Associations between cadmium exposure and cognition-related gene methylation of workers in a Guangxi metal smelter

Background  Several studies have shown that cadmium exposure is related to impaired cognitive function, but there are limited studies on the association between occupational cadmium exposure and the methylation levels of cognitive-related genes.

Objective  This study aims to determine the methylation levels of cognition-related genes klotho (KL), brain-derived neurotrophic factor (BDNF), and amyloid protein precursor (APP) of workers after exposure to heavy metal cadmium, and explore the relationships between cadmium exposure and the methylation of the three genes.

Methods  The workers of a metal smelter in Guangxi who participated in 2017 an occupational physical examination were selected as study subjects and were asked to complete a questionnaire and donate blood and urine samples. The concentration of urinary cadmium (UCd) was determined by atomic absorption spectrometry, and adjusted by urinary creatinine. According to the distribution of the adjusted UCd (P₂₅, P₂₅-P₇₅, >P₇₅), the study subjects were divided into low, medium, and high exposure groups. Workers in each exposure group were stratified according to age and gender, and 150 samples were randomly selected from each exposure group by frequency matching method. Multiplex PCR combined with MethylTarget technology was employed to detect the methylation rates of APP, BDNF, and KL genes. Analysis of variance and Mann-Whitney U test were used to test the differences in the methylation levels and CpG sites of the three genes among the three groups. Restricted cubic spline (RCS) analysis was used to evaluate the exposure-effect relationship between urinary cadmium levels and gene methylation rates.

Results  A total of 450 workers were included in final analysis, of which 377 (83.78%) were male, with a mean age of (38.88±6.87) years, and an average UCd level of 2.73 (1.04, 5.75) μg·g^-1. The average methylation rates of APP, BDNF, and KL genes were (1.52±0.34)%, (4.55±1.08)%, and (2.34±0.39)%, respectively. The methylation rates of APP gene 04 segment, KL gene, and KL gene 02 segment were different among the three exposure groups (P < 0.05). The methylation rate of APP gene 04 segment in the medium exposure group was lower than that in the low exposure group (P < 0.05); the methylation rates of KL gene and its 02 segment in the medium and high exposure groups were lower than those in the low exposure group (P < 0.05). The restricted cubic spline analysis results showed that UCd level (after lg conversion) was negatively and linearly correlated with KL gene methylation rate (P=0.035), namely KL gene methylation rate decreased with elevated UCd level.

Conclusion  Cadmium exposure may be related to lower methylation rates of KL and APP genes, and UCd level is negatively correlated with the methylation rate of KL gene.