The impact of urban particulate pollution on skin barrier function and the subsequent drug absorption

https://doi.org/10.1016/j.jdermsci.2015.01.011Get rights and content

Highlights

Abstract

Background

Ambient particulate matters (PMs) are known as inducers that adversely affect a variety of human organs.

Objectives

In this study, we aimed to evaluate the influence of PMs on the permeation of drugs and sunscreens via the skin. The role of skin-barrier properties such as the stratum corneum (SC) and tight junctions (TJs) during the delivery process was explored.

Methods

This work was conducted using both in vitro and in vivo experiments in pigs to check the responses of the skin to PMs. PMs primarily containing heavy metals (1648a) and polycyclic aromatic hydrocarbons (PAHs, 1649b) were employed to treat the skin.

Results

According to the transepidermal water loss (TEWL), 1649b but not 1648a significantly disrupted the SC integrity by 2-fold compared to the PBS control. The immunohistochemistry (IHC) of cytokeratin, filaggrin, and E-cadherin exhibited that 1649b mildly damaged TJs. The cytotoxicity of keratinocytes and skin fibroblasts caused by 1649b was stronger than that caused by 1648a. The 1649b elicited apoptosis via caspase-3 activation. The proteomic profiles showed that PMs upregulated Annexin A2 by >5-fold, which can be a biomarker of PM-induced barrier disruption. We found that the skin uptake of ascorbic acid, an extremely hydrophilic drug, was increased from 74 to 112 μg/g by 1649b treatment. The extremely lipophilic drug tretinoin also showed a 2.6-fold increase of skin accumulation. Oxybenzone and dextran absorption was not affected by PMs. The in vivo dye distribution visualized by fluorescence microscopy had indicated that 1649b intervention promoted permeant partitioning into SC.

Conclusions

Caution should be taken in exposing the skin to airborne dust due to its ability to reduce barrier function and increase the risk of drug overabsorption, although this effect was not very marked.

Introduction

Airborne pollutants, especially particulate matters (PMs), represent elements of significant environmental exposure adversely influencing human health [1]. The World Health Organization (WHO) claims that PMs result in 8 × 105 premature deaths every year, ranking PMs the 13th leading cause of mortality worldwide [2]. PMs are complex mixtures containing metals, minerals, organic toxins, and/or biological materials. Most of the studies involved relating to PMs have focused on respiratory and cardiovascular injuries. The ambient air pollution elicits oxidative stress and inflammation on lung tissues, causing epithelial barrier function degradation, cytotoxicity, and even cancer development [3]. The epidemiological evidences demonstrate a correlation between PM exposure and cardiovascular disorder-related morbidity and mortality [4]. Along with the oral and respiratory routes, the skin is the common pathway through which the xenobiotics or chemicals enter the body. The skin contributes to the important interface between the environment and the body. Alteration of the skin barrier function has resulted in the development of various cutaneous diseases [5]. PMs have been proved to induce skin, aging, allergic reactions, and delay the wound healing of the skin by topical exposure [6], [7], [8]. Until now, investigations pertaining to PMs’ impact on the skin have been far less abundant as compared to those pertaining to the respiratory and cardiovascular systems. The integrity of the skin barrier is always unideal in environmental and occupational situations [9]. The purpose of this work was to explore the effect of airborne pollution on the skin barrier, including the stratum corneum (SC) and tight junctions (TJs), both of which form a functional skin barrier.

The contents of PMs that receive the most attention for causing health problems are heavy metals and polycyclic aromatic hydrocarbons (PAHs) [10]. In this study, we employed two standard reference materials predominantly composed of heavy metals (1648a) and PAHs (1649b), respectively, issued by National Institute of Standards and Technology (NIST) of the USA. The 1648a urban PMs are the microparticles (average diameter = 5.85 μm) with soluble metal contents such as Cu, Mn, Ni, Pb, and Ti [11]. The 1649b PMs are the urban dusts with an average diameter of about 11 μm. The constituents of 1649b include PAHs, polychlorinated biphenyl (PCB) congeners, pesticides, and dioxins. SC and TJs function as a permeation barrier against the penetration of molecules [12]. The permeation barrier deterioration by PMs may accelerate drug delivery into the skin, augmenting the risk of overabsorption. The second purpose of this study was to assess the permeation profiles of some permeants via PM-treated skin. We had selected four permeants frequently used to prevent cutaneous aging or to treat skin disorders. The permeants utilized herein were ascorbic acid, oxybenzone, tretinoin, and dextran. These permeants have various molecular sizes and lipophilicities that are advantageous for comparison of permeation profiles. The traditional rodent models always overestimate the skin penetration of drugs although they are easily handled and cost-effective. In order to approximate the condition of humans, we used the pig as the animal model.

Section snippets

Materials

The standard reference materials 1648a and 1649b were supplied by NIST (Gaithersburg, MD, USA). Ascorbic acid, oxybenzone, tretinoin, fluorescein isothiocyanate (FITC)-conjugated dextran (4 kDa), and rhodamine B were purchased from Sigma–Aldrich (St. Louis, MO, USA).

Animals

Male Landrace × Yorkshire × Duroc pigs (8 weeks old) were obtained from Doctor Pig Animal Technology (Miaoli, Taiwan). The pigs were used to test the in vitro/in vivo topical PM application, physiological parameters, histology, and

Gross observation and physiological parameters

Pigs were applied as the animal model in this investigation for simulating the status of humans. Fig. 1A shows the process of topically applying PMs on the dorsal skin of the pigs. Fig. 1B depicts the close-up images of the pig skin. The skin without any treatment but pad cover (control) was intact with some hair shafts on the surface. The lightness of the skin surface for the control group was high. This could be due to the presence of sebum on the surface. The skin surface was also evaluated

Discussion

The aim of the present work was to systematically elucidate PM toxicity on skin-barrier function, especially the SC and TJs in the epidermis. We also tried to establish the permeation profiles of some commonly used drugs and sunscreens via PM-exposed skin. We found that 1649b disrupted the SC and TJs. Some proteins related to barrier function such as cytokeratin, filaggrin and E-cadherin were diminished after 1649b treatment. On the other hand, 1648a revealed a negligible role in damaging the

Conclusions

Generally, we could characterize mild damage of 1649b on the skin according to the experimental results of histology, proteomics, cell viability, and skin absorption. Most investigations have employed intact skin for evaluating drug absorption. The results from such research may not be feasible for predicting cutaneous delivery of the drugs on diseased or damaged skin. The skin model used in this work is beneficial for resolving this issue, especially the skin exposed in the rigorous

Acknowledgements

The authors are grateful to the financial support by Chang Gung University and Chang Gung Memorial Hospital (grant number: EMRPD1D901, CMRPD1B0332, and CMRPF6A0083).

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