env tox lecture 6: heavy metals in the environment

(final material)

gold king mine waste water spill in colorado (2015)

3 million gallons of waste containing cadmium, lead, copper, and other toxic metals was released into the river

major toxic metal pollution and outbreak in japan

• itai-itai disease (1912) → cadmium

• minamata disease (1956) → methylmercury

• niigata minamata disease (1964-1965) → methylmercury

sources of metals

• used widely in industries, agriculture, and domestics

• possible environmental exposure to human → geogenic, industrial, agricultural, pharmaceutical, domestic effluents, and atmospheric sources

• mines, foundries, and smelters are sources for occupational and environmental exposures

bioaccumulation and biomagnification of metals in the environment

• bioaccumulation: heavy metals (such as mercury) gradually build up within an individual organism because they are absorbed faster than they are eliminated

• biomagnification: heavy metal concentrations increase at higher levels of the food chain as predators consume contaminated prey

are metals non-biodegradable

no, they cannot be destroyed

toxic mechanisms of action of metals (general)

• functionally destroy enzymes and cellular structures

  • many metals are capable of inhibiting enzymes and structures

• mimicry → acting as mimics of essential metaks

  • essential metals are required for survival → toxic metals with similar chemical and physical properties with essential metals may compete and replace in biomolecules (e.g. Pb mimics calcium and accumulates in bones and brain)

• mediating the production of reactive oxygen species and free radicals

  • fenton radicals

what do transition metals (e.g. Fe, Cu) generate

since they can accept and donate electrons → they can generate reactive oxygen species (ROS)

why is generation of ROS so dangerous

it is one of the key toxic mechanisms of heavy metals → result in cell death, DNA damage (e.g. DNA adduct, DNA crosslink) and mutation

how do heavy metals damage proteins and interfere with their functions

1. protein dysfunction

• destruction of Fe-S clusters: heavy metals damage iron-sulfur clusters that enzymes need to function

• binding to cysteine: heavy metals bind to sulfur-containing groups in proteins, changing their structure and making them inactive

• ROS production: reactive oxygen species can indirectly damage proteins through oxidation

2. replacement of essential metals

• catalytic metal replacement: toxic metals (e.g., Pb or Cd) replace essential metals (e.g., Zn) in enzymes, disrupting their activity

• structural metal replacement: toxic metals replace metals that maintain a protein's shape, causing structural changes

oxygen is a good molecule for doing what

accepting electrons → O2 + 4e - + 4H+ = 2 H2O

generation of ROS and fenton chemistry

• oxygen = final electron acceptor → O2 has a unique property in chemical reactivity

  • if oxygen receives an electron one by one, it generates ROS

  • transition metals also catalyze the reaction to generate ROS

fenton reaction step-by-step

oxygen (O₂) accepts electrons one at a time, forming superoxide (O₂•⁻) → hydrogen peroxide (H₂O₂) → hydroxyl radical (•OH) → water (H₂O)

• iron overload: Fe²⁺ reacts with H₂O₂ through the Fenton reaction, producing harmful hydroxyl radicals (•OH) that damage DNA, proteins, and lipids

• iron deficiency: causes anemia due to insufficient hemoglobin production

natural sources of ROS in the cell