A highly persistent trace environmental contaminant and one of the most potent toxicants known is
dioxin (2,3,7,8-tetrachlorodibenzo-para-dioxin or TCDD).
TCDD induces a broad spectrum of
biological responses, including induction of
cytochrome P-450 1A1 (
CYP1A1), disruption of normal
hormone signaling pathways, reproductive and developmental defects, immunotoxicity, liver damage,
wasting syndrome, and
cancer. Its classification was upgraded from "possible human
carcinogen" (group 2B) to "human
carcinogen" (group 1) by the International Agency for Research on
Cancer (IARC) in 1997. Exposure to
TCDD may also cause changes in sex ratio, and
tumor promotion in other animals. Because of the growing public and scientific concern, toxicological studies have been initiated to analyze the short- and long-term effects of
dioxin.
TCDD brings about a wide variety of toxic and biochemical effects via
aryl hydrocarbon receptor (AhR)-mediated signaling pathways. Essential steps in this adaptive mechanism include AhR binding of
ligand in the cytoplasm of cells associated with two molecules of chaperone heatshock
protein (Hsp90) and AhR interactive protein, translocation of the receptor to the nucleus, dimerization with the
Ah receptor nuclear translocator, and binding of this heterodimeric
transcription factor (present in CYP1A) to
dioxin-responsive elements upstream of promoters that regulate the expression of genes involved in
xenobiotic metabolism.