A challenge to understand the adverse effects of welding fume exposure is the complex nature of environmental and behavioral influences. Metabolic profiles are greatly affected by diet, smoking behavior, medical history, or even time 
. Kuo et al.
recruited non-smoking, non-alcohol drinking welders for a metabolomic study, but intra-subject variation was not considered 
. Here, we excluded smoking or diabetic boilermakers to reduce such confounding effects. A self-controlled design eliminated intra-subject variation, and a two-stage design avoided chance findings in our limited sample size.
The main finding of this study is that unsaturated fatty acids are consistently reduced by respirable welding fume exposure, with a significant negative exposure-response relationship. To date, many studies have investigated the beneficial effects of EPA and DHA in neural function 
, tumor suppression 
, cardiovascular event risk reduction 
, diabetes mellitus 
, anti-inflammatory activity 
, and blood lipid reduction 
. Although the roles of DPA have not yet been systematically examined because of the lack of available pure DPA, there is some evidence that DPA has stronger beneficial health effects than EPA and DHA in vitro
. We also detected a global metabolite change, which may be explained by diet during work shift, circadian variation 
, or PM2.5
Surprisingly, the functional network built from unsaturated fatty acids includes 24 genes that showed very intense biological functions related to various diseases, including those involving endocrine system diseases, respiratory diseases, neoplasms, cardiovascular diseases, and lipid metabolism disorders. Intracellular EPA activates peroxisome proliferator-activated receptors (PPARs) 
, which are implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, and cancer (RefSeq, Jul 2008). EPA also inhibits COX-1/COX-2
, which encode proteins that may promote cell proliferation during tumor progression (RefSeq, Sep 2012). DPA activates RXRG
, a member of the retinoid X receptor family that is involved in mediating the anti-proliferative effects of retinoic acid and is down-regulated in several types of human cancers, including lung cancer 
; DPA also activates cysteine-aspartic acid protease (Caspase) family members, which are involved in cancer cell apoptosis 
. The functional network analysis strengthens the hypothesis that the decline of unsaturated fatty acids is a potential mediator of multiple health disorders in boilermakers.
Previous studies demonstrate the association of welding fume exposure on decline of heart rate variability (HRV), an important indicator of cardiovascular disease morbidity 
. Interestingly, several recent studies show that supplementation of EPA and DPA benefit HRV in healthy adults, cardiovascular disease risk populations, or in cardiovascular disease patients 
. These results strongly indicate that the metabolic change of unsaturated fatty acids is an important biological mediator of exposure-related decreases in HRV.
Despite these findings, we recognize limitations to the study: we lack metabolite information from a non-welding day, and p values were not small enough to pass multiple comparison correction due to small sample size. However, pathway-based analysis showed an acceptable FDR (q<0.2), and the two-stage, self-controlled study design helped reduce chance findings.
In summary, this exploratory study shows evidence that high dose exposure of metal welding fumes decreases unsaturated fatty acids with an exposure-response relationship. The metabolic change in unsaturated fatty acids is a potential biomarker for exposure-related health disorders for which further studies are encouraged.