),1.83 to 5.37;OR = 5.01,95%CI,2.93 to 8.54;OR = 9.42,95%CI,5.47 to 16.22)].No evidence existed of an interaction between urinary Cd concentration and renal function using urinary levels of NAG,?1?microglobulin,?2-microglobulin,U-Alb,and eGFR.The toxic effect of Cd on bone may occur in parallel to nephrotoxicity,rather than as its consequence.Urinary Cd showed positively significant relation to all of bone markers.In multivariate linear analysis,only urinary Cd,age and serum ?-CTX resulted in being significant explanatory predictors of bone mineral density.Chronic cadmium chloride(CdCl2,1.0 and 2.0 mg/kg,i.p.)treatment in female SD rats for 38 weeks,body weight,organ weight and organ body weight ratio were not statistically significant(p>0.05).No statistically significant difference in bone mineral density was found between dose groups and control group.RANKL and OPG gene expressions in MSCs were measured.RANKL expression was elevated and OPG expression was decreased.The expression of genes involved in the regulation of osteogenesis including Colla2,Osterix,Osteopontin,Runx2,Osteocalcin and ALP were down regulated.No statistically significant difference in renal injury markers and urinary Ca were found between dose groups and control group.The kidney didn't show any histopathological changes in dose groups,and HO-1,LC3B,p62,Beclin-1 expression were increase.CONCLUSION1.In all subjects,the benchmark dose and benchmark dose lower bound were 1.14(0.61)and 2.73(1.83)?g/g creatinine,with benchmark response set at 5%and 10%,respectively.The benchmark dose of urinary Cd was lower in women than in men.2.After adjustment for age,BMI,smoking status,serum albumin,and levels of renal injury markers,subjects in the second,third,and fourth quartiles of urinary Cd concentration had increased osteoporosis compared with subjects in the first quartile.The toxic effect of Cd on bone may occur in parallel to nephrotoxicity,rather than as its consequence.3.RANKL/RANK/OPG system may be involved in the pathogenesis of Cd-induced bone loss.4.?-CTX is a good biomarker for Cd-induced bone loss.5.Cd could affect the osteogenic differentiation process of MSCs directly,which might be another mechanism.6.We have developed an AOP for Cd-induced bone effects.