Formaldehyde and Brain Disorders: A Meta-Analysis and Bioinformatics Approach

Abstract

While there is significant investigation and investment in brain and neurodegenerative disease research, current understanding of the etiologies of illnesses like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and brain cancer remains limited. Environmental exposure to the pollutant formaldehyde, an emerging neurotoxin widely used in industry, is suspected to play a critical role in mediating these disorders, although findings are limited and inconsistent. Focusing on highly exposed groups, we performed a meta-analysis of human epidemiological studies of formaldehyde and neurodegenerative disease (N = 19) or brain tumors (N = 12). To assess the biological plausibility of observed associations, we then conducted a bioinformatics analysis using WikiPathways and the Comparative Toxicogenomics Database and identified candidate genes and pathways that may be related to these interactions. We reported the meta-relative risk (meta-RR) of ALS following high exposures to formaldehyde was increased by 78% (meta-RR = 1.78, 95% confidence interval, CI 1.20-2.65). Similarly, the meta-RR for brain cancer was increased by 71% (meta-RR = 1.71; 95% CI 1.07-2.73) among highly exposed individuals. Multiple sensitivity analyses did not reveal sources of heterogeneity or bias. Our bioinformatics analysis revealed that the oxidative stress genes superoxide dismutase (SOD1, SOD2) and the pro-inflammatory marker tumor necrosis factor (TNF) were identified as the top relevant genes, and the folate metabolism, vitamin B₁₂ metabolism, and the ALS pathways were highly affected by formaldehyde and related to the most brain diseases of interest. Further inquiry revealed the two metabolic pathways are also intimately tied with the formaldehyde cycle. Overall, our bioinformatics analysis supports the link of formaldehyde exposure to ALS or brain tumor reported from our meta-analysis. This new multifactorial approach enabled us to both interrogate the robustness of the epidemiological data and identify genes and pathways that may be involved in these interactions, ultimately lending strong evidence and potential biological plausibility for the association between formaldehyde exposure and brain disease.

Keywords: Amyotrophic lateral sclerosis; Brain tumor; Comparative toxicogenomics database; Human exposures; Neurodegenerative disease; WikiPathways.

Fig. 1

Study selection process for meta-analyses using PRISMA guidelines

Fig. 2

Forest plot of ALS meta-analysis using random effects model a and funnel plot of ALS studies b. Forest plot of brain tumor meta-analysis using random effects model c and funnel plot of brain tumor d

Fig. 3

Meta-relative risk of ALS mortality a and brain cancer mortality b by level of formaldehyde exposure using random effects model. The relative risks are indicated by the black lines in the middle, and the 95% confidence intervals are indicated by the upper and lower vertical black lines

Fig. 4

Summary of bioinformatics analysis approach. a. Definitions of numbers are explained in “Bioinformatics Approach” in the text. Close-up of the integrative network depicted in Supplementary Fig. 2, which contains the genes and pathways that were overlapping between two or more NDDs of interest b. The color of the nodes depicts the respective combinations of the different disease types. The turquoise gene SOD2 (in the middle) and the gray pathway Vitamin B₁₂ Metabolism (at the bottom), for example, are both observed to be affected in AD, ALS, brain tumor, PD, as well as in oNDD after formaldehyde exposure b

Fig. 5

Intersection of folate driven one-carbon pool, formaldehyde cycle, and vitamin B₁₂ pathway a. Potential mechanisms underlying formaldehyde-induced neurodegenerative disease and brain cancer b