Abstract
Background: Association of particulate matter with adverse health effects has been established in epidemiological studies and animal experiments. Epidemiological studies are difficult to undertake while animal studies are impractical for high-throughput toxicity testing. The ease and rapidity of in vitro tests emphasizes their potential for use in risk assessment of chemicals and particles. We examined the association between in vitro and in vivo responses to ambient particles, to determine the potential of cell-based assays as standalone toxicity screening tools. Methods: Assays of cytotoxicity and key inflammatory mediators were applied to determine the in vitro biological potency of a panel of urban and mineral particles in J774A.1 macrophages and A549 lung epithelial cells. The particles were also screened for the presence of AhR agonists using the Ah receptor-dependent gene induction assay and for endotoxin using the Limulus amebocyte lysate assay. A subset of the particles with a contrasting in vitro toxicity profile was delivered intratracheally in BALB/c mice to assess their in vivo biological potency. Results from various bioassays were combined within the in vitro and in vivo models. The combined potency measures were examined for associations. Results: Overall, J774A.1 cells were more sensitive to particle effects than A549 cells. Whereas the combined cytotoxicity estimates were highly correlated between the two cell lines, the combined in vitro inflammatory potency estimates were not, emphasizing functional differences of the two cell types. Secretion of inflammatory markers by J774A.1 cells was correlated with AhR ligand binding profile and endotoxin levels of particles. Particle instillation led to an acute toxicity response in BALB/c mice, with neutrophilia and release of inflammatory mediators. While the combined toxicity estimates were not correlated between in vitro and in vivo models, the combined inflammatory and integrated potency estimates (toxicity and inflammation) approached the threshold for significance (p = 0.052) in a correlation within in vitro and in vivo models, with a ranking of fine particle (DWR1), minerals (TiO2, CRI) and coarse particles (SRM-, EHC-type) from low to high potency. Conclusion: Integration of in vitro endpoints shows promise in determining adverse outcomes of particle exposures in vivo. The devised data reduction and computational approach will prove useful in the development of models for assessment of hazard potential of particles; however, distinct models may be needed for particles of different type, such as urban particles vs. mineral particles, nanomaterials.
| Original language | English (US) |
|---|---|
| Article number | 41 |
| Journal | Particle and Fibre Toxicology |
| Volume | 13 |
| Issue number | 1 |
| DOIs | |
| State | Published - 2016 |
Fingerprint
Keywords
- Aryl hydrocarbon receptor
- Correlation
- Cytotoxicity
- Endotoxin
- In vitro
- In vivo
- Inflammation
- Particulate matter
ASJC Scopus subject areas
- Toxicology
- Health, Toxicology and Mutagenesis
Cite this
Development of an integrated approach for comparison of in vitro and in vivo responses to particulate matter. / Breznan, Dalibor; Karthikeyan, Subramanian; Phaneuf, Marcelle; Kumarathasan, Prem; Cakmak, Sabit; Denison, Michael S.; Brook, Jeffrey R.; Vincent, Renaud.
In: Particle and Fibre Toxicology, Vol. 13, No. 1, 41, 2016.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Development of an integrated approach for comparison of in vitro and in vivo responses to particulate matter
AU - Breznan, Dalibor
AU - Karthikeyan, Subramanian
AU - Phaneuf, Marcelle
AU - Kumarathasan, Prem
AU - Cakmak, Sabit
AU - Denison, Michael S.
AU - Brook, Jeffrey R.
AU - Vincent, Renaud
PY - 2016
Y1 - 2016
N2 - Background: Association of particulate matter with adverse health effects has been established in epidemiological studies and animal experiments. Epidemiological studies are difficult to undertake while animal studies are impractical for high-throughput toxicity testing. The ease and rapidity of in vitro tests emphasizes their potential for use in risk assessment of chemicals and particles. We examined the association between in vitro and in vivo responses to ambient particles, to determine the potential of cell-based assays as standalone toxicity screening tools. Methods: Assays of cytotoxicity and key inflammatory mediators were applied to determine the in vitro biological potency of a panel of urban and mineral particles in J774A.1 macrophages and A549 lung epithelial cells. The particles were also screened for the presence of AhR agonists using the Ah receptor-dependent gene induction assay and for endotoxin using the Limulus amebocyte lysate assay. A subset of the particles with a contrasting in vitro toxicity profile was delivered intratracheally in BALB/c mice to assess their in vivo biological potency. Results from various bioassays were combined within the in vitro and in vivo models. The combined potency measures were examined for associations. Results: Overall, J774A.1 cells were more sensitive to particle effects than A549 cells. Whereas the combined cytotoxicity estimates were highly correlated between the two cell lines, the combined in vitro inflammatory potency estimates were not, emphasizing functional differences of the two cell types. Secretion of inflammatory markers by J774A.1 cells was correlated with AhR ligand binding profile and endotoxin levels of particles. Particle instillation led to an acute toxicity response in BALB/c mice, with neutrophilia and release of inflammatory mediators. While the combined toxicity estimates were not correlated between in vitro and in vivo models, the combined inflammatory and integrated potency estimates (toxicity and inflammation) approached the threshold for significance (p = 0.052) in a correlation within in vitro and in vivo models, with a ranking of fine particle (DWR1), minerals (TiO2, CRI) and coarse particles (SRM-, EHC-type) from low to high potency. Conclusion: Integration of in vitro endpoints shows promise in determining adverse outcomes of particle exposures in vivo. The devised data reduction and computational approach will prove useful in the development of models for assessment of hazard potential of particles; however, distinct models may be needed for particles of different type, such as urban particles vs. mineral particles, nanomaterials.
AB - Background: Association of particulate matter with adverse health effects has been established in epidemiological studies and animal experiments. Epidemiological studies are difficult to undertake while animal studies are impractical for high-throughput toxicity testing. The ease and rapidity of in vitro tests emphasizes their potential for use in risk assessment of chemicals and particles. We examined the association between in vitro and in vivo responses to ambient particles, to determine the potential of cell-based assays as standalone toxicity screening tools. Methods: Assays of cytotoxicity and key inflammatory mediators were applied to determine the in vitro biological potency of a panel of urban and mineral particles in J774A.1 macrophages and A549 lung epithelial cells. The particles were also screened for the presence of AhR agonists using the Ah receptor-dependent gene induction assay and for endotoxin using the Limulus amebocyte lysate assay. A subset of the particles with a contrasting in vitro toxicity profile was delivered intratracheally in BALB/c mice to assess their in vivo biological potency. Results from various bioassays were combined within the in vitro and in vivo models. The combined potency measures were examined for associations. Results: Overall, J774A.1 cells were more sensitive to particle effects than A549 cells. Whereas the combined cytotoxicity estimates were highly correlated between the two cell lines, the combined in vitro inflammatory potency estimates were not, emphasizing functional differences of the two cell types. Secretion of inflammatory markers by J774A.1 cells was correlated with AhR ligand binding profile and endotoxin levels of particles. Particle instillation led to an acute toxicity response in BALB/c mice, with neutrophilia and release of inflammatory mediators. While the combined toxicity estimates were not correlated between in vitro and in vivo models, the combined inflammatory and integrated potency estimates (toxicity and inflammation) approached the threshold for significance (p = 0.052) in a correlation within in vitro and in vivo models, with a ranking of fine particle (DWR1), minerals (TiO2, CRI) and coarse particles (SRM-, EHC-type) from low to high potency. Conclusion: Integration of in vitro endpoints shows promise in determining adverse outcomes of particle exposures in vivo. The devised data reduction and computational approach will prove useful in the development of models for assessment of hazard potential of particles; however, distinct models may be needed for particles of different type, such as urban particles vs. mineral particles, nanomaterials.
KW - Aryl hydrocarbon receptor
KW - Correlation
KW - Cytotoxicity
KW - Endotoxin
KW - In vitro
KW - In vivo
KW - Inflammation
KW - Particulate matter
UR - http://www.scopus.com/inward/record.url?scp=85007504242&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85007504242&partnerID=8YFLogxK
U2 - 10.1186/S12989-016-0152-6
DO - 10.1186/S12989-016-0152-6
M3 - Article
C2 - 27520027
AN - SCOPUS:85007504242
VL - 13
JO - Particle and Fibre Toxicology
JF - Particle and Fibre Toxicology
SN - 1743-8977
IS - 1
M1 - 41
ER -