Alternariol induced proliferation in primary mouse keratinocytes and inflammation in mouse skin is regulated via PGE2/EP2/cAMP/p-CREB signaling pathway.

Abstract

Alternariol (AOH) is a mycotoxin that contaminates various food stuffs as well as animal feed and may cause toxicity after consumption. However, a dermal toxic potential of AOH has not been explored so far. In the present study, skin toxicity after topical exposure of AOH and the involved mechanism/s are revealed. Single topical application of different AOH doses (12.5, 25, 50 μg/animal) caused increased bi-fold thickness as well as hyperplasia and higher production of prostaglandin E2 (PGE2) along with cAMP in the skin demonstrating its inflammatory potential. Western blot analysis showed that exposure of AOH lead to phosphorylation of CREB and increased the expression of COX-2, cyclin D1 as well as prostanoid EP2 receptor. Further studies on primary mouse keratinocytes (PMK) revealed that very low concentrations of AOH (50-500 nM) resulted in significant PMK proliferation. Additionally, using specific antagonist or agonist of prostanoid receptors, we delineated that EP2 receptor play a key role in AOH-induced PMKs proliferation. Collectively, our findings show that AOH can lead to dermal toxicity in mice by activating the EP2/cAMP/p-CREB signaling cascade.

• Authors: Megha Bansal, Neha Singh, Shamshad Alam, Saurabh Pal, G N V Satyanarayana, Dhirendra Singh, Kausar Mahmood Ansari
• Journal: Toxicology (Toxicology) Vol. 412 Pg. 79-88 (01 15 2019) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 30503586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018. Published by Elsevier B.V.

Chemical References

• Creb1 protein, mouse
• Cyclic AMP Response Element-Binding Protein
• Lactones
• Receptors, Prostaglandin E, EP2 Subtype
• Cyclic AMP
• Cyclooxygenase 2
• Dinoprostone
• alternariol

Topics

• Animals
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cyclic AMP (metabolism)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Cyclooxygenase 2 (metabolism)
• Dinoprostone (metabolism)
• Female
• Inflammation (chemically induced, metabolism, pathology)
• Keratinocytes (drug effects, metabolism)
• Lactones (toxicity)
• Mice
• Receptors, Prostaglandin E, EP2 Subtype (metabolism)
• Signal Transduction (drug effects)
• Skin (drug effects, metabolism, pathology)