bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2023,
Volume and Issue:
unknown
Published: Feb. 3, 2023
Abstract
Next
generation
risk
assessment
of
chemicals
revolves
around
the
use
mechanistic
information
without
animal
experimentation.
In
this
regard,
toxicogenomics
has
proven
to
be
a
useful
tool
elucidate
underlying
mechanisms
adverse
effects
xenobiotics.
present
study,
two
widely
used
human
in
vitro
hepatocyte
culture
systems,
namely
primary
hepatocytes
(PHH)
and
hepatoma
HepaRG
cells,
were
exposed
liver
toxicants
known
induce
cholestasis,
steatosis
or
necrosis.
Benchmark
concentration-response
modelling
was
applied
transcriptomics
gene
co-expression
networks
(modules)
order
derive
benchmark
concentrations
(BMCs)
gain
insight
into
hepatotoxic
effects.
BMCs
derived
by
modules
recapitulated
individual
genes.
Although
PHH
cells
showed
overlap
deregulated
genes
toxicants,
demonstrated
higher
responsiveness,
based
on
lower
co-regulated
modules.
Such
can
as
point
departure
(PoD)
for
assessing
module-associated
cellular
(stress)
pathways/processes.
This
approach
identified
clear
PoDs
C
max
levels
tested
drugs,
while
cosmetics
ingredients
10-100
fold
than
estimated
plasma
concentrations.
could
serve
next
practice
identify
early
responsive
at
low
BMCs,
that
linked
key
events
outcome
pathways.
turn,
assist
delineating
potential
hazards
new
test
using
systems
when
are
paired
with
chemical
exposure
assessment.
Toxins,
Journal Year:
2023,
Volume and Issue:
15(4), P. 255 - 255
Published: March 31, 2023
Aflatoxin
B1
(AFB1)
and
aflatoxin
M1
(AFM1)
are
universally
found
as
environmental
pollutants.
AFB1
AFM1
group
1
human
carcinogens.
Previous
sufficient
toxicological
data
show
that
they
pose
a
health
risk.
The
intestine
is
vital
for
resistance
to
foreign
enterotoxic
mechanisms
of
have
not
been
clarified
at
the
metabolism
levels.
In
present
study,
cytotoxicity
evaluations
were
conducted
in
NCM
460
cells
by
obtaining
their
half-maximal
inhibitory
concentration
(IC50).
toxic
effects
2.5
μM
determined
comprehensive
metabolomics
lipidomics
analyses
on
NCM460
cells.
A
combination
induced
more
extensive
metabolic
disturbances
than
either
alone.
exerted
greater
effect
group.
Metabolomics
pathway
analysis
showed
glycerophospholipid
metabolism,
fatty
acid
degradation,
propanoate
dominant
pathways
interfered
with
AFB1,
AFM1,
AFB1+AFM1.
Those
results
suggest
attention
should
be
paid
lipid
after
exposure.
Further,
was
used
explore
fluctuation
metabolism.
34
specific
lipids
differentially
mainly
attributed
14
species,
which
cardiolipin
(CL)
triacylglycerol
(TAG)
accounted
41%.
affected
CL
phosphatidylglycerol,
approximately
70%
based
11
lipids,
while
30
AFB1+AFM1,
reflected
TAG
up
77%.
This
research
first
time
disorder
caused
one
main
causes
contributing
enterotoxicity,
could
provide
new
insights
into
animals
humans.
Chemical Research in Toxicology,
Journal Year:
2024,
Volume and Issue:
37(4), P. 658 - 668
Published: March 25, 2024
Exposure
to
triclocarban
(TCC),
a
commonly
used
antibacterial
agent,
has
been
shown
induce
significant
intestine
injuries
and
colonic
inflammation
in
mice.
However,
the
detailed
mechanisms
by
which
TCC
exposure
triggered
enterotoxicity
remain
largely
unclear.
Herein,
intestinal
toxicity
effects
of
long-term
chronic
were
investigated
using
combination
histopathological
assessments,
metagenomics,
targeted
metabolomics,
biological
assays.
Mechanically,
caused
induction
aryl
hydrocarbon
receptor
(AhR)
its
transcriptional
target
cytochrome
P4501A1
(Cyp1a1)
leading
dysfunction
gut
barrier
disruption
microbial
community.
A
large
number
lipopolysaccharides
(LPS)
are
released
from
lumen
into
blood
circulation
owing
markedly
increased
permeability
leakage.
Consequently,
toll-like
receptor-4
(TLR4)
NF-κB
signaling
pathways
activated
high
levels
LPS.
Simultaneously,
classic
macrophage
phenotypes
switched
TCC,
with
marked
upregulation
M1
downregulation
M2
that
was
accompanied
striking
proinflammatory
factors
such
as
Il-1β,
Il-6,
Il-17,
Tnf-α
lamina
propria.
These
findings
provide
new
evidence
for
TCC-induced
enterotoxicity.
ALTEX,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Jan. 1, 2024
Next
generation
risk
assessment
of
chemicals
revolves
around
the
use
mechanistic
information
without
animal
experimentation.
In
this
regard,
toxicogenomics
has
proven
to
be
a
useful
tool
elucidate
underlying
mechanisms
adverse
effects
xenobiotics.
present
study,
two
widely
used
human
in
vitro
hepatocyte
culture
systems,
namely
primary
hepatocytes
(PHH)
and
hepatoma
HepaRG
cells,
were
exposed
liver
toxicants
known
induce
cholestasis,
steatosis
or
necrosis.
Benchmark
concentration-response
modelling
was
applied
transcriptomics
gene
co-expression
networks
(modules)
derive
benchmark
concentrations
(BMCs)
gain
insight
into
hepatotoxic
effects.
BMCs
derived
by
modules
recapitulated
individual
genes.
Although
PHH
cells
showed
overlap
deregulated
genes
toxicants,
demonstrated
higher
responsiveness,
based
on
lower
co-regulated
modules.
Such
can
as
point
departure
(tPOD)
for
assessing
module-associated
cellular
(stress)
pathways/processes.
This
approach
identified
clear
tPODs
maximum
systemic
concentration
(Cmax)
levels
tested
drugs,
while
cosmetics
ingredients
10-100-fold
than
estimated
plasma
concentrations.
could
serve
next
practice
identify
early
responsive
at
low
BMCs,
that
linked
key
events
outcome
pathways.
turn,
assist
delineating
potential
hazards
new
test
using
systems
when
are
paired
with
chemical
exposure
assessment.
Plain
language
summaryRisk
traditionally
been
focused
experiments.
contrast,
uses
biological
obtained
from
experiments
cell
models
animals
hazards.
Since
is
main
target
organ
toxicity,
many
(hepatocyte)
have
developed
hazard
models,
HepaRG,
toxic
chemicals.
Biological
changes
expression
measured
range
which
response
perturbed
modelling.
Genes
belonging
same
process
joined
an
average
process.
animal-free
related
expected
