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Article ; Online: Effects of inhaled tier-2 diesel engine exhaust on immunotoxicity in a rat model: A hazard identification study. Part II. Immunotoxicology.

Weatherly, Lisa M / Shane, Hillary L / Baur, Rachel / Lukomska, Ewa / McKinney, Walter / Roberts, Jenny R / Fedan, Jeffrey S / Anderson, Stacey E

Toxicology reports

2024 Volume 12, Page(s) 135–147

Abstract: Diesel exhaust (DE) is an air pollutant containing gaseous compounds and particulate matter. Diesel engines are common on gas extraction and oil sites, leading to complex DE exposure to a broad range of compounds through occupational settings. The US EPA ...

Abstract	Diesel exhaust (DE) is an air pollutant containing gaseous compounds and particulate matter. Diesel engines are common on gas extraction and oil sites, leading to complex DE exposure to a broad range of compounds through occupational settings. The US EPA concluded that short-term exposure to DE leads to allergic inflammatory disorders of the airways. To further evaluate the immunotoxicity of DE, the effects of whole-body inhalation of 0.2 and 1 mg/m
Language	English
Publishing date	2024-01-15
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	2805786-7
ISSN	2214-7500 ; 2214-7500
ISSN (online)	2214-7500
ISSN	2214-7500
DOI	10.1016/j.toxrep.2024.01.004
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Article ; Online: Systemic and immunotoxicity induced by topical application of perfluorohexane sulfonic acid (PFHxS) in a murine model.

Weatherly, Lisa M / Shane, Hillary L / Jackson, Laurel G / Lukomska, Ewa / Baur, Rachel / Cooper, Madison P / Anderson, Stacey E

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association

2024 Volume 186, Page(s) 114578

Abstract: Per- and polyfluoroalkyl substances (PFAS) are a large group of stable synthetic surfactants that are incorporated into numerous products for their water and oil resistance and have been associated with adverse health effects. The present study evaluated ...

Abstract	Per- and polyfluoroalkyl substances (PFAS) are a large group of stable synthetic surfactants that are incorporated into numerous products for their water and oil resistance and have been associated with adverse health effects. The present study evaluated the systemic and immunotoxicity of sub-chronic 28- or 10-day dermal exposure of PFHxS (0.625-5% or 15.63-125 mg/kg/dose) in a murine model. Elevated levels of PFHxS were detected in the serum and urine, suggesting that absorption is occurring through the dermal route. Liver weight (% body) significantly increased and spleen weight (% body) significantly decreased with PFHxS exposure, which was supported by histopathological changes. Additionally, PFHxS significantly reduced the humoral immune response and altered immune subsets in the spleen, suggesting immunosuppression. Gene expression changes were observed in the liver, skin, and spleen with genes involved in fatty acid metabolism, necrosis, and inflammation. Immune-cell phenotyping identified significant decreases in B-cells, NK cells, and CD11b
MeSH term(s)	Mice ; Animals ; Disease Models, Animal ; CD8-Positive T-Lymphocytes ; Sulfonic Acids/toxicity ; Fluorocarbons/analysis ; Alkanesulfonic Acids ; Environmental Pollutants
Chemical Substances	perfluorohexanesulfonic acid (355-46-4) ; Sulfonic Acids ; Fluorocarbons ; Alkanesulfonic Acids ; Environmental Pollutants
Language	English
Publishing date	2024-03-06
Publishing country	England
Document type	Journal Article
ZDB-ID	782617-5
ISSN	1873-6351 ; 0278-6915
ISSN (online)	1873-6351
ISSN	0278-6915
DOI	10.1016/j.fct.2024.114578
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Article ; Online: Exposure to the immunomodulatory chemical triclosan differentially impacts immune cell populations in the skin of haired (BALB/c) and hairless (SKH1) mice.

Baur, Rachel / Shane, Hillary L / Weatherly, Lisa M / Lukomska, Ewa / Kashon, Michael / Anderson, Stacey E

Toxicology reports

2022 Volume 9, Page(s) 1766–1776

Abstract: Workers across every occupational sector have the potential to be exposed to a wide variety of chemicals, and the skin is a primary route of exposure. Furthermore, exposure to certain chemicals has been linked to inflammatory and allergic diseases. Thus, ...

Abstract	Workers across every occupational sector have the potential to be exposed to a wide variety of chemicals, and the skin is a primary route of exposure. Furthermore, exposure to certain chemicals has been linked to inflammatory and allergic diseases. Thus, understanding the immune responses to chemical exposures on the skin and the potential for inflammation and sensitization is needed to improve worker safety and health. Responses in the skin microenvironment impact the potential for sensitization; these responses may include proinflammatory cytokines, inflammasome activation, barrier integrity, skin microbiota, and the presence of immune cells. Selection of specific mouse strains to evaluate skin effects, such as haired (BALB/c) or hairless (SKH1) mice, varies dependent on experimental design and needs of a study. However, dermal chemical exposure may impact reactions in the skin differently depending on the strain of mouse. Additionally, there is a need for established methods to evaluate immune responses in the skin. In this study, exposure to the immunomodulatory chemical triclosan was evaluated in two mouse models using immunophenotyping by flow cytometry and gene expression analysis. BALB/c mice exposed to triclosan (2%) had a higher number and frequency of neutrophils and lower number and frequency of dendritic cells in the skin compared to controls. Although these changes were not observed in SKH1 mice, SKH1 mice exposed to triclosan had a higher number and frequency of type 2 innate lymphoid cells in the skin. Taken together, these results demonstrate that exposure to an immunomodulatory chemical, triclosan, differentially impacts immune cell populations in the skin of haired and hairless mice. Additionally, the flow cytometry panel reported in this manuscript, in combination with gene expression analysis, may be useful in future studies to better evaluate the effect of chemical exposures on the skin immune response. These findings may be important to consider during strain selection, experimental design, and result interpretation of chemical exposures on the skin.
Language	English
Publishing date	2022-09-09
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	2805786-7
ISSN	2214-7500 ; 2214-7500
ISSN (online)	2214-7500
ISSN	2214-7500
DOI	10.1016/j.toxrep.2022.09.005
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Article ; Online: Systemic toxicity induced by topical application of perfluoroheptanoic acid (PFHpA), perfluorohexanoic acid (PFHxA), and perfluoropentanoic acid (PFPeA) in a murine model.

Weatherly, Lisa M / Shane, Hillary L / Lukomska, Ewa / Baur, Rachel / Anderson, Stacey E

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association

2022 Volume 171, Page(s) 113515

Abstract: Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic structurally diverse chemicals incorporated into industrial and consumer products. PFHpA, PFHxA, and PFPeA are carboxylic PFAS (C7, C6, C5, respectively) labeled as a safer alternative ... ...

Abstract	Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic structurally diverse chemicals incorporated into industrial and consumer products. PFHpA, PFHxA, and PFPeA are carboxylic PFAS (C7, C6, C5, respectively) labeled as a safer alternative to legacy carboxylic PFAS due to their shorter half-life in animals. Although there is a high potential for dermal exposure, these studies are lacking. The present study conducted analyses of serum chemistries, immune phenotyping, gene expression, and histology to evaluate the systemic toxicity of a sub-chronic 28-day dermal exposure of alternative PFAS (1.25-5% or 31.25-125 mg/kg/dose) in a murine model. Liver weight (% body) significantly increased with PFHpA, PFHxA, and PFPeA exposure and histopathological changes were observed in both the liver and skin. Gene expression changes were observed with PPAR isoforms in the liver and skin along with changes in genes involved in steatosis, fatty acid metabolism, necrosis, and inflammation. These findings, along with significant detection levels in serum and urine, support PFAS-induced liver damage and PPARα, δ, and γ involvement in alternative PFAS systemic toxicity and immunological disruption. This demonstrates that these compounds can be absorbed through the skin and brings into question whether these PFAS are a suitable alternative to legacy PFAS.
MeSH term(s)	Mice ; Animals ; Disease Models, Animal ; Alkanesulfonic Acids ; Fluorocarbons/toxicity
Chemical Substances	perfluoropentanoic acid ; perfluorohexanoic acid (ZP34Q2220R) ; perfluoro-n-heptanoic acid (375-85-9) ; Alkanesulfonic Acids ; Fluorocarbons
Language	English
Publishing date	2022-11-24
Publishing country	England
Document type	Journal Article
ZDB-ID	782617-5
ISSN	1873-6351 ; 0278-6915
ISSN (online)	1873-6351
ISSN	0278-6915
DOI	10.1016/j.fct.2022.113515
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Article ; Online: Exposure to the immunomodulatory chemical triclosan differentially impacts immune cell populations in the skin of haired (BALB/c) and hairless (SKH1) mice

Baur, Rachel / Shane, Hillary L. / Weatherly, Lisa M. / Lukomska, Ewa / Kashon, Michael / Anderson, Stacey E.

Toxicology Reports. 2022, v. 9 p.1766-1776

2022

Abstract	Workers across every occupational sector have the potential to be exposed to a wide variety of chemicals, and the skin is a primary route of exposure. Furthermore, exposure to certain chemicals has been linked to inflammatory and allergic diseases. Thus, understanding the immune responses to chemical exposures on the skin and the potential for inflammation and sensitization is needed to improve worker safety and health. Responses in the skin microenvironment impact the potential for sensitization; these responses may include proinflammatory cytokines, inflammasome activation, barrier integrity, skin microbiota, and the presence of immune cells. Selection of specific mouse strains to evaluate skin effects, such as haired (BALB/c) or hairless (SKH1) mice, varies dependent on experimental design and needs of a study. However, dermal chemical exposure may impact reactions in the skin differently depending on the strain of mouse. Additionally, there is a need for established methods to evaluate immune responses in the skin. In this study, exposure to the immunomodulatory chemical triclosan was evaluated in two mouse models using immunophenotyping by flow cytometry and gene expression analysis. BALB/c mice exposed to triclosan (2%) had a higher number and frequency of neutrophils and lower number and frequency of dendritic cells in the skin compared to controls. Although these changes were not observed in SKH1 mice, SKH1 mice exposed to triclosan had a higher number and frequency of type 2 innate lymphoid cells in the skin. Taken together, these results demonstrate that exposure to an immunomodulatory chemical, triclosan, differentially impacts immune cell populations in the skin of haired and hairless mice. Additionally, the flow cytometry panel reported in this manuscript, in combination with gene expression analysis, may be useful in future studies to better evaluate the effect of chemical exposures on the skin immune response. These findings may be important to consider during strain selection, experimental design, and result interpretation of chemical exposures on the skin.
Keywords	cytokines ; experimental design ; exposure pathways ; flow cytometry ; gene expression ; immune response ; immunophenotyping ; inflammasomes ; inflammation ; mice ; microorganisms ; neutrophils ; occupational health and safety ; toxicology ; triclosan ; Skin ; Dendritic cells ; ILC2s
Language	English
Size	p. 1766-1776.
Publishing place	Elsevier B.V.
Document type	Article ; Online
Note	Use and reproduction
ZDB-ID	2805786-7
ISSN	2214-7500
ISSN	2214-7500
DOI	10.1016/j.toxrep.2022.09.005
Database	NAL-Catalogue (AGRICOLA)

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Article: Systemic toxicity induced by topical application of heptafluorobutyric acid (PFBA) in a murine model

Weatherly, Lisa M. / Shane, Hillary L. / Lukomska, Ewa / Baur, Rachel / Anderson, Stacey E.

Food and chemical toxicology. 2021 Oct., v. 156

2021

Abstract: Heptafluorobutyric acid (PFBA) is a synthetic chemical belonging to the per- and polyfluoroalkyl substances (PFAS) group that includes over 5000 chemicals incorporated into numerous products. PFBA is a short-chain PFAS (C4) labeled as a safer alternative ...

Abstract	Heptafluorobutyric acid (PFBA) is a synthetic chemical belonging to the per- and polyfluoroalkyl substances (PFAS) group that includes over 5000 chemicals incorporated into numerous products. PFBA is a short-chain PFAS (C4) labeled as a safer alternative to legacy PFAS which have been linked to numerous health effects. Despite the high potential for dermal exposure, occupationally and environmentally, dermal exposure studies are lacking. Using a murine model, this study analyzed serum chemistries, histology, immune phenotyping, and gene expression to evaluate the systemic toxicity of sub-chronic dermal PFBA 15-day (15% v/v or 375 mg/kg/dose) or 28-day (3.75–7.5% v/v or 93.8–187.5 mg/kg/dose) exposures. PFBA exposure produced significant increases in liver and kidney weights and altered serum chemistries (all exposure levels). Immune-cell phenotyping identified significant increases in draining lymph node B-cells (15%) and CD11b + cells (3.75–15%) and skin T-cells (3.75–15%) and neutrophils (7.5–15%). Histopathological and gene expression changes were observed in both the liver and skin after dermal PFBA exposure. The findings indicate PFBA induces liver toxicity and alterations of PPAR target genes, suggesting a role of a PPAR pathway. These results demonstrate that sustained dermal exposure to PFBA induces systemic effects and raise concerns of short-chain PFAS being promoted as safer alternatives.
Keywords	T-lymphocytes ; animal models ; blood serum ; dermal exposure ; gene expression ; hepatotoxicity ; histology ; histopathology ; kidneys ; liver ; lymph nodes ; neutrophils ; peroxisome proliferator-activated receptors ; phenotype ; topical application ; toxicology
Language	English
Dates of publication	2021-10
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	782617-5
ISSN	1873-6351 ; 0278-6915
ISSN (online)	1873-6351
ISSN	0278-6915
DOI	10.1016/j.fct.2021.112528
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Prior Exposure to Ortho-Phthalaldehyde Augments IgE-Mediated Immune Responses to Didecyldimethylammonium Chloride: Potential for 2 Commonly Used Antimicrobials to Synergistically Enhance Allergic Disease.

Shane, Hillary L / Lukomska, Ewa / Weatherly, Lisa / Baur, Rachel / Anderson, Stacey E

Toxicological sciences : an official journal of the Society of Toxicology

2021 Volume 178, Issue 1, Page(s) 127–137

Abstract: Health-care workers have an increased incidence of allergic disease compared with the general public and are exposed to a variety of high-level disinfectants. Although exposure to these agents has been associated with allergic disease, findings between ... ...

Abstract	Health-care workers have an increased incidence of allergic disease compared with the general public and are exposed to a variety of high-level disinfectants. Although exposure to these agents has been associated with allergic disease, findings between epidemiology and animal studies often conflict respecting immunological mechanisms. Therefore, we hypothesized that previous exposure to a representative IgE-mediated sensitizer (ortho-phthalaldehyde [OPA]) alters immune responses to a representative T-cell-mediated sensitizer (didecyldimethlyammonium chloride [DDAC]). Here, BALB/c mice were topically exposed to OPA (0.5%) for 3 days, rested, then topically exposed to DDAC (0.0625%, 0.125%, and 0.25%) for 14 days. Coexposure resulted in phenotypic changes in draining lymph node (dLN) cells, including a decreased frequency of CD8+ T cells and increased frequency and number of B cells compared with DDAC-only treated mice. The coexposed mice also had enhanced Th2 responses, including significant alterations in: dLN Il4 (increased), B-cell activation (increased), CD8+ T-cell activation (decreased), and local and systemic IgE production (increased). These changes were not observed if mice were exposed to DDAC prior to OPA. Exposure to OPA alone shows Th2 skewing, indicated by increased activation of skin type 2 innate lymphoid cells, increased frequency and activation of draining lymph node B cells, and increased levels of type 2 cytokines. These findings suggest that the OPA-induced immune environment may alter the response to DDAC, resulting in increased IgE-mediated immune responses. This data may partially explain the discordance between epidemiological and laboratory studies regarding disinfectants and provide insight into the potential immunological implications of mixed chemical exposures.
MeSH term(s)	Animals ; B-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/drug effects ; Cytokines ; Disinfectants/toxicity ; Immunity, Innate ; Immunoglobulin E/immunology ; Mice ; Mice, Inbred BALB C ; Quaternary Ammonium Compounds/toxicity ; o-Phthalaldehyde/toxicity
Chemical Substances	Cytokines ; Disinfectants ; Quaternary Ammonium Compounds ; Immunoglobulin E (37341-29-0) ; o-Phthalaldehyde (643-79-8) ; didecyldimethylammonium (Z7F472XQPA)
Keywords	covid19
Language	English
Publishing date	2021-02-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfaa112
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Zs.A 1709: Show issues

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Article ; Online: Exposure to the anti-microbial chemical triclosan disrupts keratinocyte function and skin integrity in a model of reconstructed human epidermis.

Baur, Rachel / Kashon, Michael / Lukomska, Ewa / Weatherly, Lisa M / Shane, Hillary L / Anderson, Stacey E

Journal of immunotoxicology

2021 Volume 20, Issue 1, Page(s) 1–11

Abstract: Triclosan is an anti-microbial chemical incorporated into products that are applied to the skin of healthcare workers. Exposure to triclosan has previously been shown to be associated with allergic disease in humans and impact the immune responses in ... ...

Abstract	Triclosan is an anti-microbial chemical incorporated into products that are applied to the skin of healthcare workers. Exposure to triclosan has previously been shown to be associated with allergic disease in humans and impact the immune responses in animal models. Additionally, studies have shown that exposure to triclosan dermally activates the NLRP3 inflammasome and disrupts the skin barrier integrity in mice. The skin is the largest organ of the body and plays an important role as a physical barrier and regulator of the immune system. Alterations in the barrier and immune regulatory functions of the skin have been demonstrated to increase the risk of sensitization and development of allergic disease. In this study, the impact of triclosan exposure on the skin barrier and keratinocyte function was investigated using a model of reconstructed human epidermis. The apical surface of reconstructed human epidermis was exposed to triclosan (0.05-0.2%) once for 6, 24, or 48 h or daily for 5 consecutive days. Exposure to triclosan increased epidermal permeability and altered the expression of genes involved in formation of the skin barrier. Additionally, exposure to triclosan altered the expression patterns of several cytokines and growth factors. Together, these results suggest that exposure to triclosan impacts skin barrier integrity and function of human keratinocytes and suggests that these alterations may impact immune regulation.
MeSH term(s)	Humans ; Mice ; Animals ; Triclosan/toxicity ; Keratinocytes ; Epidermis/metabolism ; Skin ; Cytokines/metabolism ; Hypersensitivity ; Cell Differentiation
Chemical Substances	Triclosan (4NM5039Y5X) ; Cytokines
Language	English
Publishing date	2021-04-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2205064-4
ISSN	1547-6901 ; 1547-691X
ISSN (online)	1547-6901
ISSN	1547-691X
DOI	10.1080/1547691X.2022.2148781
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Zs.A 6167: Show issues

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Article ; Online: Systemic toxicity induced by topical application of heptafluorobutyric acid (PFBA) in a murine model.

Weatherly, Lisa M / Shane, Hillary L / Lukomska, Ewa / Baur, Rachel / Anderson, Stacey E

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association

2021 Volume 156, Page(s) 112528

Abstract	Heptafluorobutyric acid (PFBA) is a synthetic chemical belonging to the per- and polyfluoroalkyl substances (PFAS) group that includes over 5000 chemicals incorporated into numerous products. PFBA is a short-chain PFAS (C4) labeled as a safer alternative to legacy PFAS which have been linked to numerous health effects. Despite the high potential for dermal exposure, occupationally and environmentally, dermal exposure studies are lacking. Using a murine model, this study analyzed serum chemistries, histology, immune phenotyping, and gene expression to evaluate the systemic toxicity of sub-chronic dermal PFBA 15-day (15% v/v or 375 mg/kg/dose) or 28-day (3.75-7.5% v/v or 93.8-187.5 mg/kg/dose) exposures. PFBA exposure produced significant increases in liver and kidney weights and altered serum chemistries (all exposure levels). Immune-cell phenotyping identified significant increases in draining lymph node B-cells (15%) and CD11b + cells (3.75-15%) and skin T-cells (3.75-15%) and neutrophils (7.5-15%). Histopathological and gene expression changes were observed in both the liver and skin after dermal PFBA exposure. The findings indicate PFBA induces liver toxicity and alterations of PPAR target genes, suggesting a role of a PPAR pathway. These results demonstrate that sustained dermal exposure to PFBA induces systemic effects and raise concerns of short-chain PFAS being promoted as safer alternatives.
MeSH term(s)	Administration, Topical ; Animals ; Chemical and Drug Induced Liver Injury ; Environmental Pollutants/toxicity ; Female ; Fluorocarbons/toxicity ; Indicators and Reagents/toxicity ; Mice
Chemical Substances	Environmental Pollutants ; Fluorocarbons ; Indicators and Reagents ; perfluorobutyric acid (375-22-4)
Language	English
Publishing date	2021-08-30
Publishing country	England
Document type	Journal Article
ZDB-ID	782617-5
ISSN	1873-6351 ; 0278-6915
ISSN (online)	1873-6351
ISSN	0278-6915
DOI	10.1016/j.fct.2021.112528
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Article ; Online: Biological effects of inhaled crude oil. VI. Immunotoxicity.

Weatherly, Lisa M / Shane, Hillary L / Baur, Rachel / Lukomska, Ewa / Roberts, Jenny R / Fedan, Jeffrey S / Anderson, Stacey E

Toxicology and applied pharmacology

2022 Volume 449, Page(s) 116100

Abstract: Crude oil is an unrefined petroleum product that is a mixture of hydrocarbons and other organic material. Studies on the individual components of crude oil and crude oil exposure itself suggest it has immunomodulatory potential. As investigations of the ... ...

Abstract	Crude oil is an unrefined petroleum product that is a mixture of hydrocarbons and other organic material. Studies on the individual components of crude oil and crude oil exposure itself suggest it has immunomodulatory potential. As investigations of the immunotoxicity of crude oil focus mainly on ingestion and dermal exposure, the effects of whole-body inhalation of 300 ppm crude oil vapor [COV; acute inhalation exposure: (6 h × 1 d); or a 28 d sub-chronic exposure (6 h/d × 4 d/wk. × 4 wks)] was investigated 1, 28, and 90 d post-exposure in Sprague-Dawley rats. Acute exposure increased bronchoalveolar lavage (BAL) fluid cellularity, CD4+ and CD8+ cells, and absolute and percent CDllb+ cells only at 1 d post-exposure; additionally, NK cell activity was suppressed. Sub-chronic exposure resulted in a decreased frequency of CD4+ T-cells at 1 d post-exposure and an increased number and frequency of B-cells at 28 d post-exposure in the lung-associated lymph nodes. A significant increase in the number and frequency of B-cells was observed in the spleen at 1 d post-exposure; however, NK cell activity was suppressed at this time point. No effect on cellularity was identified in the BALF. No change in the IgM response to sheep red blood cells was observed. The findings indicate that crude oil inhalation exposure resulted in alterations in cellularity of phenotypic subsets that may impair immune function in rats.
MeSH term(s)	Animals ; Bronchoalveolar Lavage Fluid ; Inhalation Exposure/adverse effects ; Lung ; Petroleum/toxicity ; Rats ; Rats, Sprague-Dawley ; Sheep
Chemical Substances	Petroleum
Language	English
Publishing date	2022-06-06
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2022.116100
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