Detrimental health relationship between blood lead and cadmium and the red blood cell folate level

In this study of the US general population, the most remarkable finding was that serum lead and cadmium levels both had an adverse relationship with RBC folate levels. The association became stronger when the highest tertile group was compared with the lowest tertile group. To the best of our knowledge, our research is the first report investigating the relationship between cadmium levels and body folate status.

After reviewing the published articles, a few studies explored the association between lead or cadmium and folate. In animal model, folic acid supplementation seemed to have potentially protective effects against lead exposure in rat pups12. In a multicenter prospective Korean study, containing 2171 participants, serum folate levels in pregnant women were reversely associated with blood cadmium concentrations during late pregnancy13. Additionally, two small-scale studies reported that higher blood lead or cadmium levels might be associated with higher levels of serum homocysteine14,15. In a cohort with 259 participants, Pollack et al. found that in healthy, premenopausal women, blood lead and cadmium were correlated with increased levels of homocysteine, but this correlation was not strong after adjustment for corresponding confounding factors in cadmium group. Meanwhile, it was also not significant among those consuming 75th percentile of vitamin B6, vitamin B12, and folate. A Chinese-population-based study, containing 159 individuals, indicated that increasing blood lead and cadmium levels could raise the probability of a surge in homocysteine ​​levels. Although the relationship between lead and cadmium and homocysteine ​​was not robustly proven, there was still a positive trend. Many research studies have illustrated that homocysteine ​​levels were inversely related to serum folate16,17,18. In one systemic study, Ledda et al. found a similar result, showing that exposure to heavy metal, including lead and cadmium, is correlated with homocysteine ​​levels or folate serum concentrations9. Besides, the role of red cell folate in presenting an individual’s folate status has been well established8. All the data mentioned above are consistent with our findings. Unfortunately, the populations of the studies mentioned above were all too narrow to apply their results to the general population. Our investigation provided more general and large-scale evidence on this issue.

Cadmium has been proven to cause numerous adverse effects in humans via several pathways, including increased oxidative stress, impairment of the antioxidant response, enzyme inactivation, and multiple organ damage3. However, the mechanism between cadmium and folate status was unclear, and we tried to propose several possible hypotheses for it. First of all, cadmium was found to be absorbed via metal transporters in the intestinal, accumulating in the intestinal as cadmium exposure increased19, and rising animal studies found that cadmium would cause gut microbiome damage20,21,22. On the other hand, folate is primarily absorbed from the diet through the intestinal tract, and oxidative stress may interfere with the gut microbiome, resulting in folate deficiency23. They implied that cadmium accumulation in the gut might cause gut microbiota damage via ROS generation and increased oxidative stress, consequently, resulting in folate malabsorption. Second, Cd2+ was a predominant and competitive inhibitor of the enzyme24, and it could bind to numerus protein with the sulfhydryl group(-SH), leading to protein inactivation. Cadmium might interfere with the enzymes of the folate cycle, and it needs more studies to investigate the details. Third, it was well recognized that several heavy metals exert their toxicity through similar pathways. As for epigenetic effect, cadmium and arsenic (As) were both correlated with DNA methylation, and specific histone modification marks25,26,27,28. Abuawad et al. summarized the important relationship between one-carbon metabolism and arsenic methylation. Folate, as a crucial factor in one-carbon metabolism, has been proven to improve arsenic methylation capacity and to further promote arsenic elimination29,30. Although the mechanism of the elimination of cadmium was unclear, it might have had a similar pathway between one-carbon metabolism and cadmium. Finally, cadmium has been proven to be carcinogenic, and it could affect several transcription factors, such as activator protein 1 (AP-1), nuclear factor-kappa B (NF-κB), and p53. Hence, uncontrolled cell growth and division would happen due to a failure in the control of the expression of protective genes31. It might increase the requirement for folate due to abnormally increasing cell proliferation, and this hypothesis requires more research to confirm it.

Several potential limitations should be considered for our study. First, the NHANHES database is a cross-sectional study. Consequently, a causal relationship between cadmium levels and folate status could not be determined only according to this one-off health check-up program, instead of to long-standing observation study. Second, the intake of folate was not analyzed in our study. Although the dietary questionnaire used in the NHANES survey was documented, the 24-h dietary recall may not provide an indication of long-term diet nor an accurate representation of actual intake. Moreover, in spite of adjusting for multiple potentially confounding factors, there may have been other residual effects from unadjusted confounding factors of the correlation between lead and cadmium levels and folate status.

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