This study investigated the associations between the independent and joint effects of Sr exposure on the liver function of mining residents in China. According to the RCS and univariate analysis, we found that Sr was positively correlated with ALT, especially in participants under the age of 45 (OR: 2.21, 95% CI: 1.50–3.29) or in males (OR: 1.60, 95% CI: 1.22–2.15), and positively correlated with AST. In a multiple linear regression model, we found that Sr has a positive association between ALT (β = 14.86, 95% CI: 8.23, 21.50, P < 0.05) and AST (β = 9.67, 95% CI: 3.54, 15.80, P < 0.05) and that Sr had a critical impact on liver function. The results of the multiple linear regression were consistent with the results of the RCS and univariate analysis. Liu found that Sr2+ caused hepatotoxicity in zebrafish embryos, mainly manifested by hepatic macrophages and delayed yolk sac uptake (Liu, Chen et al. 2019). Another study found that urinary Sr might reduce male sperm count(Miao, Liu et al. 2021) and excessive Sr could lead to osteoporosis (Bauman, Valinietse et al. 1988). However, the mechanism of action of Sr on ALT and AST is still unclear. Possibly, excess strontium may interfere with the uptake and metabolism of calcium by hepatocytes (Pors Nielsen 2004). Our research is the first to investigate the effect of Sr on liver function in a Chinese population.
The liver was more susceptible to damage as it is the organ that accumulates the heaviest metals (Fang, Yin et al. 2021). Many studies have reported the effects of heavy metal exposure on human health (Bhagat, Nishimura et al. 2021). Fan found that many toxic metals may increase the risk of acute and chronic diseases, such as arsenic-induced diabetes (Fan, Zhu et al. 2017). Farkas found that the liver was the most important storage organ for Cu, Fe, Mn, and Zn (Farkas, Bidló et al. 2021). A study found that four Taiwanese toothed cetaceans had the highest content of Zn and Cu in the liver (Chen, Lin et al. 2020). There was a positive correlation between Mn and ALT (β = 2.98, 95% CI: 0.004, 5.96, P < 0.05). Wang found that long-term, low-dose Mn exposure could cause pathological liver changes and might be related to the inhibition of Nrf2 expression (Wang, Bao et al. 2021). While a negative correlation between Pb (β = -2.92, 95% CI: -5.32, -0.53, P < 0.05), Cu (β = -10.67, 95% CI: -19.56, -1.78, P < 0.05), and ALT. Although the hepatotoxic mechanisms of Pb remain unclear, one explanation is that Pb could stimulate the reactive oxygen species (ROS) responsible for oxidative stress and the destruction of the antioxidant defense system (Lee, Choi et al. 2019).
Yuan also found that low doses of Pb could significantly modulate hepatic superoxide dismutase (Yuan, Dai et al. 2014). TBIL had a negative correlation with Cu (β = -2.76, 95% CI: -5.45, -0.08, P < 0.05) and a positive correlation with Zn (β = 3.74, 95% CI: 0.39, 7.09, P < 0.05). Ge found that plasma copper levels were associated with a decrease in liver function, which was similar to our results (Ge, Liu et al. 2020). Clinical studies found that Cu was positively correlated with the serum levels of gamma-glutamyl transpeptidase (GGTP) in liver cirrhosis (Poznański, Sołdacki et al. 2021). Hyder found an association between urinary cadmium concentrations and liver function (Hyder, Chung et al. 2013). However, our results showed that Cd and liver function have no significant correlation, which may be due to the lower concentration of cadmium in the plasma. A low-pollution environment study showed no significant association between low concentrations of Cd and ALT, which was consistent with our results (Cave, Appana et al. 2010).
The scientific community focuses on the disease risk caused by simultaneous exposure to multiple metals, which is how the metals present in the environment. The BKMR model describes the overall effect and independent and joint associations between co-exposure to six metals and liver function. When other heavy metals were fixed at a percentile, there was a positive correlation between Sr and ALT and Sr and AST. The multiple linear regression results were consistent with the univariate analysis. Then we found that Sr, Pb, and Cu have a synergistic effect. The results of the GAMs model were consistent with those of BKMR. Howe found that simultaneous exposure to multiple metals, including As, Cd, Co, Ni, Hg, Pb, and Ti, synergistically increased health risk (Howe, Claus Henn et al. 2020). However, they found no interaction between Cd and Pb, which was in line with our study. A case-control study of trace elements and the risk of goiter showed an interaction between Pb and Sr (He, Li et al. 2021). Huang found that Pb was negatively correlated with liver function, and co-exposure would aggravate liver damage, but no interaction between Pb and Cd was found in the population survey (Huang, Pan et al. 2021). Bauman found that combined exposure to more than three heavy metals might increase health risks (Bauman, Valinietse et al. 1988).
In summary, this study analyzed the association of single Sr exposure and Sr combined exposure with liver function. The results were verified by GAMM and BKMR and provide important clues regarding Sr's health risk. However, our study sample size is limited and the cause-effect relationship between Sr exposure and liver function needs further investigation.