Association between Hair-Induced Oronasal Inflammation and Ulcerative Dermatitis in C57BL/6 Mice

Dear Editor:

Inbred strains of mice are well known to develop a variety of diseases that are strain specific or affect some strains but not others.^1,10 Not surprising, the C57BL/6 substrains (commonly abbreviated as B6), one of the most commonly used group of inbred strains in biomedical research today, get a variety of diseases, some of which affect the skin. B6 alopecia and dermatitis (also called ulcerative dermatitis or chronic ulcerative dermatitis) and barbering are 2 unrelated diseases occasionally seen in B6 mice. While they have been considered by some to be cause and effect in which excessive grooming by other mice in the box results in alopecia, excoriation, ulcers, and ultimately scarring, this is not the case. Barbering has been regarded as a form of obsessive compulsive disorder or as an expression of dominance^3,5 and is often seen in many other strains in addition to B6. Some strains, such as all the commonly used C3H substrains, do have barbering problems and also develop an autoimmune hair loss disease known as alopecia areata, which can be difficult to differentiate clinically from barbering.⁹ Alopecia areata is a very complex genetic disease not caused by barbering.¹¹

B6 alopecia and dermatitis is a mouse model for the human disease known as central centrifugal cicatricial alopecia or follicular degeneration syndrome.¹² This is another complex genetic disease. All 4 of the commonly used B6 substrains harbor a hypomorphic mutation in their alcohol dehydrogenase 4 gene (Adh4). This mutation reduces their ability to detoxify dietary vitamin A, which in turn leads to toxic, degenerative effects on hair follicles. Due to differential expression of dehydrogenase/reductase (SDR family) member 9 (DHRS9) protein (an enzyme involved in retinoic acid synthesis that regulates transcription of many genes) in the hair follicles of the various substrains of B6, the commonly used B6 substrains have different frequencies of alopecia and dermatitis.¹² Vitamin A toxicity also affects tooth development and the integrity of other epithelial structures.⁶

The recent paper describing an apparent association between hair-induced oronasal inflammation and ulcerative dermatitis in C57BL/6 mice² provides an interesting alternative perspective on this skin disease in B6 mice. Finding alopecia and impaction of hair in the gingival sulcus and other oral and nasal structures suggests a correlation, although even in this study lacks 100% concordance and the “controls” had alopecia to a lesser extent and lacked ulcers. This is not surprising because we described the same lesions as foreign body periodontitis, a common, if not universal, oral lesion in most strains of mice, with or without alopecia.⁴ In fact, in a large aging study of 30 inbred strains of laboratory mice in which detailed complete necropsies⁷ were done on over 1700 mice of multiple ages, foreign body periodontitis was found in almost every mouse, including 12-mo-old mice⁸ equivalent to those used in the Duarate-Vogel study.² None of the B6 substrains necropsied in our aging study had gross lesions consistent with B6 alopecia and dermatitis or barbering. Foreign body periodontis was the most predictable aging finding in all 30 inbred strains of mice. Hair shaft remnants were also commonly found embedded in the nasal cavity, duct of the lingual gland, and many other structures. These observations were concordant with routine disease surveillance of production colonies at The Jackson Laboratory for over 35,000 necropsies.¹⁰ Based on these observations, it is unlikely that foreign body (hair shaft) induced lesions in the nose and mouth of mice, a result of normal grooming behavior, has any direct relationship to B6 alopecia and dermatitis. These observations emphasize the need for this type of investigation² to include unaffected mice of the same strain (which was not done in the Duarte-Vogel study, in which the use of mice with alopecia but not grossly evident ulcers does not rule out B6 alopecia and dermatitis), as well as unrelated and unaffected strains.

Sincerely,

John P Sundberg, DVM, PhD, DACVP
Professor, Research and Development, The Jackson Laboratory
Björn Rozell, DDS, PhD, DVM
Professor, Department of Veterinary Disease Biology, University of Copenhagen
Helen Everts, PhD
Assistant Professor, Department of Nutrition, Ohio State University