Carcinogenic Metals

International Agency for Research on Cancer (IARC) classification

Group 1: Confirmed human carcinogensAs, Be, Cd, Cr(VI), Ni

Group 2B: Possibly carcinogenic to humansCo

A model summarizing the major mechanisms involved in Cd carcinogenesis

Categories of Genes Induced by Cd

1. Immediate early response genes (IEGs)

2. Stress response genes

3. Transcription factors

4. Translation factors

5. Miscellaneous genes

Some of the genes induced by cadmium

Translational Genes

Translation initiation factor 3Translation elongation factor 1δ

Transcription Factors

MTF1USFNFκBNrf2

FAS-initiated apoptotic cascade

Proposed pathways for ROS in Cd toxicology and carcinogenesis following acute and chronic exposures

Structure of residues 19 – 44 of β-Catenin phosphorylated on Ser 33 and 37

Oncogenic mutations in codon 33:

TCT → TAT Ser → TyrTCT → TTT Ser → Phe

The α-cadherin/β-Catenin complex connects to the actin via α-Catenin and some actin-binding proteins, forming a rigid cytoskeleton. When cells are exposed to Wnt signal, cell surface receptors are activated and block β-Catenin phosphorylation and its subsequent ubiquitination. β-Catenin is thus diverted from the proteasome, and it accumulates and enters the nucleus, where it finds a partner of the TCF/LEF family. Together, they activate new gene expression programs.

Role of β-catenin in Wnt signaling pathway

Proteasome: protein complex that degrades tagged proteins

Chromium uptake, intracellular chemistry and damage

Chromium-DNA Adducts

BO

O

OPO

O

O

BO

OP-O

O

O

Cr

L

L

LL

L

NH

N

N

O

NH2N

O

O

OP

O O

O

Cr

L

L L

L

BO

O

OPO

O

O

BO

OP-O

O

O

CrOH2

OH

Binary Adducts

phosphotriester (non mutagenic) intramolecular cross link (mutagenic)

Ternary Adducts

Cys adduct (mutagenic)

O

S

NH2

O

BO

O

OPO

O

O

BO

OP-O

O

O

Cr

OH2

OH2

ascorbate adduct (mutagenic)

O

OH

O

O

OH

HOH2O

HO

Pathways leading to observation of single-strand DNA breaks (SSB) and double-strand DNA breaks (DSB)