Retinoic acid co-treatment aggravates severity of dioxin-induced skin lesions in hairless mice via induction of inflammatory response

Stanislav G. Rudyak, Lev A. Usakin, Ekaterina A. Tverye, Anton S. Orekhov, Natalya N. Belushkina, Ralf Paus, Mikhail A. Paltsev, Andrey A. Panteleyev

Research output: Contribution to journalArticle

Abstract

Exposure to toxic halogenated polyaromatic hydrocarbons, of which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most potent, induces diverse skin pathologies in humans, including chloracne, hyperkeratosis, hamartomas, etc. While the toxic effects of TCDD have been extensively studied, effective approaches to their treatment are still lacking. Retinoids are commonly used in therapy of acneiform skin diseases. In vitro, retinoids elicit antagonistic effects on keratinocyte differentiation and proliferation, as compared to TCDD, suggesting their potential in treatment of TCDD-induced skin lesions. Nevertheless, the modulation of TCDD activity in skin by retinoids in vivo was never reported. We have used N-TERT keratinocyte cell line and hairless (hr) mice to determine if retinoic acid (RA) can lessen or reverse TCDD-induced effects in vitro and in vivo. RA co-treatment suppressed TCDD-induced changes in the expression of differentiation-associated genes and N-TERT keratinocyte viability in vitro. However, in hairless mice (in vivo), RA/TCDD co-treatment produced more severe effects, than treatment with either of the two compounds individually. RA/TCDD co-application to mouse skin strongly stimulated keratinocyte proliferation, resulting in dramatic epidermal hyperplasia. It has also led to massive immune cell infiltration into the dermis, and increased mRNA expression of inflammation markers, including IL1β, IL6 and S100A7. Thus, retinoids not only appeared ineffective in treatment of TCDD-induced skin lesions in hairless mice, but also resulted in their exaggeration. These in vivo results question previous cell culture-based claims that RA may reduce TCDD-induced skin effects and caution against the reliance on in vitro data in TCDD toxicology research.

Original languageEnglish (US)
Pages (from-to)854-861
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume506
Issue number4
DOIs
StatePublished - Dec 2 2018
Externally publishedYes

Fingerprint

Hairless Mouse
Dioxins
Tretinoin
Skin
Retinoids
Keratinocytes
Poisons
Polychlorinated Dibenzodioxins
1,4-dioxin
Chloracne
Halogenated Hydrocarbons
Skin effect
Hamartoma
Pathology
Dermis
Cell culture
Infiltration
Skin Diseases
Toxicology
Hyperplasia

Keywords

  • Ahr
  • Chloracne
  • Dioxin
  • hr
  • Psoriasis

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Retinoic acid co-treatment aggravates severity of dioxin-induced skin lesions in hairless mice via induction of inflammatory response. / Rudyak, Stanislav G.; Usakin, Lev A.; Tverye, Ekaterina A.; Orekhov, Anton S.; Belushkina, Natalya N.; Paus, Ralf; Paltsev, Mikhail A.; Panteleyev, Andrey A.

In: Biochemical and Biophysical Research Communications, Vol. 506, No. 4, 02.12.2018, p. 854-861.

Research output: Contribution to journalArticle

Rudyak, Stanislav G. ; Usakin, Lev A. ; Tverye, Ekaterina A. ; Orekhov, Anton S. ; Belushkina, Natalya N. ; Paus, Ralf ; Paltsev, Mikhail A. ; Panteleyev, Andrey A. / Retinoic acid co-treatment aggravates severity of dioxin-induced skin lesions in hairless mice via induction of inflammatory response. In: Biochemical and Biophysical Research Communications. 2018 ; Vol. 506, No. 4. pp. 854-861.
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abstract = "Exposure to toxic halogenated polyaromatic hydrocarbons, of which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most potent, induces diverse skin pathologies in humans, including chloracne, hyperkeratosis, hamartomas, etc. While the toxic effects of TCDD have been extensively studied, effective approaches to their treatment are still lacking. Retinoids are commonly used in therapy of acneiform skin diseases. In vitro, retinoids elicit antagonistic effects on keratinocyte differentiation and proliferation, as compared to TCDD, suggesting their potential in treatment of TCDD-induced skin lesions. Nevertheless, the modulation of TCDD activity in skin by retinoids in vivo was never reported. We have used N-TERT keratinocyte cell line and hairless (hr) mice to determine if retinoic acid (RA) can lessen or reverse TCDD-induced effects in vitro and in vivo. RA co-treatment suppressed TCDD-induced changes in the expression of differentiation-associated genes and N-TERT keratinocyte viability in vitro. However, in hairless mice (in vivo), RA/TCDD co-treatment produced more severe effects, than treatment with either of the two compounds individually. RA/TCDD co-application to mouse skin strongly stimulated keratinocyte proliferation, resulting in dramatic epidermal hyperplasia. It has also led to massive immune cell infiltration into the dermis, and increased mRNA expression of inflammation markers, including IL1β, IL6 and S100A7. Thus, retinoids not only appeared ineffective in treatment of TCDD-induced skin lesions in hairless mice, but also resulted in their exaggeration. These in vivo results question previous cell culture-based claims that RA may reduce TCDD-induced skin effects and caution against the reliance on in vitro data in TCDD toxicology research.",
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AU - Tverye, Ekaterina A.

AU - Orekhov, Anton S.

AU - Belushkina, Natalya N.

AU - Paus, Ralf

AU - Paltsev, Mikhail A.

AU - Panteleyev, Andrey A.

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