Facultative Skin Pigmentation Research Articles

Melanin's Journey from Melanocytes to Keratinocytes: Uncovering the Molecular Mechanisms of Melanin Transfer and Processing.

Skin pigmentation ensures efficient photoprotection and relies on the pigment melanin, which is produced by epidermal melanocytes and transferred to surrounding keratinocytes. While the molecular mechanisms of melanin synthesis and transport in melanocytes are now well characterized, much less is known about melanin transfer and processing within keratinocytes. Over the past few decades, distinct models have been proposed to explain how melanin transfer occurs at the cellular and molecular levels. However, this remains a debated topic, as up to four different models have been proposed, with evidence presented supporting each. Here, we review the current knowledge on the regulation of melanin exocytosis, internalization, processing, and polarization. Regarding the different transfer models, we discuss how these might co-exist to regulate skin pigmentation under different conditions, i.e., constitutive and facultative skin pigmentation or physiological and pathological conditions. Moreover, we discuss recent evidence that sheds light on the regulation of melanin exocytosis by melanocytes and internalization by keratinocytes, as well as how melanin is stored within these cells in a compartment that we propose be named the melanokerasome. Finally, we review the state of the art on the molecular mechanisms that lead to melanokerasome positioning above the nuclei of keratinocytes, forming supranuclear caps that shield the nuclear DNA from UV radiation. Thus, we provide a comprehensive overview of the current knowledge on the molecular mechanisms regulating skin pigmentation, from melanin exocytosis by melanocytes and internalization by keratinocytes to processing and polarization within keratinocytes. A better knowledge of these molecular mechanisms will clarify long-lasting questions in the field that are crucial for the understanding of skin pigmentation and can shed light on fundamental aspects of organelle biology. Ultimately, this knowledge can lead to novel therapeutic strategies to treat hypo- or hyper-pigmentation disorders, which have a high socio-economic burden on patients and healthcare systems worldwide, as well as cosmetic applications.

Sun Exposure Is Associated with Reduced Breast Cancer Risk among Women Living in the Caribbean: The Atabey Study in Puerto Rico.

Though inconsistent, there is evidence that sun exposure is associated with reduced breast cancer risk. Previous studies have been conducted in geographical regions with seasonal variation in UV radiation, including periods of low to no exposure, and among participants mostly of European descent. Puerto Rico has no significant seasonal fluctuation, with continuous exposure to very high UV radiation. We conducted a population-based case-control study of breast cancer among women in metropolitan San Juan, Puerto Rico, examining a cumulative sun exposure index (SEI) based on a comparison of reflectance of sun-exposed and non-exposed skin. A chromameter was used to measure skin reflectance and estimate the difference between constitutive (unexposed) and facultative (exposed) skin pigmentation in 307 cases and 328 controls. Breast cancer risk factors were ascertained with interviewer-administered questionnaires. OR and 95% confidence intervals (CI) were estimated with unconditional logistic regression. Adjusted breast cancer odds were lower for the highest tertile of the SEI (ORadj = 0.47; 95% CI, 0.29-0.74). Results were similar within strata of estrogen receptor status. In analyses stratified by constitutive skin pigmentation, among participants with darker skin color, breast cancer risk was lower with more sun exposure (ORadj = 0.33; 95% CI, 0.16-0.70). We found lower risk of breast cancer associated with greater sun exposure in a population living with high, continuous sun exposure. This beneficial finding should be placed in the context of other effects of sun exposure. Sun exposure is a modifiable factor that may contribute, directly or indirectly, to lower breast cancer risk.

Pigment genes not skin pigmentation affect UVB-induced vitamin D.

Skin pigmentation is believed to contribute to the generally low serum 25-hydroxyvitamin D (25(OH)D) concentrations observed in darker-skinned persons. The influence of measured skin pigmentation on UVB-induced 25(OH)D increase was investigated together with 9 demographic and 13 genetic parameters (pigment SNPs). Forty participants representing a wide range in measured skin pigmentation were exposed to identical UVB doses on identical body areas over nine weeks with weekly measurements of serum 25(OH)D. This study took place in Denmark during winter, a period with negligible ambient UVB, so variation in 25(OH)D synthesis was not influenced by latitude, season, sun and clothing habits. The increase in 25(OH)D concentration displayed considerable variation (range: 2.9 to 139 nmol L-1). Constitutive and facultative skin pigmentation exerted separate influence on the variation of the UVB-induced linear 25(OH)D increase. However, this influence was statistically non-significant in the presence of separate significant pigment SNPs. The variation in the 25(OH)D increase in the combined linear model was not explained by measured skin pigmentation but by sex, height, age and seven SNPs located in the ASIP, MTAP, MIR196A29 and Solute Carrier Family genes. This linear model including individual intercepts and the 10 parameters influencing the slope explained 77.4% of the variation. This study confirmed the influence of sex, age and height on 25(OH)D increase and found that pigment genes provided a better relation to UVB-induced 25(OH)D increase compared to the actual measured skin pigmentation. Therefore, only investigating skin pigmentation obscures other causal parameters for low 25(OH)D.

The role of natural and UV‐induced skin pigmentation on low‐fluence IPL‐induced side effects: A randomized controlled trial

The risk of adverse skin effects following light-based hair removal is greater in pigmented skin based on the theory of selective photothermolysis. Thus sunlight-induced pigment i.e., facultative pigmentation, increases the risk of adverse skin effects, perhaps disproportionately. The aim of this study was to evaluate the influence of constitutive and facultative skin pigmentation on low-fluence intense pulsed light (IPL)-induced adverse skin effects. Twenty-one subjects with Fitzpatrick skin type II-IV were enrolled. Two buttock blocks were randomized to receive 0 or 8 solar simulated ultraviolet radiation (UVR) exposures of consecutively increasing Standard Erythema Doses (2-4 SED). Each block was subdivided into four sites, randomized to receive IPL of 0, 7, 8, or 10 J/cm(2) , once a week for 3 weeks. Biopsies were taken 16-24 hours after the first IPL exposure and subjects were seen 1 and 4 weeks after the last IPL exposure. Outcome measures were: (i) skin reactions, (ii) pain, (iii) mRNA expression of pigment-markers microphthalmia-associated transcription factor (MITF) and pro-opiomelanocortin (POMC), and (iv) clinical appearance of biopsy wounds. Skin pigmentation increased after UVR (baseline median 13.8%, after UVR 28.1%, P = 0.0001) in all skin types. Subjects reported low pain intensities (median 1.5, scale 0-10) and experienced transient erythema immediately after IPL exposure. No persistent erythema, blisters, crusting, textual, or pigment changes were observed. The risk of erythema and pain intensities increased with IPL dose and skin pigmentation (P < 0.03). There was no difference in pain or skin reactions in skin with similar degree of natural and facultative pigmentation (P ≥ 0.104). Expression of cellular pigment-markers was not influenced by IPL exposure, neither in constitutive nor in facultative pigmented skin. Clinical appearance of biopsy wounds was unaffected by IPL exposure. The prevalence and intensity of low-fluence IPL-induced adverse skin effects depended on IPL dose and skin pigmentation regardless of the origin, i.e., constitutive versus UV induced.

Constitutive and Relative Facultative Skin Pigmentation among Victorian Children Including Comparison of Two Visual Skin Charts for Determining Constitutive Melanin Density

Our aim was to examine the association between ethnicity, phenotype, sun behavior and other characteristics, and constitutive and relative facultative skin pigmentation. A total of 191 participants were recruited, with a mean age of 7.6 years (SD 3.4), during 2009-2011 from Maternal and Child Health Centres (MCHC) and schools in Melbourne, Australia. Parental questionnaire data were obtained on sun behavior and examination consisted of noting the child's natural skin, hair and eye color, ethnicity, nevi count and spectrophotometric melanin density (MD). Constitutive skin pigmentation was estimated from buttock MD. Relative facultative skin pigmentation was estimated by hand compared with buttock absorption. Ethnicity, hair color and skin color were associated with constitutive and facultative skin pigmentation on univariate analysis. Higher ambient ultraviolet radiation (UVR) in the past month, greater freckling, greater nevi and increased sun exposure over the past year were related to darker facultative skin pigmentation. Sun exposure over the life course was not. The two skin charts accounted for 39.7% and 21.4% of buttock MD, respectively. Relative facultative skin pigmentation is associated with recent UVR levels, not life-course sun exposure. Relative facultative skin pigmentation may not be a useful measure of sun exposure over the early life course. Skin color charts can be used to assess constitutive skin pigmentation if spectrophotometry is not available.

Tanning predicts bone mass but not structure in adolescent females living in Hawaii

To evaluate the relationship between facultative skin pigmentation, which predicts circulating levels of plasma 25-hydroxymitamin D, and several measures of bone mass and structure in a cross sectional sample of adolescent females living in Hawaii. Our sample was composed of adolescent females (n = 94) living in Hawaii where seasonal sun exposure is minimal, and who self-identified as either white (n = 16) or Asian (n = 78). Bone mineral content (BMC) of the total body, the lumbar spine and the hip, and cross sectional area (CSA) and section modulus (Z) at the proximal femur were quantified using DXA. Facultative skin pigmentation was measured at the forehead and non-facultative skin pigmentation was measured at the inner arm using a Chroma Meter CR-200b colorimeter. There were no significant differences between ethnic groups in terms of skin pigmentation. The difference between a* taken at the forehead and inner upper arm significantly predicted BMC at the lumbar spine, total hip, and total body. Other measures of skin pigmentation were not significant predictors of any other measure of skeletal integrity. The difference between facultative and non-facultative skin pigmentation for a* is a significant predictor BMC, but not bone structure. Our findings are limited by an inability to control for long term UVA and UVB exposure and lack of a measure of serum 25(OH)D status. Further research is needed to examine these questions, particularly in populations who live at high latitudes where a winter season limits vitamin D(3) synthesis.

α-MSH regulates intergenic splicing of MC1R and TUBB3 in human melanocytes

Alternative splicing enables higher eukaryotes to increase their repertoire of proteins derived from a restricted number of genes. However, the possibility that functional diversity may also be augmented by splicing between adjacent genes has been largely neglected. Here, we show that the human melanocortin 1 receptor (MC1R) gene, a critical component of the facultative skin pigmentation system, has a highly complex and inefficient poly(A) site which is instrumental in allowing intergenic splicing between this locus and its immediate downstream neighbour tubulin-β-III (TUBB3). These transcripts, which produce two distinct protein isoforms localizing to the plasma membrane and the endoplasmic reticulum, seem to be restricted to humans as no detectable chimeric mRNA could be found in MC1R expressing mouse melanocytes. Significantly, treatment with the MC1R agonist α-MSH or activation of the stress response kinase p38-MAPK, both key molecules associated with ultraviolet radiation dermal insult and subsequent skin tanning, result in a shift in expression from MC1R in favour of chimeric MC1R-TUBB3 isoforms in cultured melanocytes. We propose that these chimeric proteins serve to equip melanocytes with novel cellular phenotypes required as part of the pigmentation response.

Vitamin D Production after UVB Exposure Depends on Baseline Vitamin D and Total Cholesterol but Not on Skin Pigmentation

UVB radiation increases serum vitamin D level expressed as 25-hydroxyvitamin-D(3) (25(OH)D), but the influence of skin pigmentation, baseline 25(OH)D level, and total cholesterol has not been well characterized. To determine the importance of skin pigmentation, baseline 25(OH)D level, and total cholesterol on 25(OH)D production after UVB exposure, 182 persons were screened for 25(OH)D level. A total of 50 participants with a wide range in baseline 25(OH)D levels were selected to define the importance of baseline 25(OH)D level. Of these, 28 non-sun worshippers with limited past sun exposure were used to investigate the influence of skin pigmentation and baseline total cholesterol. The participants had 24% of their skin exposed to UVB (3 standard erythema doses) four times every second or third day. Skin pigmentation and 25(OH)D levels were measured before and after the irradiations. Total cholesterol was measured at baseline. The increase in 25(OH)D level after UVB exposure was negatively correlated with baseline 25(OH)D level (P<0.001) and positively correlated with baseline total cholesterol level (P=0.005), but no significant correlations were found with constitutive or facultative skin pigmentation. In addition, we paired a dark-skinned group with a fair-skinned group according to baseline 25(OH)D levels and found no differences in 25(OH)D increase after identical UVB exposure.

Vitamin D Level in Summer and Winter Related to Measured UVR Exposure and Behavior

The influence of the summer UVR exposure on serum-25-hydroxyvitamin D (25(OH)D) in late summer and winter was investigated in an open study on 25 healthy, adult volunteers. The UVR exposure dose in standard erythema dose (SED) was monitored continuously during a summer season with personal, electronic wristwatch UVR dosimeters and sun exposure diaries. Constitutive and facultative skin pigmentation was measured in September. 25(OH)D was measured in September and February and was in mean 82 nmol/L +/- 25 (mean +/- SD) in September and 56 nmol/L +/- 19 (mean +/- SD) in February. The received cumulative UVR dose measured during a mean of 121 days was 156 SED +/- 159 (mean +/- SD). The following UVR exposure parameters correlated with 25(OH)D in September and February, respectively: (1) The cumulative UVR dose (r = 0.53; P < 0.01) and (r = 0.43; P = 0.03); (2) Mean daily hours with UVR measurements monitored by the dosimeter (r = 0.64, P = 0.001) and (r = 0.53; P = 0.007); (3) Days "with sun-exposed upper body" (r = 0.58, P = 0.003) and (r = 0.50; P = 0.01); (4) Facultative pigmentation (r = 0.47; P < 0.02) and (r = 0.7; P < 0.001); (5) Constitutive pigmentation (r = 0.06, n.s.) and (r = 0.43, P = 0.03). Neither days "sunbathing" nor days with "sunscreen applied" correlated with 25(OH)D. The fall in 25(OH)D during winter was dependent on the entry value.

Melanosomal pH Controls Rate of Melanogenesis, Eumelanin/Phaeomelanin Ratio and Melanosome Maturation in Melanocytes and Melanoma Cells

The skin pigment melanin is produced in melanocytes in highly specialized organelles known as melanosomes. Melanosomes are related to the organelles of the endosomal/lysosomal pathway and can have a low internal pH. In the present study we have shown that melanin synthesis in human pigment cell lysates is maximal at pH 6.8. We therefore investigated the role of intramelanosomal pH as a possible control mechanism for melanogenesis. To do this we examined the effect of neutralizing melanosomal pH on tyrosinase activity and melanogenesis in 11 human melanocyte cultures and in 3 melanoma lines. All melanocyte cultures (9 of 9) from Caucasian skin as well as two melanomacell lines with comparable melanogenic activity showed rapid (within 24 h) increases in melanogenesis in response to neutralization of melanosomal pH. Chemical analysis of total melanin indicated a preferential increase in eumelanin production. Electron microscopy revealed an accumulation of melanin and increased maturation of melanosomes in response to pH neutralization. In summary, our findings show that: (i) near neutral melanosomal pH is optimal for human tyrosinase activity and melanogenesis; (ii) melanin production in Caucasian melanocytes is suppressed by low melanosomal pH; (iii) the ratio of eumelanin/phaeomelanin production and maturation rate of melanosomes can be regulated by melanosomal pH. We conclude that melanosomal pH is an essential factor which regulates multiple stages of melanin production. Furthermore, since we have recently identified that pink locus product (P protein) mediates neutralization of melanosomal pH, we propose that P protein is a key control point for skin pigmentation. We would further propose that the wide variations in both constitutive and facultative skin pigmentation seen in the human population could be associated with the high degree of P-locus polymorphism.

Facultative skin pigmentation in caucasians: an objective biological indicator of lifetime exposure to ultraviolet radiation?

To investigate age and gender trends in facultative and constitutive skin pigmentation we measured skin pigmentation non-invasively and objectively by skin reflectance spectroscopy in 653 caucasians (336 females and 317 males; mean age 38 years, range 0-85) who were not using artificial tanning devices. In all subjects, measurements were performed in the late winter and pre-spring period at five sites exposed to ultraviolet (UV) radiation: the forehead, the upper chest, the upper back and the lateral and medial aspects of the upper arm, and in UV-unexposed buttock skin. Constitutive pigmentation at the buttocks was highest in the first years of life and then decreased substantially during the first two decades of life (P < 0.01). After the age of 25 years, buttock pigmentation remained at a constant level (P = 0.20). There was no gender difference in constitutive pigmentation. Facultative skin pigmentation increased with age for all the measured sites with the highest levels found at the lateral aspect of the upper arm. Based on observations in this study we propose the idea of a 'sun exposure index' (SEI) for individuals, based on objective measurements of skin pigmentation. The SEI is calculated as the increase in facultative pigmentation above the constitutive level and is expressed as a percentage of the constitutive level. The SEI appeared to be related to cumulative lifetime UV exposure and may be used in epidemiological research as an objective estimate of UV exposure at different body sites in caucasians.