Interesting article in PLoS Biology about how chemically diverse toxicants target common pathways in the human body..

[Guest guest]

The paragraphs that I am posting here are an introduction that I had

not seen before to a really interesting paper in last February's PLoS

Biology. (the second link)

From what I have read, the pathways involved are also targeted by

(numerous) mycotoxins. The is an important paper.

.. . . . . . . .

Diverse Toxic Chemicals Disrupt Cell Function through a Common Path

http://biology.plosjournals.org/perlserv/?request=get-document & doi=10.1371%2Fjou\

rnal.pbio.0050041

Liza Gross

Commentary on:

Chemically Diverse Toxicants Converge on Fyn and c-Cbl to Disrupt

Precursor Cell Function (this is the actual paper being discussed,

worth reading)

http://biology.plosjournals.org/perlserv/?request=get-document & doi=10.1371%2Fjou\

rnal.pbio.0050035

Zaibo Li, Tiefei Dong, Pröschel, Mark Noble

When technological advances in the 1930s provided the means to

synthesize chemicals from petroleum and natural gas, the petrochemical

industry ramped up production of diverse species of novel compounds

without testing their safety. By 1940, a billion pounds of synthetic

petrochemicals were produced each year. Of the more than 38 million

chemicals reported in the scientific literature, 80,000 to 150,000 are

used in commercial production. A report from the Harvard School of

Public Health, published in The Lancet last November, warned that " a

substantial number " of these chemicals—which show up in everything

from cosmetics and textiles to rubber ducks and pacifiers—may be

capable of damaging the human brain, particularly during development.

Any hope of developing large-scale toxicological screening methods

depends on determining whether diverse toxic chemicals act through

common pathways. Though few such mechanistic pathways have been

identified so far, diverse toxicants can make cells more oxidized.

Oxidative stress results when harmful free radicals or other

" pro-oxidants " overwhelm the cell's anti-oxidant machinery, disrupting

normal function. But changes in oxidative state also control multiple

normal cellular functions, raising the possibility that toxicants

might also affect these normal processes by making cells more

oxidized. The significance of these oxidative effects—particularly,

whether they might constitute a unifying principle of toxicity—has

been unclear, however, in part because different toxicants increase

oxidation through different mechanisms, and because the relationship

between their harmful effects and their effects on oxidative status

are not well understood.

In a new study, Chemically Diverse Toxicants Converge on Fyn and c-Cbl

to Disrupt Precursor Cell Function

http://biology.plosjournals.org/perlserv/?request=get-document & doi=10.1371%2Fjou\

rnal.pbio.0050035

Zaibo Li and colleagues provide evidence for a novel general principle

of toxicology by showing that toxicants with different chemical

properties converge on activation of the same regulatory pathway with

similar results. The authors monitored the response of progenitor

cells isolated from the developing central nervous system to two metal

toxicants, methylmercury and lead, and an organochlorine herbicide,

paraquat. They found that each toxicant disrupted normal cell function

by making cells more oxidized, and setting off a chain reaction that

ultimately inhibited signaling pathways required for cell division.

Significantly, these effects occurred at environmentally relevant,

low-level exposures for lead and methylmercury.

When mercury emitted from coal-fired power plants settles in wetlands

or bodies of water, bacteria living in sediments transforms it into

methylmercury—which is particularly toxic to the developing brain.

(Photo: National Parks Service)

The authors studied the chemicals' effects in cells called

oligodendrocyte precursor cells (OPCs), which give rise to the

myelin-forming oligodendrocytes of the central nervous system. OPCs

are particularly suited to toxicant screening, the authors explain,

because of their sensitivity to small changes in oxidative (or redox)

state, which determines whether the cells divide or differentiate.

(When a cell or molecule undergoes an increase in oxidation state, it

is oxidized; when it undergoes a decrease, it is reduced.) Previous

studies by these authors have shown that redox changes in the range of

15%–20% can greatly alter responsiveness to extracellular signaling

molecules, and that such changes may help regulate the normal

development of these cells. For example, OPCs that are slightly more

reduced undergo extensive cell division when grown in the presence of

the cell-division stimulator platelet-derived growth factor (PDGF). In

contrast, OPCs that are more oxidized, within normal physiological

redox ranges, undergo differentiation.

Exposing OPCs to low levels of methylmercury, similar to those found

in the environment, made the cells 20% more oxidized—and inhibited

cell division (as indicated by the number of cells in the synthesis

phase of the cell cycle). For example, methylmercury levels as low as

20 nM (equivalent to four parts per billion) caused a 25% drop in the

percentage of cells that underwent cell division in response to PDGF

stimulation. Each year, methylmercury is detected in the cord blood of

600,000 infants at levels equal to or above those producing these

effects.

Reduced cell division, the authors show, resulted from disrupted PDGF

signaling: proteins normally activated by PDGF signaling (for example,

Erk1/2 and Akt) were inhibited by exposure to methylmercury (analyzed

at the still sublethal exposure level of 30 nM), which also reduced

the abundance of PDGF's receptor, PDGFRα. To find out which part of

the PDGF pathway methylmercury targeted, the authors exposed OPCs to

neurotrophin-3 (NT-3), a signaling molecule that also activates

Erk1/2, a downstream component of multiple signaling pathways. Since

neither Erk1/2 nor TrkC, the NT-3 receptor, were affected by the

toxicant, they concluded that it must act upstream of this component.

These results suggested that methylmercury might activate an

enzyme—the ubiquitin ligase c-Cbl—that targets PDGFRα for degradation.

This possibility seemed especially attractive since c-Cbl doesn't

target TrkC and is activated by Fyn, an enzyme previously shown to be

activated by oxidative stress. And that's what the authors found:

methylmercury activates Fyn, which then activates c-Cbl, which in turn

reduces PDGFRα levels by targeting the receptor for degradation.

Methylmercury's effects could be blocked by suppressing Fyn or c-Cbl

with appropriate molecular constructs, by overexpressing PDGFRα, or by

inhibiting Fyn activation with the pharmacological blocker PP1.

The pro-oxidants lead and paraquat (which differ chemically both from

each other and from methylmercury) produced the same effects as

methylmercury on OPCs and on the PDGF pathway (about 20% increased

oxidation, Fyn and c-Cbl activation, Erk1/2 suppression, and reduced

PDGFRα levels). Fyn activation, and all its observed consequences,

could be blocked by neutralizing the redox changes caused by all three

toxicants with the anti-oxidant drug N-acetyl-L-cysteine. Additional

experiments showed that the toxicants caused similar reductions in two

other targets of c-Cbl (c-Met and EGFR), further bolstering the

hypothesis that these diverse toxicants converge on the same pathway

to disrupt cell function.

But could these results predict the effects of toxicant exposure in

developing animals? To find out, the authors exposed mice to

methylmercury from conception to 21 days after birth (by providing the

chemical to mothers in their drinking water). As predicted by the OPC

experiments, the mice had reduced levels of the two c-Cbl targets,

PDGFRα. and EGFR, in the tissue of three brain regions. In contrast,

TrkC levels, which c-Cbl does not target, were unaffected—just as

predicted by the in vitro experiments. Methylmercury produced these

effects, and also reduced OPC division in vivo, at doses 75%–90% below

those previously considered a low dose for mice.

Sixty years after the dawn of the petrochemical era, health effects

are known for just a fraction of its bounty. And many of these

chemicals—including lead, mercury, and a long list of

organochlorines—now even contaminate human breast milk. While this

study demonstrates that even low levels of diverse toxicants can

disrupt the developing nervous system, it also provides a framework

for analyzing a wide range of toxic chemicals based on their

pro-oxidant activity. In so doing, it provides a strategy for quickly

assessing the physiological effects of many of the toxic chemicals

pervading our environment—the first step in identifying agents that

might protect the most vulnerable among us.