The Cutaneous Lesions of Dioxin Exposure: Lessons from the Poisoning of Victor Yushchenko

Abstract

Several million people are exposed to dioxin and dioxin-like compounds, primarily through food consumption. Skin lesions historically called "chloracne" are the most specific sign of abnormal dioxin exposure and classically used as a key marker in humans. We followed for 5 years a man who had been exposed to the most toxic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), at a single oral dose of 5 million-fold more than the accepted daily exposure in the general population. We adopted a molecular medicine approach, aimed at identifying appropriate therapy. Skin lesions, which progressively covered up to 40% of the body surface, were found to be hamartomas, which developed parallel to a complete and sustained involution of sebaceous glands, with concurrent transcriptomic alterations pointing to the inhibition of lipid metabolism and the involvement of bone morphogenetic proteins signaling. Hamartomas created a new compartment that concentrated TCDD up to 10-fold compared with serum and strongly expressed the TCDD-metabolizing enzyme cytochrome P450 1A1, thus representing a potentially significant source of enzymatic activity, which may add to the xenobiotic metabolism potential of the classical organs such as the liver. This historical case provides a unique set of data on the human tissue response to dioxin for the identification of new markers of exposure in human populations. The herein discovered adaptive cutaneous response to TCDD also points to the potential role of the skin in the metabolism of food xenobiotics.

Human and rodent aryl hydrocarbon receptor (AHR): from mediator of dioxin toxicity to physiologic AHR functions and therapeutic options

“…In support, TCDD treatment of ex vivo sebaceous gland-rich skin culture led to atrophic sebaceous glands and increased expression of the keratinocyte differentiation marker keratin 10 (Ju et al, 2011). In conclusion, TCDD dysregulates AHR functions leading to exhaustion of stem/progenitor cells and atrophy of sebaceous glands, similar to findings in vivo (Saurat et al, 2012). These findings point to the importance of identifying AHR target cells and its cross-talking partners in mechanistic studies.…”

“…The oral TCDD poisoning of Victor Yushchenko in 2004 demonstrated inflammatory injury of the gastrointestinal tract and after 2 weeks the development of chloracne (Saurat et al, 2012). Concomitant accumulation of TCDD in sebum lasted for over 2 years leading to sustained activation of AHR in sebaceous gland tissue.…”

“…Inflammatory reactions have been frequently observed in the skin and gastrointestinal tract of poisoned individuals (Saurat et al, 2012;Bock, 2016). TCDD-mediated inflammation is initiated by rapid increase of intracellular Ca 2 + , phospholipase A2 and Cox-2 activation.…”

The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology

“…Chloracne, hyperpigmentation, and thickening of the skin on palms and soles have been reported after exposure to a number of dioxin-like agents. Chloracne, the hallmark of dioxin toxicity in humans, is characterized by epidermal hyperplasia, disappearance of sebaceous glands, and multiple epithelial cysts, which are now described as hamartomas (Saurat et al, 2012). The same pathologic responses to TCDD, including hyperkeratosis, epidermal hyperplasia, sebaceous gland involution, and intraepidermal keratinous cysts have earlier been described in mice homozygous for mutations in the hairless gene (hr/h) but not in other naked mice (Puhvel et al, 1982).…”

“…The hairless protein is now known to be a nuclear receptor corepressor that regulates hair regeneration by interacting with Wnt/b-catenin signaling (Beaudoin et al, 2005). Because the sebaceous gland and hair follicle epithelium have the same cellular source for renewal, chloracne is now suggested to be caused by a switch from a sebaceous to epidermal type of differentiation mediated through transient activation of the nuclear protooncogene c-Myc, which is a target of the Wnt/b-catenin pathway (Panteleyev and Bickers, 2006;Saurat et al, 2012). A recent study with TCDD treatment of human skin samples exposed ex vivo and cultured human SZ95 sebocytes supports this suggestion.…”