Skin Barrier in Atopic Dermatitis.

A compromised permeability barrier is a hallmark of atopic dermatitis (AD). Localized to the outermost skin layer, the stratum corneum (SC) is critically dependent on terminal differentiation of epidermal keratinocytes, which transform into protein-rich corneocytes surrounded by extracellular lamellae of unique epidermal lipids, conferring permeability barrier function. These structures are disrupted in AD. A leaky barrier is prone to environmental insult, which in AD elicits type 2-dominant inflammation, in turn resulting in a vicious cycle further impairing the SC structure. Therapies directed at enforcing SC structure and anti-inflammatory strategies administered by topical and systemic route as well as UV therapy have differential effects on the permeability barrier. The expanding armamentarium of therapeutic modalities for AD treatment warrants optimization of their effects on permeability barrier function.

"Outside-to-inside," "inside-to-outside," and "intrinsic" endogenous pathogenic mechanisms in atopic dermatitis: keratinocytes as the key functional cells involved in both permeability barrier dysfunction and immunological alterations.

Permeability barrier disruption has been shown to induce immunological alterations (i.e., an "outside-to-inside" pathogenic mechanism). Conversely, several inflammatory and immunological mechanisms reportedly interrupt permeability barrier homeostasis (i.e., an "inside-to-outside" pathogenic mechanism). It is now widely recognized that alterations of even a single molecule in keratinocytes can lead to not only permeability barrier dysfunction but also to immunological alterations. Such a simultaneous, bidirectional functional change by keratinocytes is herein named an "intrinsic" pathogenic mechanism. Molecules and/or pathways involved in this mechanism could be important not only as factors in disease pathogenesis but also as potential therapeutic targets for inflammatory cutaneous diseases, such as atopic dermatitis, psoriasis, and prurigo nodularis. Elevation of skin surface pH following permeability barrier abrogation comprises one of the key pathogenic phenomena of the "outside-to-inside" mechanism. Not only type 2 cytokines (e.g., IL-4, IL-13, IL-31) but also type 1 (e.g. IFN-γ), and type 3 (e.g., IL-17, IL-22) as well as several other inflammatory factors (e.g. histamine) can disrupt permeability barrier homeostasis and are all considered part of the "inside-to-outside" mechanism. Finally, examples of molecules relevant to the "intrinsic" pathogenic mechanism include keratin 1, filaggrin, and peroxisome proliferator-activated receptor-α (PPARα).

Link between obesity and atopic dermatitis: Does obesity predispose to atopic dermatitis, or vice versa?

Two serious health conditions, obesity and atopic dermatitis (AD), share some pathological features such as insulin resistance, leptin resistance and inflammation, and a growing body of evidence suggests a link between obesity and AD. Obesity predisposes an individual to and/or worsens AD, whereas AD increases the risk of obesity. Obesity and AD's interactions are mediated by cytokines, chemokines and immune cells. Obese individuals with AD are more resistant to anti-inflammatory therapy, while weight loss can alleviate AD. In this review, we summarize the evidence linking AD and obesity. We also discuss the pathogenic role of obesity in AD, and vice versa. Because of the connection between these two conditions, mitigation of one could possibly prevent the development of or alleviate the other condition. Effective management of AD and weight loss can enhance the wellness of individuals with both of these conditions. However, proper clinical studies are warranted to validate this speculation.

Stratum corneum hydration inversely correlates with certain serum cytokine levels in the elderly, possibly contributing to inflammaging.

BACKGROUND: Chronic, low-grade inflammation, also termed 'inflammaging', has been linked to the development of some aging-associated disorders. Recent studies suggest that inflammaging is attributable to aging-associated epidermal dysfunction. However, abnormality in which epidermal function contributes to inflammaging is not clear. OBJECTIVE: We delineated the correlation of epidermal functions with circulating levels of proinflammatory cytokines in the elderly. METHODS: Blood sample was collected from a total of 255 participants aged ≥ 65 years. Epidermal biophysical properties were measured on the left forearm and the right shin. Serum cytokine levels were measured by Multiplex Luminex Assays. RESULTS: Neither skin surface pH nor transepidermal water loss rates (TEWL) correlated with serum cytokine levels except TEWL on the right shin for TNFa (p < 0.05). In contrast, stratum corneum hydration levels on both the forearm and the shin correlated negatively with serum cytokine levels (p < 0.05). CONCLUSION: Reduced stratum corneum hydration likely contributes to inflammaging.

Targeting Skin Barrier Function in Atopic Dermatitis.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in the general population. Skin barrier dysfunction is the central abnormality leading to AD. The cause of skin barrier dysfunction is complex and rooted in genetic mutations, interactions between the immune pathway activation and epithelial cells, altered host defense mechanisms, as well as environmental influences that cause epithelial cell activation and release of alarmins (such as thymic stromal lymphopoietin) that can activate the type 2 immune pathway, including generation of interleukins 4 and 13, which induces defects in the skin barrier and increased allergic inflammation. These inflammatory pathways are further influenced by environmental factors including the microbiome (especially Staphylococcus aureus), air pollution, stress, and other factors. As such, AD is a syndrome involving multiple phenotypes, all of which have in common skin barrier dysfunction as a key contributing factor. Understanding mechanisms leading to skin barrier dysfunction in AD is pointing to the development of new topical and systemic treatments in AD that helps keep skin borders secure and effectively treat the disease.

Excess psoriasis and psoriatic arthritis mortality during the COVID-19 pandemic in the United States: A nationwide population-based study from 2010 to 2021.

BACKGROUND: Little is known about mortality trends among patients with psoriasis (PsO) and psoriatic arthritis (PsA) in the United States. OBJECTIVES: To ascertain mortality trends of PsO and PsA between 2010 and 2021, focusing on the effects of the COVID-19 pandemic. METHODS: We collected data from the National Vital Statistic System and calculated age-standardized mortality rates (ASMR) and cause-specific mortality for PsO/PsA. We evaluated observed versus predicted mortality for 2020-2021 based on trends from 2010 to 2019 with joinpoint and prediction modelling analysis. RESULTS: Among 5810 and 2150 PsO- and PsA-related deaths between 2010 and 2021, ASMR for PsO dramatically increased between 2010-2019 and 2020-2021 (annual percentage change [APC] 2.07% vs. 15.26%; p < 0.01), leading to a higher observed ASMR (per 100,000 persons) than predicted for 2020 (0.27 vs. 0.22) and 2021 (0.31 vs. 0.23). The excess mortality of PsO was 22.7% and 34.8% higher than that in the general population in 2020 (16.4%, 95% CI: 14.9%-17.9%) and 2021 (19.8%, 95% CI: 18.0%-21.6%) respectively. Notably, the ASMR rise for PsO was most pronounced in the female (APC: 26.86% vs. 12.19% in males) and the middle-aged group (APC: 17.67% vs. 12.47% in the old-age group). ASMR, APC and excess mortality for PsA were similar to PsO. SARS-CoV-2 infection contributed to more than 60% of the excess mortality for PsO and PsA. CONCLUSIONS: Individuals living with PsO and PsA were disproportionately affected during the COVID-19 pandemic. Both ASMRs increased at an alarming rate, with the most pronounced disparities among the female and middle-aged groups.

Alterations in epidermal function in type 2 diabetes: Implications for the management of this disease.

Epidermal function is regulated by numerous exogenous and endogenous factors, including age, psychological stress, certain skin disorders, ultraviolet irradiation and pollution, and epidermal function itself can regulate cutaneous and extracutaneous functions. The biophysical properties of the stratum corneum reflect the status of both epidermal function and systemic conditions. Type 2 diabetes in both murine models and humans displays alterations in epidermal functions, including reduced levels of stratum corneum hydration and increased epidermal permeability as well as delayed permeability barrier recovery, which can all provoke and exacerbate cutaneous inflammation. Because inflammation plays a pathogenic role in type 2 diabetes, a therapy that improves epidermal functions could be an alternative approach to mitigating type 2 diabetes and its associated cutaneous disorders.

Cetacean epidermal specialization: A review.

Cetacean skin continues to be the investigative focus of researchers from several different scientific disciplines. Yet, most research on the basic functions of lipo-keratinocytes, which constitute most of the cetacean epidermis, providing the first layer of protection against various environmental aggressors (including an ever-increasing level of pollutants), is restricted to specialized literature on the permeability barrier only. In this review, we have attempted to bring together much of the recent research on the functional biology of cetacean skin, including special adaptations at the cellular, genetic and molecular level. We have correlated these data with the cetacean permeability barrier's unique structural and metabolic adaptations to fully aquatic life, including the development of secondary barriers to ward off challenges such as biofouling as well as exposure to extreme cold for the epidermis, which is outside of the insulation provided by blubber. An apparent contradiction exists between some of the reported gene loss for lipogenic enzymes in cetacean skin and the high degree of cetacean epidermal lipogenesis, as well as loss of desmocollin 1 and desmoplakin genes [while immunolocalization of these proteins is reported (Journal of Anatomy, 234, 201)] warrants a re-evaluation of the gene loss data.

Mitochondrial Activity Is Upregulated in Nonlesional Atopic Dermatitis and Amenable to Therapeutic Intervention.

Previous work has shown increased expression of genes related to oxidative stress in nonlesional atopic dermatitis (ADNL) skin. Although mitochondria are key regulators of ROS production, their function in AD has never been investigated. Energy metabolism and the oxidative stress response were studied in keratinocytes (KCs) from patients with ADNL or healthy controls. Moreover, ADNL human epidermal equivalents were treated with tigecycline or MitoQ. We found that pyruvate and glucose were used as energy substrates by ADNL KCs. Increased mitochondrial oxidation of (very) long-chain fatty acids, associated with enhanced complexes I and II activities, was observed in ADNL KCs. Metabolomic analysis revealed increased tricarboxylic acid cycle turnover. Increased aerobic metabolism generated oxidative stress in ADNL KCs. ADNL human epidermal equivalents displayed increased mitochondrial function and an enhanced oxidative stress response compared with controls. Treatment of ADNL human epidermal equivalents with tigecycline or MitoQ largely corrected the AD profile, including high p-65 NF-κB, abnormal lamellar bodies, and cellular damage. Furthermore, we found that glycolysis supports but does not supersede mitochondrial metabolism in ADNL KCs. Thus, aerobic metabolism predominates in ADNL but leads to oxidative stress. Therefore, mitochondria could be a reservoir of potential therapeutic targets in atopic dermatitis.

Atopic Dermatitis: The Fate of the Fat.

Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease in which dry and itchy skin may develop into skin lesions. AD has a strong genetic component, as children from parents with AD have a two-fold increased chance of developing the disease. Genetic risk loci and epigenetic modifications reported in AD mainly locate to genes involved in the immune response and epidermal barrier function. However, AD pathogenesis cannot be fully explained by (epi)genetic factors since environmental triggers such as stress, pollution, microbiota, climate, and allergens also play a crucial role. Alterations of the epidermal barrier in AD, observed at all stages of the disease and which precede the development of overt skin inflammation, manifest as: dry skin; epidermal ultrastructural abnormalities, notably anomalies of the lamellar body cargo system; and abnormal epidermal lipid composition, including shorter fatty acid moieties in several lipid classes, such as ceramides and free fatty acids. Thus, a compelling question is whether AD is primarily a lipid disorder evolving into a chronic inflammatory disease due to genetic susceptibility loci in immunogenic genes. In this review, we focus on lipid abnormalities observed in the epidermis and blood of AD patients and evaluate their primary role in eliciting an inflammatory response.

Regulatory Role of Nitric Oxide in Cutaneous Inflammation.

Nitric oxide (NO), a signaling molecule, regulates biological functions in multiple organs/tissues, including the epidermis, where it impacts permeability barrier homeostasis, wound healing, and antimicrobial defense. In addition, NO participates in cutaneous inflammation, where it exhibits pro-inflammatory properties via the cyclooxygenase/prostaglandin pathway, migration of inflammatory cells, and cytokine production. Yet, NO can also inhibit cutaneous inflammation through inhibition of T cell proliferation and leukocyte migration/infiltration, enhancement of T cell apoptosis, as well as through down-regulation of cytokine production. Topical applications of NO-releasing products can alleviate atopic dermatitis in humans and in murine disease models. The underlying mechanisms of these discrepant effects of NO on cutaneous inflammation remain unknown. In this review, we briefly review the regulatory role of NO in cutaneous inflammation and its potential, underlying mechanisms.

Optimizing emollient therapy for skin barrier repair in atopic dermatitis.

OBJECTIVE: We compared the principal characteristics of over-the-counter moisturizers with physiological lipid-based barrier repair therapy (BRT). DATA SOURCES: An extended literature reported that moisturizers are considered standard ancillary therapy for anti-inflammatory skin disorders such as atopic dermatitis (AD). Additional studies have found that physiological lipid-based BRT can comprise effective, stand-alone therapy for pediatric AD. RESULTS: Not all moisturizers are beneficial-some negatively impact skin function, and in doing so, they risk inducing or exacerbating inflammation in patients with AD. The frequent self-reported occurrences of sensitive skin in patients with AD could reflect the potential toxicity of such formulations. A still unanswered question is whether improper formulations could also prove to be counterproductive in other types of sensitive skin, such as rosacea. In contrast, we found how physiological lipid-based BRT (when comprised of the 3 key stratum corneum lipids in sufficient quantities and at an appropriate molar ratio) can correct the barrier abnormality, thereby reducing inflammation in AD and possibly in other inflammatory dermatoses, such as adult eczemas and possibly even psoriasis. CONCLUSION: We provide guidelines for the appropriate dispensation of moisturizers and physiological lipid-based, BRT for the treatment of AD. Both over-the-counter (Atopalm) and prescription (EpiCeram) products are available in the United States with these characteristics.

Role of nitric oxide in regulating epidermal permeability barrier function.

Nitric oxide (NO), a free radical molecule synthesized by nitric oxide synthases (NOS), regulates multiple cellular functions in a variety of cell types. These NOS, including endothelial NOS (eNOS), inducible NOS (iNOS) and neural NOS (nNOS), are expressed in keratinocytes. Expression levels of both iNOS and nNOS decrease with ageing, and insufficient NO has been linked to the development of a number of disorders such as diabetes and hypertension, and to the severity of atherosclerosis. Conversely, excessive NO levels can induce cellular oxidative stress, but physiological levels of NO are required to maintain the normal functioning of cells, including keratinocytes. NO also regulates cutaneous functions, including epidermal permeability barrier homeostasis and wound healing, through its stimulation of keratinocyte proliferation, differentiation and lipid metabolism. Topical applications of a diverse group of agents which generate nitric oxide (called NO donors) such as S-nitroso-N-acetyl-D,L-penicillamine (SNAP) can delay permeability barrier recovery in barrier-disrupted skin, but iNOS is still required for epidermal permeability barrier homeostasis. This review summarizes the regulatory role that NO plays in epidermal permeability barrier functions and the underlying mechanisms involved.

Ichthyosis and hereditary cornification disorders in dogs.

The stratum corneum (SC), the outermost layer of the epidermis, serves a crucial role in maintaining body hydration and protection from environmental insults. When the stratum corneum is injured or when the genetic blueprints are flawed, the body is at risk of dehydration, secondary infections and allergen sensitization. Advancements in veterinary dermatology have revealed a wide gamut of disease from relatively benign to lethal that specifically arise from flawed structural proteins, enzymes or lipids needed to create the corneocytes and lipid bilayers of the SC. Some conditions closely mimic their human counterparts while others are unique to the dog. This review will focus on forms of ichthyosis in the dog.

La cornéogénèse est le processus par lequel les kératinocytes subissent une différenciation terminale de la couche basale de l'épiderme à la couche cornée hautement spécialisée (SC). Les termes cornéogénèse et kératinisation sont souvent utilisés comme synonymes ; la différence résulte de leur dérivation grecque (keras) versus latine (cornu). Les cornéocytes entièrement différenciés finissent par se répandre dans l'environnement sous forme de squame. En microscopie optique avec coloration de routine, les couches les plus externes de l'épiderme apparaissent sous la forme de minces disques éosinophiles entrelacés (arrangement dit "en tissage") qui est un artefact créé par la perte de lipides intercellulaires pendant le traitement des tissus (Figure 1). Bien qu'historiquement ignorés en tant que débris tissulaires, le SC est maintenant connu pour être indispensable à la fois pour maintenir l'hydratation du corps et pour se protéger des agressions environnementales. En effet, l'acquisition du SC hydrophobe était une réalisation évolutive majeure qui a permis la colonisation terrestre des terres par des mammifères aquatiques intrépides. Il convient de noter que nos connaissances actuelles sur la fonction de barrière cutanée et le processus de cornéogénèse reposent en grande partie sur des études sur des souris sans poils, immunocompétentes (c'est-à-dire Skh1) et sur la peau humaine. Cependant, nos chiens de compagnie peuvent également fournir de nombreuses informations. Les modèles murins d'ingénierie (par exemple, les knock-out Pnlp1 et Nipal4) d'ichtyose congénitale autosomique récessive (ARCI) sont généralement mortels à la naissance, tandis que les chiens avec un ARCI comparable vivent en bonne santé malgré une mise à l'échelle excessive. Il est bien établi que certaines maladies spontanées chez le chien (par exemple, la dermatite atopique) imitent davantage les conditions humaines que les modèles murins induits chimiquement ou génétiquement. Cette revue se concentre sur ces troubles chez le chien et, le cas échéant, les conditions comparables chez l'homme.

La cornificación es el proceso mediante el cual los queratinocitos experimentan una diferenciación terminal desde la capa basal de la epidermis hasta el estrato córneo (SC) altamente especializado. Los términos cornificación y queratinización se utilizan a menudo como sinónimos; la diferencia resulta de su derivación griega (keras) versus latina (cornu). Los corneocitos completamente diferenciados eventualmente se desprenden al medio ambiente como escamas. En la microscopía óptica con tinción de rutina, las capas más externas de la epidermis aparecen como discos entrelazados eosinófilos delgados (la denominada disposición de "tejido en cesta"), que es un artefacto creado por la pérdida de lípidos intercelulares durante el procesamiento del tejido (Figura 1). Si bien históricamente se ha ignorado como restos de tejido, ahora se sabe que el SC es indispensable tanto para mantener la hidratación corporal como para protegerlo de las agresiones ambientales. De hecho, la obtención del SC hidrofóbico fue un logro evolutivo importante que permitió la colonización terrestre de la tierra por intrépidos mamíferos acuáticos. Cabe señalar que nuestro conocimiento actual de la función de la barrera cutánea y el proceso de cornificación se basa en gran medida en estudios en ratones inmunocompetentes sin pelo (es decir, Skh1) y piel humana; sin embargo, nuestros perros de compañía también pueden proporcionar información abundante.2 Los modelos de ratón genéticamente seleccionados (p. ej., knockouts de Pnlp1 y Nipal4) con ictiosis congénita autosómica recesiva (ARCI) suelen ser letales al nacer, mientras que los perros con ARCI comparables viven vidas saludables a pesar de la descamación excesiva. 4 Está bien establecido que algunas enfermedades espontáneas en los perros (por ejemplo, la enfermedad atópica de la piel) imitan las condiciones humanas más que los modelos de ratón inducidos química o genéticamente.5 Esta revisión se centra en estos trastornos en los perros y, en momentos apropiados, en los condiciones comparables en humanos.

Cornificação é o processo pelo qual os queratinócitos sofrem diferenciação terminal desde a camada basal da epiderme até o altamente especializado estrato córneo (SC). Os termos cornificação e queratinização são frequentemente usados como sinônimos; a diferença resulta de sua derivação grega (keras) versus latina (cornu). Os corneócitos totalmente diferenciados são eventualmente eliminados no ambiente na forma de escamas. À microscopia ótica com corantes de rotina, as camadas mais externas da epiderme aparecem como discos eosinofílicos entrelaçados finos (o chamado arranjo em bolsa de cesto), que é um artefato criado pela perda de lipídios intercelulares durante o processamento do tecido (Figura 1). Embora historicamente tenha sido considerado como debris teciduais, o SC agora é conhecido por ser indispensável tanto para manter a hidratação corporal quanto para proteção contra agressões ambientais. De fato, o SC hidrofóbico foi uma importante conquista evolutiva que permitiu a colonização terrestre da terra por intrépidos mamíferos aquáticos1 . É de grande relevância notar que o nosso conhecimento atual da função de barreira da pele e do processo de cornificação é amplamente baseado em estudos em camundongos sem pelos, imunocompetentes (ex: Skh1) e pele humana; no entanto, nossos cães de companhia também podem fornecer insights abundantes.2 Modelos de camundongos projetados (por exemplo, nocautes Pnlp1 e Nipal4) de ictiose congênita autossômica recessiva (ARCI) normalmente são letais no nascimento, enquanto cães com ARCI comparáveis vivem vidas saudáveis apesar da descamação excessiva.3, 4 Já bem estabelecido que algumas doenças espontâneas em cães (por exemplo, dermatite atópica) imitam as condições humanas mais do que modelos de camundongos induzidos quimicamente ou geneticamente.5 Esta revisão enfoca esses distúrbios em cães e, quando apropriado, o condições comparáveis em humanos.

Effect of sunflower seed oil emollient therapy on newborn infant survival in Uttar Pradesh, India: A community-based, cluster randomized, open-label controlled trial.

BACKGROUND: Hospitalized preterm infants with compromised skin barrier function treated topically with sunflower seed oil (SSO) have shown reductions in sepsis and neonatal mortality rate (NMR). Mustard oil and products commonly used in high-mortality settings may possibly harm skin barrier integrity and enhance risk of infection and mortality in newborn infants. We hypothesized that SSO therapy may reduce NMR in such settings. METHODS AND FINDINGS: This was a population-based, cluster randomized, controlled trial in 276 clusters in rural Uttar Pradesh, India. All newborn infants identified through population-based surveillance in the study clusters within 7 days of delivery were enrolled from November 2014 to October 2016. Exclusive, 3 times daily, gentle applications of 10 ml of SSO to newborn infants by families throughout the neonatal period were recommended in intervention clusters (n = 138 clusters); infants in comparison clusters (n = 138 clusters) received usual care, such as massage practice typically with mustard oil. Primary analysis was by intention-to-treat with NMR and post-24-hour NMR as the primary outcomes. Secondary analysis included per-protocol analysis and subgroup analyses for NMR. Regression analysis was adjusted for caste, first-visit weight, delivery attendant, gravidity, maternal age, maternal education, sex of the infant, and multiple births. We enrolled 13,478 (52.2% male, mean weight: 2,575.0 grams ± standard deviation [SD] 521.0) and 13,109 (52.0% male, mean weight: 2,607.0 grams ± SD 509.0) newborn infants in the intervention and comparison clusters, respectively. We found no overall difference in NMR in the intervention versus the comparison clusters [adjusted odds ratio (aOR) 0.96, 95% confidence interval (CI) 0.84 to 1.11, p = 0.61]. Acceptance of SSO in the intervention arm was high at 89.3%, but adherence to exclusive applications of SSO was 30.4%. Per-protocol analysis showed a significant 58% (95% CI 42% to 69%, p < 0.01) reduction in mortality among infants in the intervention group who were treated exclusively with SSO as intended versus infants in the comparison group who received exclusive applications of mustard oil. A significant 52% (95% CI 12% to 74%, p = 0.02) reduction in NMR was observed in the subgroup of infants weighing ≤1,500 g (n = 589); there were no statistically significant differences in other prespecified subgroup comparisons by low birth weight (LBW), birthplace, and wealth. No severe adverse events (SAEs) were attributable to the intervention. The study was limited by inability to mask allocation to study workers or participants and by measurement of emollient use based on caregiver responses and not actual observation. CONCLUSIONS: In this trial, we observed that promotion of SSO therapy universally for all newborn infants was not effective in reducing NMR. However, this result may not necessarily establish equivalence between SSO and mustard oil massage in light of our secondary findings. Mortality reduction in the subgroup of infants ≤1,500 g was consistent with previous hospital-based efficacy studies, potentially extending the applicability of emollient therapy in very low-birth-weight (VLBW) infants along the facility-community continuum. Further research is recommended to develop and evaluate therapeutic regimens and continuum of care delivery strategies for emollient therapy for newborn infants at highest risk of compromised skin barrier function. TRIAL REGISTRATION: ISRCTN Registry ISRCTN38965585 and Clinical Trials Registry-India (CTRI/2014/12/005282) with WHO UTN # U1111-1158-4665.

Phenotypic overlap between atopic dermatitis and autism.

BACKGROUND: Autism, a childhood behavioral disorder, belongs to a large suite of diseases, collectively referred to as autism spectrum disorders (ASD). Though multifactorial in etiology, approximately 10% of ASD are associated with atopic dermatitis (AD). Moreover, ASD prevalence increases further as AD severity worsens, though these disorders share no common causative mutations. We assessed here the link between these two disorders in the standard, valproic acid mouse model of ASD. In prior studies, there was no evidence of skin involvement, but we hypothesized that cutaneous involvement could be detected in experiments conducted in BALB/c mice. BALB/c is an albino, laboratory-bred strain of the house mouse and is among the most widely used inbred strains used in animal experimentation. METHODS: We performed our studies in valproic acid (VPA)-treated BALB/c hairless mice, a standard mouse model of ASD. Mid-trimester pregnant mice received a single intraperitoneal injection of either valproic acid sodium salt dissolved in saline or saline alone on embryonic day 12.5 and were housed individually until postnatal day 21. Only the brain and epidermis appeared to be affected, while other tissues remain unchanged. At various postnatal time points, brain, skin and blood samples were obtained for histology and for quantitation of tissue sphingolipid content and cytokine levels. RESULTS: AD-like changes in ceramide content occurred by day one postpartum in both VPA-treated mouse skin and brain. The temporal co-emergence of AD and ASD, and the AD phenotype-dependent increase in ASD prevalence correlated with early appearance of cytokine markers (i.e., interleukin [IL]-4, 5, and 13), as well as mast cells in skin and brain. The high levels of interferon (IFN)γ not only in skin, but also in brain likely account for a significant decline in esterified very-long-chain N-acyl fatty acids in brain ceramides, again mimicking known IFNγ-induced changes in AD. CONCLUSION: Baseline involvement of both AD and ASD could reflect concurrent neuro- and epidermal toxicity, possibly because both epidermis and neural tissues originate from the embryonic neuroectoderm. These studies illuminate the shared susceptibility of the brain and epidermis to a known neurotoxin, suggesting that the atopic diathesis could be extended to include ASD.