Metal exposure has been associated with risk of various
cardio-metabolic
disorders, and investigation on the association between exposure to
multiple metals and metabolic responses may reveal novel clues to
the underlying mechanisms. Based on a metabolome-wide association
study of 17 plasma metals with untargeted metabolomic profiling of
189 serum metabolites among 1992 participants within the Dongfeng–Tongji
cohort, we replicated two metal-associated pathways, linoleic acid
metabolism and aminoacyl-tRNA biosynthesis, with novel metal associations
(false discovery rate, FDR < 0.05), and we also identified two
novel pathways, including biosynthesis of unsaturated fatty acids
and alpha-linolenic acid metabolism, as associated with metal exposure
(FDR < 0.05). Moreover, two-way orthogonal partial least-squares
analysis showed that five metabolites, including aspartylphenylalanine,
free fatty acid 14:1, uridine, carnitine C14:2, and LPC 18:2, contributed
most to the joint covariation between the two data matrices (12.3%,
8.3%, 8.0%, 7.4%, and 7.3%, respectively). Further BKMR analysis showed
significant positive joint associations of plasma Al, As, Ba, and
Zn with aspartylphenylalanine and of plasma Ba, Co, Mn, and Pb with
carnitine C14:2, when all the metals were at the 55th percentiles
or above, compared with the median. We also found significant interactions
between As and Ba in the association with aspartylphenylalanine (P for interaction = 0.048) and between Ba and Pb in the
association with carnitine C14:2 (P for interaction
< 0.001). Together, these findings may provide new insights into
the mechanisms underlying the adverse health effects induced by metal
exposure.