The relationship between co-exposure to multiple heavy metals and liver damage
Introduction
Liver disease, including hepatitis, cirrhosis, liver abscess, primary liver cancer, etc., is a leading cause of disease and death worldwide [1]. According to studies in Europe and Asia, the burden on the population due to the increased prevalence of liver disease has continued to increase in recent years [2], [3]. In China, liver disease directly or indirectly affects about 300 million people, liver cancer has even become the second leading cause of cancer-related death, China contributes 51 % of the world's annual deaths due to liver cancer [4]. At the same time, the liver also interacts with other organs [5], [6], [7], for example, liver disease may lead to abnormal cardiac function even if the patient does not have cardiovascular disease [8], [9].
In addition to long-term alcohol abuse, abnormal lipid metabolism, immune dysfunction, drugs, hepatitis virus, etc. have been proved to be related to the etiology of liver disease [10], [11], [12], [13], [14], A growing number of studies have found that heavy metal exposure can also lead to a decline in liver function [14], [15]. Heavy metal pollution in the atmosphere and soil is equally serious not only in smelting, mining, and industrial activities [16], [17], often difficult to be biodegraded, and can be enriched under the bio-magnification of the food chain. and finally enter the human body, where they interact strongly with proteins and enzymes, making them inactive, and may also accumulate in some organs, causing chronic poisoning. Diet has become another important source of heavy metal exposure. The relationship between heavy metals and liver dysfunction has been verified by many epidemiological studies and animal experiments. A study from South Korea found that heavy metal exposure (Pb, Cd, Hg) was associated with liver damage in adults [18], another study in oil-contaminated areas in Nigeria found that crude oil pollution was associated with elevated levels of heavy metals, leading to increased risk of liver and kidney toxicity [19]. Considering that there are some large enterprises with high pollution near the survey area, such as aluminum plants, power plants, lime plants and cement plants. Whether the Cr, Co, Cd and Pb heavy metal pollution generated by these factories will cause liver function damage to local residents is our concern, so we finally chose Cr, Co, Cd and Pb as the exposure parameters. Total bilirubin (TB), direct bilirubin (DB), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) are considered by researchers to be important markers reflecting the anabolic function of the liver [20], [21], when liver cells are damaged, blood levels of aspartate aminotransferase, alanine aminotransferase and bilirubin are significantly increased [22], [23]. At the same time,the detection of TB, DB, AST and ALT is usually common and convenient in clinical practice. Therefore, we choose these four indicators as parameters representing liver function. Therefore, we investigated the relationship between heavy metals (Cr, Co, Cd, Pb) and liver function indexes. An animal study found that exposure to cadmium chloride resulted in increased ALT and AST activity in rat serum [24]. Similarly, many studies from the population have also provided relevant evidence. The levels of Fe, Cd and Cu in the blood of rural residents in Southwest China are positively correlated with the level of ALT, and the level of blood Cu in the population in the Cd-contaminated area is positively correlated with the level of AST [25]. A case-control study in children aged 4–12 in a primary school in India showed that the levels of TB, ALP, SGOT, and SGPT were significantly increased in Pb-exposed subjects [15], a cross-sectional study in Korea also found that blood cadmium concentrations in adults were significantly associated with liver enzyme levels (AST, ALT, ALP) [26]. However, a meta-analysis also found that chromium supplementation had no significant effect on BMI, SBP, ALT, and AST [27].
Most of the studies on the effects of the above metal elements on liver function, whether epidemiological studies or animal experiments focus on the effects of a single metal element on liver function, and there are few studies on the combined effects of metal mixture exposure on liver function. Although some studies have evaluated the effect of mixtures of metal elements (As, Cd, and Pb) on liver function in mining populations [28], the heavy metal pollution in the environment of the mining area is serious, and the people in this area are exposed to too much toxic heavy metals, which seriously endangers human health[29], In the general population, exposure to high concentrations of metal element mixtures is less likely, and extrapolation is limited.
In this cross-sectional study, participants aged 35–74 years in rural Ningxia, China, assessed the serum levels of four heavy metals (Cr, Co, Cd, Pb) and measured liver function indicators (TB, DB, ALT, AST), a statistical method called Bayesian Kernel Machine Regression Model (BKMR) was used by us to assess the combined effect of co-exposure to four heavy metals on biomarkers of liver injury to overcome the inability of traditional statistical methods to Potential interactions and nonlinear non-additive relationships between heavy metals considered [30], it was also possible to determine which metals in the heavy metal mixture contributed more to liver damage.
Section snippets
Study population
Our study is the baseline of the Ningxia cohort study, which is a prospective study and is part of the national key research and development project "Precision Medicine Research" in the northwest region of the natural population cohort. Considering the consistency of the residents, the stability of the population, and the local economic and medical conditions, two towns were selected as the research sites in Wuzhong City and Shizuishan City of Ningxia, both located in the Yellow River basin.The
Characteristics of participants and metals correlation study
The basic characteristics of the participants have been shown in Table 1, including general demographic characteristics, liver function indexes, and serum metal distribution.
Table S1 shows the correlation of metals with liver function index, indicating that there is a significant correlation between the metal elements and four liver function indexes.
Figure S1 shows the correlation between metal elements with low to moderate correlation. The Spearman correlation between the four metal elements
Discussion
The study found that when we used TB, DB, AST, and ALT levels to measure liver function, using the BKMR model, we could observe that the metal element mixture had a positive combined effect on TB, DB, and AST levels, and a negative combined effect on ALT levels, but only the combined effect of metal element mixture on DB level was significant, specifically, the positive combined effect of metal element mixture on DB level was statistically significant when all four metal elements were at their
Conclusions
In conclusion, concurrent exposure to higher concentrations of heavy metal mixtures (Cr, Co, Cd, and Pb) in rural China was associated with decreased liver function, on which the effect of lead on liver function should be focused. The prevention and control of heavy metal pollution should be strengthened, the discharge of industrial waste should be strictly controlled, and the monitoring and management of heavy metals in daily necessities and crops should be strengthened to reduce the harm of
Ethics approval and consent to participate
This study was approved by the Ethics Review Board of Ningxia Medical University (Ethics ID 2018–012). Signed informed consent was obtained from all participants before the study has begun.
Funding
This study was funded by the National Key Research and Development Program of China (grant number: 2017YFC0907204), the National Natural Science Foundation of China (grant number: 81860603), and the Key Research and Development Program of Ningxia Hui Autonomous Region (grant number: 2021BEG02026).
The funders did not involve in the study design, data collection, data analysis, data interpretation, or writing of this manuscript.
Authors’ contributions
Yuhong Zhang and Yi Zhao designed the study and drafted the outline. Jiangwei Qiu, Ling Fan, Xiaowei Liu, and Xiuying Liu helped supervise the field activities and collected the data. Zhenqi Chang, Jiangwei Qiu, Kai Wang, and Ling Fan conducted the laboratory work. Zhenqi Chang and Jiangwei Qiu organized and analyzed the data. Zhenqi Chang and Jiangwei Qiu wrote the original draft, and reviewed and edited the manuscript. Yuhong Zhang and Yi Zhao critically reviewed and revised the manuscript.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Acknowledgments
We thank all the participants and all the staff working for the China Northwest Natural Population Cohort: Ningxia Project (CNC-NX).
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These authors contributed equally to this work.