Cutaneous Exposure Research Articles

Cutaneous lewisite exposure causes acute lung injury.

Lewisite is a strong vesicating and chemical warfare agent. Because of the rapid transdermal absorption, cutaneous exposure to lewisite can also elicit severe systemic injury. Lewisite (2.5, 5.0, and 7.5 mg/kg) was applied to the skin of Ptch1+/- /SKH-1 mice and acute lung injury (ALI) was assessed after 24 hours. Arterial blood gas measurements showed hypercapnia and hypoxemia in the lewisite-exposed group. Histological evaluation of lung tissue revealed increased levels of proinflammatory neutrophils and a dose-dependent increase in structural changes indicative of injury. Increased inflammation was also confirmed by altered expression of cytokines, including increased IL-33, and a dose-dependent elevation of CXCL1, CXCL5, and GCSF was observed in the lung tissue. In the bronchoalveolar lavage fluid of lewisite-exposed animals, there was a significant increase in HMGB1, a damage-associated molecular pattern molecule, as well as elevated CXCL1 and CXCL5, which coincided with an influx of neutrophils to the lungs. Complete blood cell analysis revealed eosinophilia and altered neutrophil-lymphocyte ratios as a consequence of lewisite exposure. Mean platelet volume and RBC distribution width, which are predictors of lung injury, were also increased in the lewisite group. These data demonstrate that cutaneous lewisite exposure causes ALI and may contribute to mortality in exposed populations.

Nettle Agent Phosgene Oxime Toxicity and Related Mechanism from its Dermal Exposure

Phosgene Oxime (dichloroform oxime; CX), an urticant or nettle agent categorized as a vesicant, is a potential chemical threat agent. Its exposure causes rapid toxicity, severe pain with dermal symptoms including erythema (redness), urticaria, blanching, itching hives, necrosis and systemic effects. Due to its fast penetration, severe dermal injury, and instant lethal toxic effects resulting in high mortality, CX could be weaponized with other chemical threat agents to enhance their deleterious effects. Skin damage with erythema, necrosis and inflammation following cutaneous exposure to CX and vesicants, e.g. sulfur mustard (SM; mustard gas), nitrogen mustard (NM) and lewisite (L), is similar; however, CX also causes severe skin injury with immediate urticaria and blanching as well as mortality. The skin urticaria from CX resembles urticaria caused by allergic and non‐allergic reactions to various environmental substances and can occur alone or can be associated with lethal allergic reaction, anaphylaxis. CX is one of the least studied vesicating agent with no effective treatment available. In the present study, we exposed the dorsal skin of SKH‐1 hairless mice with neat CX for 0.5 and 1.0 min using two 12 mm vapor caps, and studied different parameters associated with its pathophysiology. Clinical data from our study showed that CX exposure leads to acute skin lesions (edema, erythema, necrosis, urticaria and blanching) as well as decreases in heart and respiratory rate, drop in body temperature, vasculature dilation and blood congestion in multiple organs indicating urticaria and anaphylaxis. Histopathological analysis showed a CX‐induced increase of over 2‐fold in the mouse skin epidermal thickness at 2 hr and 14 days following 0.5 min and 1.0 min exposures, respectively. Similarly, 1.5–2.0‐fold increase in dermal plus hypodermal thickening was observed at all study time points following 0.5 and 1.0 min CX exposures. Dermal fibrosis, necrotic blood vessels, hyperkeratosis, cell death and an increase in inflammatory cells was also observed at day 1 and 14 following 0.5 min CX exposure. Edema, necrosis and dying fat cells were observed within 2 hr in the skin of both the CX exposure groups. CX induced an increase in mast cell degranulation within 30 min of its exposure which peaked to over 90% at 24 hr post exposure and was associated with increased histamine and tryptase levels. In addition, an increase in the level of MMP9 and DNA damage maker (pH2AX) in skin tissues was also observed. The results from our completed studies suggest that mast cells could be important players in CX‐ and probably other vesicating agents‐induced toxicity. Hence, molecular markers and cytokines associated with CX‐induced mast cell degranulation as well as inflammatory and DNA damage responses are being evaluated to identify the signaling pathways and key molecular targets for further therapeutic approaches to counteract toxicity from CX cutaneous exposure in case of a chemical emergency.

Peanut applied to the skin of nonhuman primates induces antigen-specific IgG but not IgE.

IntroductionPrevious studies in humans support the dual‐allergen exposure hypothesis, and several studies in mouse models have demonstrated that cutaneous exposure to disrupted or intact skin can lead to sensitization to peanut. However, the field lacks definitive evidence that cutaneous exposure leads to peanut allergy in humans or other primates.MethodsPeanut extract was applied to the shaved back of the neck of four male and four female African green monkeys three times per week for 4 weeks. An oral food challenge (OFC) was performed the following week by gavage of 200 mg of peanut protein, and vital signs were monitored for 30 minutes post‐OFC. Blood was collected at baseline, day 11, day 32, and 30 minutes post‐OFC. Total IgE, and peanut‐specific immunoglobulin E (IgE) and immunoglobulin G (IgG) were quantified in serum collected throughout the 4 weeks. Histamine was measured in serum collected 30 minutes post‐OFC.ResultsPeanut‐specific IgE was undetectable at any time points in any of the monkeys, and there was no consistent increase in total IgE. During the oral challenge, none of the monkeys experienced allergic symptoms and histamine levels did not change. However, seven of the eight monkeys produced increasing peanut‐specific IgG by day 32, indicating that repeated skin exposure to peanut is immunogenic.ConclusionsSkin exposure to peanut did not lead to sensitization in this study, and monkeys did not experience anaphylaxis upon peanut challenge. However, monkeys produced increased peanut‐specific IgG throughout peanut exposure, indicating that repeated skin exposure to peanut is immunogenic.

In hot water: effects of climate change on Vibrio-human interactions.

Sea level rise and the anthropogenic warming of the world's oceans is not only an environmental tragedy, but these changes also result in a significant threat to public health. Along with coastal flooding and the encroachment of saltwater farther inland comes an increased risk of human interaction with pathogenic Vibrio species, such as Vibrio cholerae, V. vulnificus and V. parahaemolyticus. This minireview examines the current literature for updates on the climatic changes and practices that impact the location and duration of the presence of Vibrio spp., as well as the infection routes, trends and virulence factors of these highly successful pathogens. Finally, an overview of current treatments and methods for the mitigation of both oral and cutaneous exposures are presented.

Zoonotic Diseases from Horses: A Systematic Review.

Background: Worldwide, horses play critical roles in recreation, food production, transportation, and as working animals. Horses' roles differ by geographical region and the socioeconomic status of the people, but despite modern advances in transportation, which have in some ways altered humans contact with horses, potential risks for equine zoonotic pathogen transmission to humans occur globally. While previous reports have focused upon individual or groups of equine pathogens, to our knowledge, a systematic review of equine zoonoses has never been performed. Methods: Using PRISMA's systematic review guidelines, we searched the English literature and identified 233 previous reports of potential equine zoonoses found in horses. We studied and summarized their findings with a goal of identifying risk factors that favor disease transmission from horses to humans. Results: These previous reports identified 56 zoonotic pathogens that have been found in horses. Of the 233 articles, 13 involved direct transmission to humans (5.6%).The main potential routes of transmission included oral, inhalation, and cutaneous exposures. Pathogens most often manifest in humans through systemic, gastrointestinal, and dermatological signs and symptoms. Furthermore, 16.1% were classified as emerging infectious diseases and thus may be less known to both the equine and human medical community. Sometimes, these infections were severe leading to human and equine death. Conclusions: While case reports of zoonotic infections directly from horses remain low, there is a high potential for underreporting due to lack of knowledge among health professionals. Awareness of these zoonotic pathogens, their disease presentation in horses and humans, and their associated risk factors for cross-species infection are important to public health officials, clinicians, and people with recreational or occupational equid exposure.

The impact of airborne pollution on atopic dermatitis: a literature review.

The increasing prevalence of atopic dermatitis (AD) parallels a global rise in industrialization and urban living over recent decades. This shift in lifestyle is accompanied by greater cutaneous exposure to environmental pollutants during the course of daily activities. The objectives of this review are to highlight the effects of airborne pollution on epidermal barrier function, examine evidence on the relationship between pollutants and AD, synthesize a proposed mechanism for pollution-induced exacerbation of AD, and identify potential methods for the reduction and prevention of pollutant-induced skin damage. The literature review was done by searching the PubMed, Embase and Google Scholar databases. Inclusion criteria were invitro and animal studies, clinical trials and case series. Non-English-language publications, review articles and case reports were excluded. Pollutants induce cutaneous oxidative stress and have been shown to damage skin barrier integrity by altering transepidermal water loss, inflammatory signalling, stratum corneum pH and the skin microbiome. AD represents a state of inherent barrier dysfunction, and both long- and short-term pollutant exposure have been linked to exacerbation of AD symptoms and increased AD rates in population studies. Airborne pollutants have a detrimental effect on skin barrier integrity and AD symptoms, and appear to pose a multifaceted threat in AD through several parallel mechanisms, including oxidative damage, barrier dysfunction, immune stimulation and propagation of the itch-scratch cycle. Future research is needed to elucidate specific mechanisms of pollution-induced epidermal barrier dysfunction and to identify efficacious methods of skin barrier repair and protection against pollutant-driven damage.

Viruses in Skin Cancer (VIRUSCAN): Study Design and Baseline Characteristics of a Prospective Clinic-Based Cohort Study.

Accumulating evidence suggests that cutaneous viral infections are risk factors for the development of keratinocyte carcinomas. The Viruses in Skin Cancer (VIRUSCAN) Study, a prospective cohort study, was established in 2014 to investigate the risk of keratinocyte carcinoma associated with cutaneous human papillomavirus and polyomavirus infection and the possible interaction with ultraviolet radiation exposure (UVR). VIRUSCAN incorporates repeated measures of viral infection using multiple markers of infection and quantitative measures of UVR using a spectrophotometer. Participants were recruited between July 14, 2014 and August 31, 2017 at the University of South Florida Dermatology Clinic in Tampa, FL. After excluding 124 individuals with prevalent keratinocyte carcinomas at baseline, 1,179 participants (53.2% women, 46.8% men, all ages 60 years and older) were followed for up to 4 years with routine skin exams occurring every 6 to 12 months. Here, we present the VIRUSCAN Study design, methods, and baseline characteristics, including demographics, sun exposure behavior, quantitative UVR exposure measurements, and cutaneous viral prevalence, for the full study cohort. The VIRUSCAN Study will provide critical temporal evidence needed to assess the causality of the role cutaneous viral infections play in the development of keratinocyte carcinomas, as well as the potential interaction between cutaneous viral infections and UVR exposure. Study findings will be valuable in future development of novel keratinocyte carcinoma prevention strategies.

Late effects of cutaneous 3-methylcholanthrene exposure on DNA damage-related pleiotropic growth factors and oxidative stress markers in mice

Skin is the body's first defence against direct exposure to variety of chemicals. Polycyclic aromatic hydrocarbons such as 3-methylcholanthrene (3-MC) are common in polluted urban air and have a potential of producing harmful effects. Moreover, their late effects can occur months or years after exposure.We aimed to investigate the long-term effects of 3-MC induced dermal toxicity on the expression of markers of apoptosis, pleiotropic cytokines, and oxidative stress and to determine the protective effect of cisplatin.Groups were designed as control (group 1), 3-MC applied (group 2) and 3-MC+cisplatin applied mice (group 3). Cutaneous expressions of TGFβ, PDGFA, PDGFC, bFGF, PDGFRα, USP28, and Ki67 were evaluated with qPCR. Total oxidant (TOS), total antioxidant (TAS) and oxidative stress index (OSI) values were determined in liver and kidney tissues.The expression levels of TGFβ, PDGFRα, USP-28, Ki67, and PDGFA were decreased significantly in MC applied groups. Renal TAS levels were significantly lower in group-3. Liver and kidney OSI values were increased in both groups 2 and 3.The results indicated that low dose 3-MC caused oxidative stress and downregulated apoptotic and cytokine markers in the long term and cisplatin had no ameliorative effects on this degeneration processes (Tab. 3, Fig. 3, Ref. 32). Text in PDF www.elis.sk.

DERMAL ABSORPTION OF DIQUAT AND POTENTIAL OCCUPATIONAL RISK

The aim: The toxicological-hygienic assessment of dermal absorption of diquat in terms of potential risk of its bioavailability in professional use. Materials and methods: The object of the study was cutaneous exposure of diquat, determined in toxicological experiments of different duration (data of scientific literature) and at the stage of state testing of pesticide preparations based on diquat dibromide (data of a full-scale hygiene experiment, prognostic model of risk assessment), the technical concentrate of diquat dibromide (active substance content not less than 377 g / kg) contains relevant supplements, the content of which is regulated by the Food and Agriculture Organization. Results and conclusions: Due to the high risk of the diquat adverse effects affecting the personnel, general public and environment, the European Union has introduced administrative decisions to forbid plant protection products containing the diquat. Fulfillment of the conditions of the Association Agreement between Ukraine and the European Union indicates the need to develop common regulations and risk assessment methods aimed at ensuring high level of protection of human health and the environment.

Toxic effects of cutaneous and oral exposure to aluminum and magnesium nanoparticles on brain tissue in rats

In this study, it was aimed to research the effects of cutaneous and oral exposure to aluminum nanoparticles (Al-NPs) and magnesium nanoparticles (Mg-NPs) on the brain tissue, which is vitally important in terms of its structure and functions. The study was performed on Wister-Albino rats, which were divided into 10 groups, such as control groups (groups 1 and 2), groups, to which Al and Mg NPs were applied as 500 mg/kg and 1500 mg/kg orally (groups 3-6) and 1000 mg/kg and 2000 mg/kg cutaneously (groups 7-10). The dosages were administered as a single dose. While brain tissue and serum MDA levels as well as brain tissue TNF-α and IL-6 levels have significantly increased in the group, to which 1500 mg/kg Mg-NPs was applied orally, significant decreases have also been observed in brain tissue GPX and SOD levels of the same group. Additionally, meaningful decreases in brain tissue SOD levels and significant increases in TNF-α and IL-6 levels have been observed in the group, to which 1500 mg/kg Al-NP was applied orally. On the other hand, it was found that brain tissue GPX and SOD levels of the group, to which 2000 mg/kg Mg-NP was applied cutaneous, have been decreased significantly. Histopathological examinations have also supported these findings. At the end of the study, it was observed that the toxic effect of Al and Mg NPs has varied, depending on the application method, dosage and duration.

Melanin has a Small Inhibitory Effect on Cutaneous Vitamin D Synthesis: A Comparison of Extreme Phenotypes

Epidemiology suggests that melanin inhibits cutaneous vitamin D3 synthesis by UVR. Laboratory investigations assessing the impact of melanin on vitamin D production have produced contradictory results. We determined the effect of melanin on vitamin D3 photosynthesis in healthy young volunteers (n= 102) of Fitzpatrick skin types II-VI (white to black). Participants, irrespective of skin type, were exposed to the same suberythemal UVR dose, to 85% body surface area, using solar simulated UVR or narrowband UVB (311 nm). This was repeated five times with intervals of 3-4 days between UVR exposures. Blood was taken before, during, and after the irradiation and assessed for serum 25-hydroxyvitamin D3 (25[OH]D3) as a marker of vitamin D3 status. Linear UVR dose-dependent increases in 25(OH)D3 were highly significant (P ≤ 7.7 x 10-11). The ratios of regression slopes of the different skin type groups were compared, and only skin type II was significantly steeper than the other groups. Comparisons between extreme skin types II and VI showed melanin inhibition factors of approximately 1.3-1.4, depending on the UVR source. We conclude that the inhibitory effect of melanin on vitamin D3 synthesis is small, compared with erythema, but that this difference may be sufficient to explain the epidemiological data.

Metabolism and genotoxicity of polycyclic aromatic hydrocarbons in human skin explants: mixture effects and modulation by sunlight.

Cutaneous exposure to carcinogenic polycyclic aromatic hydrocarbons (PAH) occurs frequently in the industrialized workplace. In the present study, we addressed this topic in a series of experiments using human skin explants and organic extracts of relevant industrial products. PAH mixtures were applied topically in volumes containing either 10 or 1nmol B[a]P. We first observed that although mixtures were very efficient at inducing expression of CYP450 1A1, 1A2, and 1B1, formation of adducts of PAH metabolites to DNA, like those of benzo[a]pyrene diol epoxide (BPDE), was drastically reduced as the complexity of the surrounding matrix increased. Interestingly, observation of a nonlinear, dose-dependent response with the least complex mixture suggested the existence of a threshold for this inhibitory effect. We then investigated the impact of simulated sunlight (SSL) on the effects of PAH in skin. SSL was found to decrease the expression of CYP450 genes when applied either after or more efficiently before PAH treatment. Accordingly, the level of DNA-BPDE adducts was reduced in skin samples exposed to both PAH and SSL. The main conclusion of our work is that both increasing chemical complexity of the mixtures and co-exposure to UV radiation decreased the production of adducts between DNA and PAH metabolites. Such results must be taken into account in risk management.

Гігієнічне нормування флупірадифурону та обґрунтування регламентів безпечного застосування інсектициду на його основі для захисту виноградників, яблунь, груш і капусти

ABSTRACT. Flupyradifurone is an insecticide recommended to protect vineyards, apple, pear trees and cabbage in agriculture. For the state registration in Ukraine, toxicological and hygienic assessment of flupyradifurone and its insecticidal product Sivanto Prime 200 SL was performed. Acceptable daily intake of flupyradifurone for human was justified at the level of 0.02 mg/kg; hygienic standards for flupyradifurone and regulations for the safe use of insecticide Sivanto Prime 200 SL, in agriculture were developed. Objective. Toxicological and hygienic assessment of flupyradifurone and its insecticidal preparation, evaluation of the risk of rural labourers and population exposure. Methods. Expert and analytical, toxicological, physical and chemical, statistical and hygienic. Results. Based on acute toxicity parameters for different ways of exposure, flupyradifurone and Sivanto Prime 200 SL are rated as hazard class II. Long-term effects (carcinogenicity, mutagenicity and teratogenicity, reproductive and developmental toxicity) are not limiting criteria when assessing flupyradifurone hazard. Field trials have shown that residual flupyradifurone was not detectable in grapes, apples, pears and cabbage during harvesting. Occupational risk degree under inhalation and cutaneous exposure of labours to flupyradifurone was within the acceptable level. Conclusion. Use of flupyradifurone-based insecticide Sivanto Prime 200 SL for the protection of vineyards, apple, pear trees and cabbage as per agricultural and hygienic standards and regulations will not lead to contamination of agricultural products and environmental objects and will be safe for the population. Keywords: insecticide, flupyradifurone, toxicological properties, hygienic standards and regulations, hazard assessment.

Polycyclic Aromatic Hydrocarbons Exposure Assessment in a Refractory Brick Production.

In a refractory brick manufacturing company a qualitative and quantitative determination of the sources of occupational exposure to polycyclic aromatic hydrocarbons (PAHs) was obtained in order to validate targeted hygiene measurements. The study included the assessment of PAHs contamination of work surfaces by wipe-sampling, cutaneous exposure by hand washing, contamination of personal protective equipments (gloves) by extraction in solvent, and airborne PAHs concentration in atmospheric samples. Biomonitoring was also carried out by measurement of urinary 1-hydroxypyrene (1-OHPU) in three groups of workers (packaging, production, and controls). The surface contamination sampling was performed in production, packaging, and in other departments (external area) in theory less contaminated by PAHs. Two different areas were identified within the production, one included surfaces that were regularly cleaned (A area) and one included data from non-cleaned surfaces (B area). To confirm the source of exposure, a clear correspondence was observed between the percentage of the single compounds in the binder and those measured in wipes and air samples. As far as the wipes are concerned, the concentrations of phenanthrene, anthracene, fluoranthene, pyrene, benzo(a)pyrene (BaP), and the total PAHs mixture were higher in the B area than the A area of production. The same happened between the A area and the other two departments. According to results of the statistical analysis, these differences were significant. These results were confirmed by the hand washing data and the analysis of PPE. On the other hand, a marked difference does not exist between the packaging department and the external area. In air samples, the differences were much less evident with only higher concentrations of anthracene and total PAHs between production as a whole and the other two departments. Biological monitoring showed 1-OHPU values significantly higher in production workers than in packaging workers. In conclusion, the analysis of the wipes demonstrated that the production B area has a higher surface contamination compared to the production A area and the packaging department. In the absence of a significant difference in air concentrations of PAHs between A and B areas, this is attributable to surfaces not subject to cleaning. Results confirm that the measurement of surface contamination represents a valid tool for the assessment of sources of exposure to PAHs in the workplace.

Cutaneous Exposure to Clinically Relevant Lone Star Ticks Promotes IgE Production and Hypersensitivity through CD4+ T Cell- and MyD88-Dependent Pathways in Mice.

Tick-borne allergies are a growing public health concern and have been associated with the induction of IgE-mediated food allergy to red meat. However, despite the increasing prevalence of tick bite-induced allergies, the mechanisms by which cutaneous exposure to ticks leads to sensitization and the production of IgE Abs are poorly understood. To address this question, an in vivo approach was used to characterize the IgE response to lone star tick proteins administered through the skin of mice. The results demonstrated that tick sensitization and challenge induced a robust production of IgE Abs and supported a role for IgE-mediated hypersensitivity reactions in sensitized animals following oral administration of meat. The induction of IgE responses was dependent on cognate CD4+ T cell help during both the sensitization phase and challenge phase with cutaneous tick exposure. In addition, IgE production was dependent on B cell-intrinsic MyD88 expression, suggesting an important role for TLR signaling in B cells to induce IgE responses to tick proteins. This model of tick-induced IgE responses could be used to study the factors within tick bites that cause allergies and to investigate how sensitization to food Ags occurs through the skin that leads to IgE production.

A keratinocyte and integrated fibroblast culture model for studying particulate matter-induced skin lesions and therapeutic intervention of fucosterol

Increased levels of particulate matter (PM) air pollutants in East Asia have resulted in detrimental health impacts increasing morbidity and mortality. Epidemiological studies suggest a possible relation between the cutaneous exposure of PM and increased oxidative stress and inflammation which lead to skin lesions. The present study utilizes an integrated cell culture model of keratinocytes and fibroblasts to mimic viable skin layers and investigate the possible effects of PM exposure after penetration through corneocytes. The skin perfection is upheld by homeostatic functionality of epidermal cells and the integrity of connective tissues. Exposure to xenobiotics could alter the skin cell homeostasis aggravating premature skin aging. Stimulation of HaCaT keratinocytes by PM collected from Beijing, China (CPM) increased the intracellular ROS levels triggering a cascade of events aggravating inflammatory responses and connective tissue degradation. In HDF fibroblasts, treatment with preconditioned keratinocyte culture media augmented inflammatory responses, cellular differentiation, and connective tissue degradation. Above events were marked by the increased intracellular ROS, inflammatory mediators, pro-inflammatory cytokines, matrix metalloproteinases (MMP)-1 and -2 levels, collagenase, and elastase activity. Fucosterol treatment of keratinocytes dose-dependently attenuated the detrimental effects both in keratinocytes and fibroblasts restoring the conditions near to physiological levels. Further evaluations could be advanced on developing fucosterol, in forms such as rejuvenating cosmeceuticals which could attenuate detrimental responses of CPM exposure.

Endocrine aryl hydrocarbon receptor signaling is induced by moderate cutaneous exposure to ultraviolet light

Links between solar UV exposure and immunity date back to the ancient Greeks with the development of heliotherapy. Skin contains several UV-sensitive chromophores and exposure to sunlight can produce molecules, such as vitamin D3, that act in an endocrine manner. We investigated the role of the aryl hydrocarbon receptor (AHR), an environmental sensor and ligand-regulated transcription factor activated by numerous planar compounds of endogenous, dietary or environmental origin. 15- to 30-minute exposure of cells to a minimal erythemal dose of UVB irradiation in vitro induced translocation of the AHR to the nucleus, rapidly inducing site-specific DNA binding and target gene regulation. Importantly, ex vivo studies with Ahr wild-type or null fibroblasts showed that serum from mice whose skin was exposed to a 15 min UVB dose, but not control serum, contained agonist activity within 30 min of UV irradiation, inducing AHR-dependent gene expression. Moreover, a 15-min cutaneous UVB exposure induced AHR site-specific DNA binding and target gene regulation in vivo within 3–6 hr post-irradiation in blood and in peripheral tissues, including intestine. These results show that cutaneous exposure of mice to a single minimal erythemic dose of UVB induces rapid AHR signaling in multiple peripheral organs, providing compelling evidence that moderate sun exposure can exert endocrine control of immunity through the AHR.

Allergen-induced histaminergic and non-histaminergic activation of itch C-fiber nerve terminals in mouse skin

Acute cutaneous exposure to allergen often leads to itch, but seldom pain. The effect of mast cell activation on cutaneous C-fibers was studied using innervated isolated mouse skin preparation that allows for intra-arterial delivery of chemicals to the nerve terminals in the skin. Allergen (ovalbumin) injection into the isolated skin of actively sensitized mice strongly stimulated chloroquine (CQ)-sensitive C-fibers (also referred to as “itch” nerves); on the other hand, CQ-insensitive C-fibers were activated only modestly, if at all. The histamine H1 receptor antagonist pyrilamine abolished itch C-fibers response to histamine, but failed to significantly reduce the response to ovalbumin. Ovalbumin also strongly activated itch C-fibers in skin isolated from Mrgpr-cluster Δ−/− mice. When pyrilamine was studied in the Mrgpr-cluster Δ−/− mice thereby eliminating the influence of both histamine H1 and Mrgpr receptors (MrgprA3 and C11 are selectively expressed by itch nerves), the ovalbumin response was very nearly eliminated. The data indicate that the acute activation of itch C-fibers in mouse skin is largely secondary to the combined effect of activation of histamine H1 and Mrpgr receptors.

TLR4 in skin cancer: From molecular mechanisms to clinical interventions.

The health and economic burden imposed by skin cancer is substantial, creating an urgent need for the development of improved molecular strategies for its prevention and treatment. Cutaneous exposure to solar ultraviolet (UV) radiation is a causative factor in skin carcinogenesis, and TLR4-dependent inflammatory dysregulation is an emerging key mechanism underlying detrimental effects of acute and chronic UV exposure. Direct and indirect TLR4 activation, upstream of inflammatory signaling, is elicited by a variety of stimuli, including pathogen-associated molecular patterns (such as lipopolysaccharide) and damage-associated molecular patterns (such as HMGB1) that are formed upon exposure to environmental stressors, such as solar UV. TLR4 involvement has now been implicated in major types of skin malignancies, including nonmelanoma skin cancer, melanoma and Merkel cell carcinoma. Targeted molecular interventions that positively or negatively modulate TLR4 signaling have shown promise in translational, preclinical, and clinical investigations that may benefit skin cancer patients in the near future.

SUN-LB052 Sexual Precocity in a Male Toddler Caused by Inadvertent Prolonged Exposure to Exogenous Testosterone

Background: Unintentional exposure to cutaneous androgen products leading to virilization has previously been described in children, however, continues to be an overlooked cause of precocious sexual development. Clinical Case: A 16-month-old boy presented for a second opinion consultation regarding sexual precocity. Parents noticed enlargement of his penis and appearance of sparse pubic hair at about 4 months of age, prompting referral to an endocrinologist by 10 months. A comprehensive evaluation was performed. The bone age was advanced at 13-15 months and his total testosterone was 243 ng/dL (normal < 20 ng/dL). An ACTH stimulation test was negative for disorders of steroid biosynthesis. Ultrasound examination showed normal testes and no evidence of adrenal or hepatic masses. A Lupron stimulation test, performed at 14 months of age, showed a peak LH of 1.41 mIU/mL (normal < 5 mIU/mL) and peak total testosterone of 21 ng/dL (reference range ≤ 5 ng/dL). The patient was diagnosed with familial gonadotropin-independent male-limited sexual precocity, a rare condition caused by activating mutations of the LHCGR (luteinizing hormone/choriogonadotropin receptor) gene. Treatment with bicalutamide and anastrozole was prescribed. Owing to parental concern about side effects of the prescribed medications, they did not start the recommended treatment and sought a second opinion. On exam, his length was > 99th percentile for age, stretched penile length 7.5 cm (mean ± standard deviation for this age: 4.82 ± 0.44 cm), mid-shaft diameter 2 cm, and testes 2 mL bilaterally. The scrotum was thin and pendulous and there were a few pubic hairs at the base of the penis. His total testosterone was < 10 ng/dL, LH < 0.1 mIU/mL, and hCG < 0.1 mIU/mL (all normal). Ultrasound of the testes was normal. After the visit, a more thorough history was obtained from the mother. She remembered that the child’s maternal grandfather, who provided direct care to the patient in the first year of life while she attended school, used transdermal testosterone gel daily for treatment of hypogonadism. Since the grandfather’s absence after the patient’s first birthday, the child has not had any further progression of his secondary sex characteristics. On follow-up visit at 17 months of age, patient’s exam was stable. Genetic testing for mutations of the LHCGR gene was negative. Conclusion: Exogenous exposure to transdermal androgens should be kept high on the differential diagnosis for children presenting with evidence of peripheral sexual precocity as it can save patients unnecessary and costly work-up and intervention. Physicians should also be aware of their own anchoring biases, especially when evaluating patients for a second opinion of rare diagnoses. Lastly, adult endocrinologists should be mindful in counseling patients prescribed topical testosterone agents about the risk of cutaneous exposure to female partners and children. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.