Global R&D, Avon Products, Inc., brand-new Technology Department, Suffern, new York, USA

Correspondence: Avon Products, Inc., brand-new Technology Department, 1 Avon Pl., Suffern, NY 10901, USA. E-mail: gertrude.costin

Laboratory of cabinet Biology, national Cancer Institute, nationwide Institutes the Health, Bethesda, Maryland, USA

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Global R&D, Avon Products, Inc., brand-new Technology Department, Suffern, new York, USA

Correspondence: Avon Products, Inc., brand-new Technology Department, 1 Avon Pl., Suffern, NY 10901, USA. E-mail: gertrude.costin

Laboratory of cabinet Biology, nationwide Cancer Institute, national Institutes that Health, Bethesda, Maryland, USA

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All organisms, from simple invertebrates to complicated human beings, exist in different colors and also patterns, i beg your pardon arise indigenous the distinctive distribution of pigments transparent the body. Pigmentation is extremely heritable, being regulated by genetic, environmental, and endocrine determinants that modulate the amount, type, and also distribution that melanins in the skin, hair, and eyes. In enhancement to its duties in camouflage, warmth regulation, and cosmetic variation, melanin protects against UV radiation and also thus is critical defense mechanism in person skin against harmful factors. Gift the largest organ of the body the is always under the influence of internal and external factors, the skin frequently reacts to those agents by modifying the constitutive pigmentation pattern. The emphasis of this review is to administer an updated rundown of crucial physiological and also biological components that boost pigmentation and the mechanisms whereby they carry out so. We think about endo-crine components that induce momentary (e.g., during pregnancy) or irreversible (e.g., throughout aging) alters in skin color, environmental factors (e.g., UV), certain drugs, and also chemical compounds, etc. Expertise the mechanisms by which different factors and compounds induce melanogenesis is of an excellent interest phar-maceutically (as treatment for pigmentary diseases) and cosmeceutically (e.g., to architecture tanning assets with potential to reduce skin cancer risk).—Costin, G-E., Hearing, V. J. Human skin pigmentation: melanocytes modulate skin color in an answer to stress. FASEB J. 21, 976–994 (2007)

HUMAN SKIN exist IN A WIDE variety of various colors and gradations, ranging from white come brown to black. This is due to the existence of a chemically inert and also stable pigment recognized as melanin, i m sorry is produced deep inside the skin but is shown as a mosaic at the surface ar of the body. Melanin is as such responsible because that the many striking polymorphic properties of humans and also for the most obvious and thoroughly discussed element of human being geographical variability: skin color. As well as its function in defining ethnicity, melanin plays an essential role in defending the body versus harmful UV rays and also other ecological challenges. Minor transforms in the physiological standing of the person body or exposure come harmful external components can affect pigmentation patterns either in transitory (such together in pregnancy) or long-term (e.g., age spots) manners.

To understand pigmentation that the skin and also the components that affect it, one must emphasis on the complex cellular and also molecular interactions in between melano-cytes and also keratinocytes, which with each other compose the epidermal melanin unit. Every one of the other varieties of cells distributed within various layers the the skin and also the intracellular signaling pathways regularly overlapping and also involving cross-talking should be thought about also.

In this review, we carry out an update of current knowledge concerning the impacts of endocrine and also environmental components on skin pigmentation and the mechanisms by which they function. This evaluation emphasizes the the skin reacts to tension through every its cellular and also molecular components, which kind a complicated, sophisticated, and also highly sensitive signaling network.


The skin plays really important role, offering a large physical barrier against mechanical, chemical, and also microbial determinants that may impact the physiological condition of the body (1). In addition to those functions, the skin additionally acts together an immune network and, v its pigments, offers a distinctive defense system against UV radiation (UV-R) (2). Thus, melanocytes deliver mela-nosomes through their dendrites come keratinocytes, where they form the melanin hat that mitigate UV-induced DNA damage in person epidermis. The skin"s layers are represented by the epidermis, the dermis (whose structure will be debated in more detail below), and the hypodermis, the latter consisting of fatty tissue that connect the dermis to underlying skeletal components (Fig. 1A).


framework of the skin. A) The different layers and components. Collagen, elastin, and other contents of the extracellular procession (ECM) the the dermis space not represented. B) great of the epidermis. The stratum lucidum usually current in thick epidermis such as palms and soles is not included; it is usually located between the stratum granulosum and also stratum corneum and also consists of flattened cells v no nuclei. Merkel cell (stratum basale) and also Langerhans’ cells (stratum spinosum) space not represented either. Dashboard B based on and also modified indigenous A. H. Robins (1991) organic Perspectives on person Pigmentation, pp. 2, Cambridge college Press, Cambridge, UK.


The epidermis is one external, stratified epithelium devoid of blood or nerve offers of ∼5–100 μm thickness (which deserve to reach 600 μm top top palms and also soles) (3). It is composed of several distinct cell populations; keratinocytes and melanocytes space the key constitu-ents, of which the very first comprise ∼95% the the epidermis and are arranged in 4 layers, as adheres to (Fig. 1B).

Stratum basale (also recognized as the stratum germina-tivum) is a solitary layer of cell attached come a noncellular basement membrane that separates the epidermis from the dermis. The stratum basale consists mostly of basal keratinocytes, which have actually stem cell-like properties, and at the very least two different species of neural crest-derived cells: Merkel cell (neuroendocrine cells responsible because that the transmission of touch sensation through the cutaneous nerves) and melanocytes.

Stratum spinosum consists of irregular polyhedral ker-atinocytes v some restricted capacity because that cell division. Likewise found below are the bone marrow-derived sentinel cell of the immune system called Langerhans’ cells, which represent the antigen-presenting cell of the skin and also play a vital role in immunological reactions such together allergic contact dermatitis.

Stratum granulosum has flattened, polyhedral nondividing keratinocytes developing granules the a protein called keratinohyalin. This granules increase in size and number together the cell nuclei progressively degenerate and also the cells die. These cells flatten as splitting cells under them increasingly push them towards the skin surface.

Stratum corneum includes nonviable, but biochemically energetic cells called corneocytes. The keratinocytes continue to differentiate as they relocate from the basal layer come the stratum corneum, the result being cornified cells the contain numerous keratin and also lack cytoplas-mic organelles. The is these cornified cell that provide a barrier versus the physical and also chemical agents in the setting that might adversely impact the body. Much more specifically, this epidermal barrier functions to alleviate transepidermal water loss from within and to prevent intrusion by infectious agents and noxious building material from without (4).


The dermis isa2to4mm-thick class of connective tissue and also fibroblasts that residences the neural, vascular, lymphatic, and secretory apparatus of the skin (Fig. 1A). The key cell type, fibroblasts, is required for synthesis and also degradation the the extracellular matrix (ECM) (1). This matrix is a complicated structure written of highly organized collagen, elastic, and also reticular fibers. The dermis likewise hosts multifunctional cells of the immune system such as macrophages and mast cells, the latter being may be to cause allergic reactions by secreting bioactive mediators such together histamine. Structures within the dermis include: 1) Excretory and also secretory glands (sebaceous, eccrine, and also apocrine). Sebaceous glands secrete triglyceride and also cholesterol-rich sebum that lubricate the skin and also keep that supple and waterproof. They space often linked with hair shafts. 2) Hair follicles and nails: in enhancement to generating the hair shaft, the hair follicle provides a safety niche to numerous stem cell populaces in the skin, including keratinocyte stem cells, melanocyte stem cells, a populace of epidermal neural stakes stem cells, and the dermal stem cabinet compartment, well-known as the dermal papilla (5, 6). These stem cell are required most visibly throughout wound healing. 3) Sensory nerve receptor of Merkel and also Meissner"s corpuscles (for touch), Pacinian corpuscles (for pressure), and also Ruffini corpuscles (mechano-receptors).

In the dermis, collagen gives the skin through tensile strength and tissue integrity whereas elastin gives elasticity and also resiliency. As well as collagen and elastic fibers, the dermis consists of the extrafibrillar matrix, i m sorry is extracellular and also composed the a facility mixture that proteoglycans, glycoproteins, glycosamino-glycans, water, and also hyaluronic acid. The most far-ranging glycosaminoglycans, which tie to proteins to form the proteoglycans the the skin, space chondroitin sulfate, dermatan sulfate, keratin sulfate, heparan sul-fate, and heparin. The most important proteoglycans that the skin space versican, i m sorry is involved in assuring the tightness of the skin, and perlecan, i m sorry is found in basement membranes. Glycoproteins, such as laminins, matrilins, fibronectin, fibronectin, tenascins, etc., are affiliated in cell adhesion, cell migration, and also cell-cell communication, which space extremely crucial processes taking place in the skin.

Melanocytes, melanosomes, and melanin

Melanin biosynthesis is a complicated pathway that shows up in highly dedicated cells, called melanocytes, within membrane-bound organelles described as melano-somes (7). Melanosomes room transferred via dendrites to neighboring keratinocytes, where they beat a crucial role in photoprotection. The anatomical relationship in between keratinocytes and also melanocytes is known as “the epidermal melanin unit” and also it has actually been approximated that every melanocyte is in contact with ∼40 keratino-cytes in the basal and suprabasal great (8).

Several important steps must happen for the ideal synthesis and distribution of melanin, as adheres to (9).

1. The advance of melanocyte precursor cells (melanoblasts) and also their migration indigenous the neural crest come peripheral website

Prospective melanocytes, known as melanoblasts, have from the neural crest start in the second month of person embryonic life and migrate throughout the mesenchyme the the arising embryo. Castle reach particular target sites, greatly the dermis, epidermis, and also hair follicles, the uveal tract of the eye, the stria vasculare, the vestibular organ and the endolymphatic sac of the ear, and also leptomeninges the the brain. In humans, this migration procedure takes place between the 10th and also the 12th wk of breakthrough for the dermis and also ∼2 wk later on for the epidermis (1).

The survival and migration that neural crest-derived cells during embryogenesis is very dependent on interactions between particular receptors top top the cell surface and their extracellular ligands. Because that example, stole factor, formerly known as mast cell development factor, KIT ligand, or stem cell element (SCF), binding the KIT receptor on melanocytes and melanoblasts. Mutations in the KIT gene to decrease the capability of the KIT receptor come be caused by the steel factor and are responsible for at the very least one form of human piebaldism (10). See for other examplesof genes that regulate pigmentation and, once mutant, are connected in pigmentary disorders.

2. Differentiation the melanoblasts right into melanocytes

Once melanoblasts have actually reached their last destinations, they distinguish into melanocytes, i beg your pardon at about the 6th month of fetal life are already established at epidermal-dermal junction website (1).

3. Survival and also proliferation that melanocytes

Melanocytes have actually been established within fetal epidermis as early on as 50 job ofgestation. Dermal melanocytes decrease in number during gestation and virtually disappear through birth, conversely, epidermal melanocytes established at the epidermal-dermal junction continue to proliferate and also start to create melanin.

4. Formation of melanosomes and production the melanins

Once established in situ, melanocytes start developing melanosomes, extremely organized elliptic membrane-bound oribelles in i m sorry melanin synthesis takes place. They deserve to be detected making use of electron microscopy (EM) as early as throughout the 4th month of gestation.

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Melanosomes are commonly divided into four maturation step (I—IV) determined by your structure and also the quantity, quality, and arrangement the the melanin produced (Fig. 2) (11, 12). Nascent melanosomes are assembled in the perinuclear region near the Golgi stacks, receiving every enzymatic and structural proteins required for melanogenesis. Phase I melanosomes space spherical vacuoles lacking tyrosinase (TYR) task (the key enzyme affiliated in melanogenesis) and also have no inner structural components. However, TYR deserve to be detected in the Golgi vesicles, and it has been displayed that that is consequently trafficked to phase II melano-somes. In ~ this point, the presence and also correct processing of Pmel17, vital melanosomal structural protein, determine the revolution of stage I melanosomes come elongated, fibrillar organelles known as phase II melanosomes (12, 13); they contain tyrosinase and also exhibit minimal deposition of melanin. After ~ this, melanin synthesis starts and also the colours is uniformly deposited on the internal fibrils, in ~ which time the melanosomes space termed as stage III. Your last developmental phase (IV) is recognize in very pigmented melanocytes; this melanosomes room either elliptical or ellipsoidal, electron-opaque early to complete melaniza-tion, and have minimal TYR activity. The developmental stages detailed over refer mostly to eu-melano-somes (containing black-brown pigments); however, they room quite similar to pheo-melanosomes (containing yellow-reddish melanin), the only difference being the the latter remain round and also are no fibrillar throughout maturation.