Cell communication & regulation
                                       - target of toxicants

                                        Cell communication

                             Signal transduction - target of toxicants

- Regulation of cell life / death (apoptosis)

      - metabolism

      - proliferation

      - differentiation

      - death (apoptosis)



- Signalling

      - "network" of general pathways

      - similar in all cells / different cell-specific effects



                                       Signalling disruption

- Consequences of signalling disruption

      - unwanted changes in proliferation/differentiation/apoptosis

-> cell transformation (carcinogenicity)

-> embryotoxicity

-> immunotoxicity

-> reproduction toxicity

.... other chronic types of toxicity

                                 Signal transduction - principles

: major processes
– protein-(de)phosphorylation (PKinases, PPases)

       - secondary messengers (cAMP / IP3, PIP2, DAG, Ca2+, AA)



1: Membrane receptors (G-protein, kinases)
-> PKA activation:     cAMP



2: Membrane receptors -> PLC / PKC activation
-> PKC activation:      IP3, PIP2, DAG, Ca2+, AA



3: Cytoplasmic (nuclear) receptors





Membrane receptors (PKs): G-proteins





1: Membrane receptors (PKs)

-> Adenylate cyclase -> cAMP -> PKA – modulation



                                 Mitogen Activated Protein Kinases
                                    (MAPK) – dependent effects



2: Membrane receptors
-> Phospholipase C:

      PIPs ->   DAG   -> PKC / arachidonic acid
               + IP3 -> Ca^2+



                                             Crosstalk

                                             Examples

ER-dependent estrogenicity (DDE) [other lecture]

      xenoestrogenicity, binding to ER + activation



ER-independent estrogenicity (PAHs)

      modulation of PKs/PPases: phosphorylation
-> activation of ER-dependent genes



AhR-dependent anti-estrogenicity, retinoid toxicity
modulation of estrogen / retinoid levels
[other lectures]

            AhR -> CYPs -> steroid-metabolism
     PAHs/POPs -> inhibition of Aromatase (CYP19)

PAHs significantly potentiate the effect
of 17b-estradiol (via increased phosporylation of ER)

                                             Examples

Microcystins -> liver tumor promotion

      inhibition of PPases [other lecture]



Immunotoxicity

      - (Cyano)bacterial lipopolysaccharides,
heavy metals ...
- Cholera toxin

          - AC: cAMP -> effects



PAHs -> Inhibition of Gap-junctions

      - Gap-junctional intercellular communication







                           Toxicity to membrane gradients and transport

- Semipermeability of membranes:
several key functions
    - cytoplasmic membrane:
         signalling, neural cells Na+/K+ gradient
    - mitochondrial membrane:

              electrone flow -> ATP synthesis
    - endoplasmatic reticulum
         Ca^2+ signalling



- Membrane fusion / transport
neurotransmitter release





Membrane gradient
disruption

Ion transfer ("ionofors") antibiotics
(K+, Ca2+, Mg2+)















                                 Ion Channel BLOCKERS / ACTIVATORS

Neuromodulators (drugs)               Neurotoxins (cyanobacterial)











Botulotoxin, Tetanotoxin
- proteases (!)
- selective inhibition of neutrotransmitter release (membrane vesicles)

Cytoskeleton as target of toxicants
microtubules / actin-myosin

Cytoskeleton – function
- intracellular transport
- cell replication and division (mitotic poisons)
- muscle movement
- membrane (vesicles) fusion

                               TOXINS: effects on (DE)POLYMERIZATION

                               TOXINS: effects on (DE)POLYMERIZATION