Cadmium (Cd) is a toxic metal and a cumulative environmental pollutant. The main route of Cd exposure is diet and cigarette smoke. Cd is associated with many human health problems, including cancer, heart disease and diabetes mellitus (DM). DM and diabetes-related kidney disease are serious, world-wide health problems. Although there is no direct evidence linking Cd to DM, Cd exposure alters blood glucose levels and potentiates diabetic nephropathy. The insulin/insulin-like growth factor signaling (IIS) pathway regulates multiple biological functions including glucose metabolism and longevity. C. elegans, which has an IIS pathway homologous to that of mammals, was used to investigate mechanistic links among Cd, transcription, and insulin signaling. The focus of this investigation was the C. elegans Cd-responsive gene
cdr-1, whose transcription is up-regulated almost 800-fold exclusively by Cd in intestinal cells. Regulatory factors and pathways that control
cdr-1 transcription were identified by using an integrated transgenic strain of C. elegans containing GFP under the control of the 5'-regulatory region of
cdr-1. In a candidate screen, genes involved in various stress response pathways were tested for their potential role in controlling
cdr-1 expression. Genes were knocked out either by genetic crosses to known loss-of-function mutants or by RNAi. Changes in
cdr-1 transcription were determined by measuring GFP expression or by qRT-PCR. The expression of
cdr-1, in both the absence and presence of Cd (100 mM, 5 h) was suppressed when genes in the IIS pathway;
daf-2,
age-1,
daf-18,
pdk-1,
akt-1,
akt-2,
sgk-1 and
daf-16; were knocked down. Knock down of IIS pathway-related genes;
skn-1,
hsf-1,
pha-4,
pop-1,
lin-14,
tor-2,
ras-1, and
wnk-1; also inhibited Cd-inducible
cdr-1 expression. Furthermore, knock down of
pdk-1,
hsf-1 and
skn-1 significantly suppressed Cd-induced
cdr-1 transcript level indicating that these three genes play key roles in regulating Cd-inducible
cdr-1 expression. These results suggest that the IIS pathway mediates Cd-inducible
cdr-1 transcription. In addition, they support a model where Cd exposure could induce elevated blood glucose levels by directly affecting the IIS pathway. The mechanism by-which Cd activates the IIS pathway is currently being investigated.