Doctor of Philosophy
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent organic pollutant that causes toxicity by activating the aryl hydrocarbon receptor (AHR). Activation of the AHR has been linked to an increased risk of developing skin diseases including chloracne and atopic dermatitis (AD). We investigated the effects of perinatal exposure to TCDD on the development of the epidermal barrier and the susceptibility to skin diseases in C57BL/6J mice. Mice were exposed in utero to 5 g/ kg bw TCDD on embryonic day 12 and the cutaneous effects were studied from postnatal day 1 (P1) through adult life. TCDD-exposed pups exhibited diffuse epidermal hyperplasia at birth; however, this effect did not persist. TCDD-exposed animals did not develop AD-related pathologies including skin lesions, increased serum IgE and Th2 immune responses between birth to P135. At P21, TCDD-exposed skin exhibited sebaceous gland hypoplasia, reminiscent of chloracne, that was reversible by P35. Analysis of the skin microbiome identified a change in bacterial community structure between control and treated mice at P21, that was no longer evident by P35. Similarly, CYP1A1 and CYP1B1 RNA and protein expression increased transiently in TCDD-exposed skin at P13-21. Both CYP1A1 and CYP1B1 protein expression co-localized with leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1)-expressing progenitor cells at the infundibulum. CYP1B1 also co-localized with leucine rich repeat containing G protein-coupled receptor 6 (LGR6)-expressing progenitor cells at the junctional zone. Parallel studies with human keratinocytes showed that activation of the AHR with TCDD increased terminal differentiation. Surprisingly, knockdown of the AHR resulted in increased keratinocyte differentiation. We determined that levels of cyclin-dependent kinase inhibitor 1B (CDKN1B) were increased in these AHR knockdown cells. Further studies are required to explore the relationship between AHR, CDKN1B, cell cycle, and cell differentiation. In conclusion, perinatal exposure of mice to TCDD resulted in a chloracne-like phenotype in the skin, without evidence of atopy. The identity of specific skin cells affected by TCDD will aid ongoing research into the mechanisms of chloracne which include sebaceous gland dysmorphogenesis and epidermal hyperplasia.
Dissertation or thesis originally submitted to ProQuest
Bhuju, Jyoti, "ARYL HYDROCARBON RECEPTOR ACTIVATION AND ITS ROLE IN SKIN PHYSIOLOGY AND TOXICOLOGY" (2021). Electronic Theses and Dissertations. 2459.