SUMMARYColor variation is a frequent evolutionary substrate for camouflage in small mammals but t... more SUMMARYColor variation is a frequent evolutionary substrate for camouflage in small mammals but the underlying genetics and evolutionary forces that drive color variation in natural populations of large mammals are mostly unexplained. The American black bear, Ursus americanus, exhibits a range of colors including the cinnamon morph which has a similar color to the brown bear, U. arctos, and is found at high frequency in the American southwest. Reflectance and chemical melanin measurements showed little distinction between U. arctos and cinnamon U. americanus individuals. We used a genome-wide association for hair color as a quantitative trait in 151 U. americanus individuals and identified a single major locus (P < 10−13). Additional genomic and functional studies identified a missense alteration (R153C) in Tyrosinase-related protein 1 (TYRP1) that impaired protein localization and decreased pigment production. Population genetic analyses and demographic modeling indicated that t...
Objective: Neuromelanin (NM) of the human substantia nigra (SN) has long been proposed as a key f... more Objective: Neuromelanin (NM) of the human substantia nigra (SN) has long been proposed as a key factor contributing to dopaminergic neuron vulnerability in Parkinson's disease (PD). NM consists of pheomelanin and eumelanin moieties. Evidence supports that pheomelanin and eumelanin possess distinct chemical and biological characteristics. The present study aimed to investigate the relative composition and specific roles of pheomelanin and eumelanin moieties of NM in PD. Methods: Pheomelanin and eumelanin components of NM in postmortem SN tissues from patients with PD were assessed by chemical degradation methods and compared with those from control subjects as well as patients with Alzheimer's disease (AD). Additionally, synthetic pheomelanin and eumelanin were used to investigate their differential impacts on dopaminergic neuronal survival in a mouse model of PD overexpressing alpha-synuclein in the SN. Results: We identified increased L-3,4-dihydroxyphenylalanine (DOPA) phe...
Chemical leukoderma is an acquired depigmentation of the skin caused by repeated exposure to spec... more Chemical leukoderma is an acquired depigmentation of the skin caused by repeated exposure to specific agents damaging to epidermal melanocytes. Case reports of chemical leukoderma have been associated with some consumer products. To date, there are no well-accepted approaches for evaluating and minimizing this risk. To this end, a framework is presented that evaluates the physical and chemical characteristics of compounds associated with chemical leukoderma and employs structure-activity relationship (SAR) read-across and predictive metabolism tools to determine whether a compound is at increased risk of evoking chemical leukoderma. In addition to in silico approaches, the testing strategy includes in chemico quinone formation and in vitro melanocyte cytotoxicity assays to dimension the risk as part of an overall weight of evidence approach to risk assessment. Cosmetic ingredients raspberry ketone, undecylenoyl phenylalanine, tocopheryl succinate, p-coumaric acid, resveratrol, resveratrol dimethyl ether, sucrose dilaurate, tranexamic acid, niacinamide and caffeic acid are evaluated in this framework and compared to positive controls rhododendrol and hydroquinone. Overall, this framework is considered an important step toward mitigating the risk of chemical leukoderma for compounds used in consumer products.
It is known that melanin pigments composed of black to dark brown eumelanin (EM) and yellow to re... more It is known that melanin pigments composed of black to dark brown eumelanin (EM) and yellow to reddish-brown pheomelanin (PM) are widely distributed in vertebrates. Melanin pigments in vertebrate are produced in melanocytes which are distributed in the epidermis, hair follicles, choroid, iris, inner ear, and other tissues. The diversity of the color in the internal and external tissues in vertebrates is mainly attributed to the quantity and ratio of EM and PM. Melanin pigments are highly oxidized and complex pigments. It is thus important to analyze these two types of melanin pigments in studies of the biochemical and genetic bases of pigmentation in vertebrates. Two microanalytical methods to perform the simultaneous measurement of eumelanin and pheomelanin were established to characterize melanin and melanogenesis. In this chapter, we explain microanalytical application with the chemical degradation of melanin and focus on internal and external melanins produced by pigment cells in vertebrates: mammals, birds, fish, reptiles, and amphibians. By using these methods for the evaluation of the "chemical phenotype," the mutual triangular relationship among "chemical phenotype," "visual phenotype," and "genotype" is reviewed.
Oculocutaneous albinism (OCA) 6 is a non‐syndromic type of OCA that has distinct ocular symptoms ... more Oculocutaneous albinism (OCA) 6 is a non‐syndromic type of OCA that has distinct ocular symptoms and variable cutaneous hypopigmentation. The causative gene of OCA6 is SLC24A5, which encodes NCKX5, a K+‐dependent Na+/Ca2+ exchanger 5. NCKX5 is involved in the maturation of melanosomes, but its function is still unclear. In this study, we characterized a Japanese patient with OCA6. Genetic analysis revealed compound heterozygous variants in SLC24A5, c.590 + 1dupG, and c.598G>A (p.G200R). To clarify the functional significance of the missense variant, we generated a knock‐in (KI) mouse model carrying the mouse homolog of the G200R variant using the CRISPR/Cas9 system. Chemical analysis showed decreased amounts of eumelanin in the hair and skin of KI mice, while levels of benzothiazine units in pheomelanin were significantly increased in their hair. Retinal pigment was also decreased in KI mice. Notably, a histopathologic study revealed a significant pigment loss in the retinal pigm...
Effects of low temperature on the color of red sea bream (Pagrus major) were investigated. In col... more Effects of low temperature on the color of red sea bream (Pagrus major) were investigated. In colorimetric evaluation using L*a*b* system the fish reared under low-temperature (10•Ž) for two months lost their L* value compared to control (bred under 22•Ž) while no change was observed in a* and b* value. No significant difference was found in blood test (GOT, GPT, ALP, gamma-GTP, total bilirubin, direct bilirubin, indirect bilirubin and bile acid). We also examined the properties of the •gyellowed•h juvenile red seabream which sometimes occur in winter season in Fisheries Laboratory of Kinki University. The b* value was significantly lower than that of control while no significant difference could be found in L* value. The blood test showed no clear difference in direct and indirect bilirubin conc as well as in other measurements. We also examined the concentration of yellow melanin (pheomelanin), however, no significant gap could be found in nomal and yellowed red seabream, indicati...
Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine sk... more Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.
Post‐inflammatory hyperpigmentation (PIH) is a common cutaneous condition that can cause a disfig... more Post‐inflammatory hyperpigmentation (PIH) is a common cutaneous condition that can cause a disfigured appearance. However, the pathophysiology of PIH remains poorly understood, at least in part, because an appropriate animal model for research has not been established. In order to analyze the pathomechanism of PIH, we successfully induced PIH in a hairless version of transgenic mice (hk14‐SCF Tg/HRM) that have a human‐type epidermis containing melanin by repeated hapten application of 2,4‐dinitrofluorobenzene. Histopathologic observation showed epidermal hyperplasia, predominant infiltrations of inflammatory cells, and melanin‐containing cells in the dermis just after elicitation of the atopic dermatitis‐like condition. At week 2, the findings were similar to the characteristics of PIH, that is, an increase of melanin without spongiosis or liquid degeneration in the epidermis and an increase in dermal melanophages. Dynamic analysis of melanin showed that the melanin in the dermis re...
DNA methylation and subsequent oxidation of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC) ... more DNA methylation and subsequent oxidation of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC) catalyzed by the TET family enzymes are key epigenetic events regulating development and stem cell differentiation in mammals, while genetic ablation of all three Tet genes is embryonic lethal. Here, we show that 5hmC level and Tet1/2/3 expression display dynamic changes in the developing hair follicles (HFs), as well as during the hair cycle. High level of 5hmC and high expression of Tet2 and Tet3 were seen in differentiating hair matrix keratinocytes (KCs), outer and inner root sheaths, hair shaft and dermal papilla. To explore the role of Tet1/2/3 in the control of HF development and cycling, we used mice with Shh-Cre mediated ablation of all three Tet genes (Shh-Cre/ Tet1 fl/fl /Tet2 fl/fl / Tet3 fl/fl) as a conditional triple knockout (TKO) model. Consistent with the expression pattern of Shh gene, Cre expression was seen in the HF placodes, as well as in a cluster of hair matrix KCs whose progenies form the hair shaft. Shh-Cre mediated Tet triple knockout resulted in a significant decrease in the hair shaft length in all bended hair types (auchen, zigzag), as well as an increase in the number of straight (guard, awl) hairs compared to controls. These differences were accompanied by a marked decrease of Bmpr1a/1b in the hair shaft KCs from TKO mice, as well as with the decreased pSmad1 expression. Furthermore, hMeDIP-seq analyses of primary mouse KCs revealed 5hmC peaks at the Bmpr1b gene promoter, as well as at several enhancers located in close vicinity to the Bmpr1a/2 genes, while depicted by H3K27ac/ H3K4me1 ChIPseq analyses. These data demonstrate the role of Tet-mediated DNA hydroxymethylation controlling hair shaft-specific KC differentiation and hair shaft formation, as well as regulating transcription of Bmpr1a/1b/2 and activity of the enhancers adjacent to these genes in KCs.
Alcohol induces various cutaneous changes, such as palmar erythema and jaundice. However, alcohol... more Alcohol induces various cutaneous changes, such as palmar erythema and jaundice. However, alcohol-induced skin hyperpigmentation due to melanin deposition has not been reported. Aldehyde dehydrogenase 2 (ALDH2), one of 19 human ALDH isozymes, metabolizes endogenous and exogenous aldehydes to their respective carboxylic acids. Reduced ALDH2 greatly affects acetaldehyde metabolism, leading to its accumulation in the body after the consumption of alcohol and the consequent development of a wide range of phenotypes. In the present study, we report a novel phenotype manifesting in a mouse model with the altered expression of ALDH2. Aldh2 knockout (Aldh2+/− and Aldh2−/−) and wild-type (Aldh2+/+) mice were fed a standard solid rodent chow and a bottle of ethanol solution at concentrations of 0%, 3%, 10%, or 20% (v/v) for more than 10 weeks. The intensity of their skin pigmentation was evaluated by macroscopic observation. Ethanol-exposed Aldh2+/− and Aldh2−/− mice exhibited dose-dependent skin pigmentation in areas of hairless skin, including the soles of the paws and tail; no such changes were observed in wild-type mice. The intensity of skin pigmentation correlated with the number of Aldh2 alleles that were altered in the mice (i.e., 0, 1 and 2 for Aldh2+/+, Aldh2+/−, Aldh2−/−, respectively). Interestingly, the skin pigmentation changes reversed upon the discontinuation of ethanol. The histological examination of the pigmented skin demonstrated the presence of melanin-like deposits, mainly in the epidermis. In conclusion, we report a novel finding that the intake of ethanol induces skin hyperpigmentation in an ALDH2 activity-dependent manner.
BACKGROUND. Oculocutaneous albinism (OCA) results in reduced melanin synthesis, skin hypopigmenta... more BACKGROUND. Oculocutaneous albinism (OCA) results in reduced melanin synthesis, skin hypopigmentation, increased risk of UV-induced malignancy, and developmental eye abnormalities affecting vision. No treatments exist. We have shown that oral nitisinone increases ocular and fur pigmentation in a mouse model of one form of albinism, OCA-1B, due to hypomorphic mutations in the Tyrosinase gene. METHODS. In this open-label pilot study, 5 adult patients with OCA-1B established baseline measurements of iris, skin, and hair pigmentation and were treated over 12 months with 2 mg/d oral nitisinone. Changes in pigmentation and visual function were evaluated at 3-month intervals. RESULTS. The mean change in iris transillumination, a marker of melanin, from baseline was 1.0 ± 1.54 points, representing no change. The method of iris transillumination grading showed a high intergrader reliability (intraclass correlation coefficient ≥ 0.88 at each visit). The number of letters read (visual acuity) improved significantly at month 12 for both eyes (right eye, OD, mean 4.2 [95% CI, 0.3, 8.1], P = 0.04) and left eye (OS, 5 [1.0, 9.1], P = 0.003). Skin pigmentation on the inner bicep increased (M index increase = 1.72 [0.03, 3.41], P = 0.047). Finally, hair pigmentation increased by both reflectometry (M index [17.3 {4.4, 30.2}, P = 0.01]) and biochemically. CONCLUSION. Nitisinone did not result in an increase in iris melanin content but may increase hair and skin pigmentation in patients with OCA-1B. The iris transillumination grading scale used in this study proved robust, with potential for use in future clinical trials. TRIAL REGISTRATION. ClinicalTrials.gov NCT01838655. FUNDING. Intramural program of the National Eye Institute.
Sex allocation is the parental resource allocation to sons versus daughters. Given the different ... more Sex allocation is the parental resource allocation to sons versus daughters. Given the different benefits and costs of investments in sons and daughters, females should adjust the brood sex ratio according to their own quality to maximize their fitness. In the barn swallow Hirundo rustica, as in many other passerines, females should increase the proportion of sons in their broods with increasing maternal body size, because rearing sons is particularly costly to small females with low feeding capacity, and because reproductive success in the barn swallow, which may depend on rearing conditions, varies more in males. However, evidence supporting this prediction is lacking, even in this model species of sex allocation. Using the Asian subspecies of the barn swallow H. r. gutturalis, we confirmed this prediction. Larger mothers with a longer keel had more sons in their brood. We found that male nestlings invested more in pheomelanin pigmentation compared with female nestlings, while they had shorter wing lengths, indicating that male nestlings are costly to rear compared with female nestlings. Smaller mothers that are at a disadvantage in provisioning may not retard the nestling period by producing daughters, which reduces their parental investment and thus saves their residual reproductive value. This breeding strategy might be particularly beneficial to Japanese barn swallows that breed in environments with high nest predation.
The diversity of pigmentation in the skin, hair, and eyes of humans has been largely attributed t... more The diversity of pigmentation in the skin, hair, and eyes of humans has been largely attributed to the diversity of pH in melanosomes with an acidic pH being proposed to suppress melanin production, especially eumelanogenesis. We previously showed that an acidic pH greatly suppresses the late stage of eumelanogenesis after the dopachrome stage. The oxidation of tyrosine by tyrosinase in the presence of cysteine forms cysteinyldopa isomers, which are further oxidized to give rise to pheomelanin via benzothiazine intermediates. However, how those steps are controlled by pH has not been characterized. We therefore examined whether pheomelanin synthesis is chemically promoted at an acidic pH. We found that pheomelanin production either from dopa or tyrosine in the presence of cysteine by tyrosinase was greatest at pH values of 5.8-6.3, while eumelanin production was suppressed at pH 5.8. This suggests that mixed melanogenesis is chemically shifted to more pheomelanic states at a weakly ...
SUMMARYColor variation is a frequent evolutionary substrate for camouflage in small mammals but t... more SUMMARYColor variation is a frequent evolutionary substrate for camouflage in small mammals but the underlying genetics and evolutionary forces that drive color variation in natural populations of large mammals are mostly unexplained. The American black bear, Ursus americanus, exhibits a range of colors including the cinnamon morph which has a similar color to the brown bear, U. arctos, and is found at high frequency in the American southwest. Reflectance and chemical melanin measurements showed little distinction between U. arctos and cinnamon U. americanus individuals. We used a genome-wide association for hair color as a quantitative trait in 151 U. americanus individuals and identified a single major locus (P < 10−13). Additional genomic and functional studies identified a missense alteration (R153C) in Tyrosinase-related protein 1 (TYRP1) that impaired protein localization and decreased pigment production. Population genetic analyses and demographic modeling indicated that t...
Objective: Neuromelanin (NM) of the human substantia nigra (SN) has long been proposed as a key f... more Objective: Neuromelanin (NM) of the human substantia nigra (SN) has long been proposed as a key factor contributing to dopaminergic neuron vulnerability in Parkinson's disease (PD). NM consists of pheomelanin and eumelanin moieties. Evidence supports that pheomelanin and eumelanin possess distinct chemical and biological characteristics. The present study aimed to investigate the relative composition and specific roles of pheomelanin and eumelanin moieties of NM in PD. Methods: Pheomelanin and eumelanin components of NM in postmortem SN tissues from patients with PD were assessed by chemical degradation methods and compared with those from control subjects as well as patients with Alzheimer's disease (AD). Additionally, synthetic pheomelanin and eumelanin were used to investigate their differential impacts on dopaminergic neuronal survival in a mouse model of PD overexpressing alpha-synuclein in the SN. Results: We identified increased L-3,4-dihydroxyphenylalanine (DOPA) phe...
Chemical leukoderma is an acquired depigmentation of the skin caused by repeated exposure to spec... more Chemical leukoderma is an acquired depigmentation of the skin caused by repeated exposure to specific agents damaging to epidermal melanocytes. Case reports of chemical leukoderma have been associated with some consumer products. To date, there are no well-accepted approaches for evaluating and minimizing this risk. To this end, a framework is presented that evaluates the physical and chemical characteristics of compounds associated with chemical leukoderma and employs structure-activity relationship (SAR) read-across and predictive metabolism tools to determine whether a compound is at increased risk of evoking chemical leukoderma. In addition to in silico approaches, the testing strategy includes in chemico quinone formation and in vitro melanocyte cytotoxicity assays to dimension the risk as part of an overall weight of evidence approach to risk assessment. Cosmetic ingredients raspberry ketone, undecylenoyl phenylalanine, tocopheryl succinate, p-coumaric acid, resveratrol, resveratrol dimethyl ether, sucrose dilaurate, tranexamic acid, niacinamide and caffeic acid are evaluated in this framework and compared to positive controls rhododendrol and hydroquinone. Overall, this framework is considered an important step toward mitigating the risk of chemical leukoderma for compounds used in consumer products.
It is known that melanin pigments composed of black to dark brown eumelanin (EM) and yellow to re... more It is known that melanin pigments composed of black to dark brown eumelanin (EM) and yellow to reddish-brown pheomelanin (PM) are widely distributed in vertebrates. Melanin pigments in vertebrate are produced in melanocytes which are distributed in the epidermis, hair follicles, choroid, iris, inner ear, and other tissues. The diversity of the color in the internal and external tissues in vertebrates is mainly attributed to the quantity and ratio of EM and PM. Melanin pigments are highly oxidized and complex pigments. It is thus important to analyze these two types of melanin pigments in studies of the biochemical and genetic bases of pigmentation in vertebrates. Two microanalytical methods to perform the simultaneous measurement of eumelanin and pheomelanin were established to characterize melanin and melanogenesis. In this chapter, we explain microanalytical application with the chemical degradation of melanin and focus on internal and external melanins produced by pigment cells in vertebrates: mammals, birds, fish, reptiles, and amphibians. By using these methods for the evaluation of the "chemical phenotype," the mutual triangular relationship among "chemical phenotype," "visual phenotype," and "genotype" is reviewed.
Oculocutaneous albinism (OCA) 6 is a non‐syndromic type of OCA that has distinct ocular symptoms ... more Oculocutaneous albinism (OCA) 6 is a non‐syndromic type of OCA that has distinct ocular symptoms and variable cutaneous hypopigmentation. The causative gene of OCA6 is SLC24A5, which encodes NCKX5, a K+‐dependent Na+/Ca2+ exchanger 5. NCKX5 is involved in the maturation of melanosomes, but its function is still unclear. In this study, we characterized a Japanese patient with OCA6. Genetic analysis revealed compound heterozygous variants in SLC24A5, c.590 + 1dupG, and c.598G>A (p.G200R). To clarify the functional significance of the missense variant, we generated a knock‐in (KI) mouse model carrying the mouse homolog of the G200R variant using the CRISPR/Cas9 system. Chemical analysis showed decreased amounts of eumelanin in the hair and skin of KI mice, while levels of benzothiazine units in pheomelanin were significantly increased in their hair. Retinal pigment was also decreased in KI mice. Notably, a histopathologic study revealed a significant pigment loss in the retinal pigm...
Effects of low temperature on the color of red sea bream (Pagrus major) were investigated. In col... more Effects of low temperature on the color of red sea bream (Pagrus major) were investigated. In colorimetric evaluation using L*a*b* system the fish reared under low-temperature (10•Ž) for two months lost their L* value compared to control (bred under 22•Ž) while no change was observed in a* and b* value. No significant difference was found in blood test (GOT, GPT, ALP, gamma-GTP, total bilirubin, direct bilirubin, indirect bilirubin and bile acid). We also examined the properties of the •gyellowed•h juvenile red seabream which sometimes occur in winter season in Fisheries Laboratory of Kinki University. The b* value was significantly lower than that of control while no significant difference could be found in L* value. The blood test showed no clear difference in direct and indirect bilirubin conc as well as in other measurements. We also examined the concentration of yellow melanin (pheomelanin), however, no significant gap could be found in nomal and yellowed red seabream, indicati...
Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine sk... more Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.
Post‐inflammatory hyperpigmentation (PIH) is a common cutaneous condition that can cause a disfig... more Post‐inflammatory hyperpigmentation (PIH) is a common cutaneous condition that can cause a disfigured appearance. However, the pathophysiology of PIH remains poorly understood, at least in part, because an appropriate animal model for research has not been established. In order to analyze the pathomechanism of PIH, we successfully induced PIH in a hairless version of transgenic mice (hk14‐SCF Tg/HRM) that have a human‐type epidermis containing melanin by repeated hapten application of 2,4‐dinitrofluorobenzene. Histopathologic observation showed epidermal hyperplasia, predominant infiltrations of inflammatory cells, and melanin‐containing cells in the dermis just after elicitation of the atopic dermatitis‐like condition. At week 2, the findings were similar to the characteristics of PIH, that is, an increase of melanin without spongiosis or liquid degeneration in the epidermis and an increase in dermal melanophages. Dynamic analysis of melanin showed that the melanin in the dermis re...
DNA methylation and subsequent oxidation of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC) ... more DNA methylation and subsequent oxidation of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC) catalyzed by the TET family enzymes are key epigenetic events regulating development and stem cell differentiation in mammals, while genetic ablation of all three Tet genes is embryonic lethal. Here, we show that 5hmC level and Tet1/2/3 expression display dynamic changes in the developing hair follicles (HFs), as well as during the hair cycle. High level of 5hmC and high expression of Tet2 and Tet3 were seen in differentiating hair matrix keratinocytes (KCs), outer and inner root sheaths, hair shaft and dermal papilla. To explore the role of Tet1/2/3 in the control of HF development and cycling, we used mice with Shh-Cre mediated ablation of all three Tet genes (Shh-Cre/ Tet1 fl/fl /Tet2 fl/fl / Tet3 fl/fl) as a conditional triple knockout (TKO) model. Consistent with the expression pattern of Shh gene, Cre expression was seen in the HF placodes, as well as in a cluster of hair matrix KCs whose progenies form the hair shaft. Shh-Cre mediated Tet triple knockout resulted in a significant decrease in the hair shaft length in all bended hair types (auchen, zigzag), as well as an increase in the number of straight (guard, awl) hairs compared to controls. These differences were accompanied by a marked decrease of Bmpr1a/1b in the hair shaft KCs from TKO mice, as well as with the decreased pSmad1 expression. Furthermore, hMeDIP-seq analyses of primary mouse KCs revealed 5hmC peaks at the Bmpr1b gene promoter, as well as at several enhancers located in close vicinity to the Bmpr1a/2 genes, while depicted by H3K27ac/ H3K4me1 ChIPseq analyses. These data demonstrate the role of Tet-mediated DNA hydroxymethylation controlling hair shaft-specific KC differentiation and hair shaft formation, as well as regulating transcription of Bmpr1a/1b/2 and activity of the enhancers adjacent to these genes in KCs.
Alcohol induces various cutaneous changes, such as palmar erythema and jaundice. However, alcohol... more Alcohol induces various cutaneous changes, such as palmar erythema and jaundice. However, alcohol-induced skin hyperpigmentation due to melanin deposition has not been reported. Aldehyde dehydrogenase 2 (ALDH2), one of 19 human ALDH isozymes, metabolizes endogenous and exogenous aldehydes to their respective carboxylic acids. Reduced ALDH2 greatly affects acetaldehyde metabolism, leading to its accumulation in the body after the consumption of alcohol and the consequent development of a wide range of phenotypes. In the present study, we report a novel phenotype manifesting in a mouse model with the altered expression of ALDH2. Aldh2 knockout (Aldh2+/− and Aldh2−/−) and wild-type (Aldh2+/+) mice were fed a standard solid rodent chow and a bottle of ethanol solution at concentrations of 0%, 3%, 10%, or 20% (v/v) for more than 10 weeks. The intensity of their skin pigmentation was evaluated by macroscopic observation. Ethanol-exposed Aldh2+/− and Aldh2−/− mice exhibited dose-dependent skin pigmentation in areas of hairless skin, including the soles of the paws and tail; no such changes were observed in wild-type mice. The intensity of skin pigmentation correlated with the number of Aldh2 alleles that were altered in the mice (i.e., 0, 1 and 2 for Aldh2+/+, Aldh2+/−, Aldh2−/−, respectively). Interestingly, the skin pigmentation changes reversed upon the discontinuation of ethanol. The histological examination of the pigmented skin demonstrated the presence of melanin-like deposits, mainly in the epidermis. In conclusion, we report a novel finding that the intake of ethanol induces skin hyperpigmentation in an ALDH2 activity-dependent manner.
BACKGROUND. Oculocutaneous albinism (OCA) results in reduced melanin synthesis, skin hypopigmenta... more BACKGROUND. Oculocutaneous albinism (OCA) results in reduced melanin synthesis, skin hypopigmentation, increased risk of UV-induced malignancy, and developmental eye abnormalities affecting vision. No treatments exist. We have shown that oral nitisinone increases ocular and fur pigmentation in a mouse model of one form of albinism, OCA-1B, due to hypomorphic mutations in the Tyrosinase gene. METHODS. In this open-label pilot study, 5 adult patients with OCA-1B established baseline measurements of iris, skin, and hair pigmentation and were treated over 12 months with 2 mg/d oral nitisinone. Changes in pigmentation and visual function were evaluated at 3-month intervals. RESULTS. The mean change in iris transillumination, a marker of melanin, from baseline was 1.0 ± 1.54 points, representing no change. The method of iris transillumination grading showed a high intergrader reliability (intraclass correlation coefficient ≥ 0.88 at each visit). The number of letters read (visual acuity) improved significantly at month 12 for both eyes (right eye, OD, mean 4.2 [95% CI, 0.3, 8.1], P = 0.04) and left eye (OS, 5 [1.0, 9.1], P = 0.003). Skin pigmentation on the inner bicep increased (M index increase = 1.72 [0.03, 3.41], P = 0.047). Finally, hair pigmentation increased by both reflectometry (M index [17.3 {4.4, 30.2}, P = 0.01]) and biochemically. CONCLUSION. Nitisinone did not result in an increase in iris melanin content but may increase hair and skin pigmentation in patients with OCA-1B. The iris transillumination grading scale used in this study proved robust, with potential for use in future clinical trials. TRIAL REGISTRATION. ClinicalTrials.gov NCT01838655. FUNDING. Intramural program of the National Eye Institute.
Sex allocation is the parental resource allocation to sons versus daughters. Given the different ... more Sex allocation is the parental resource allocation to sons versus daughters. Given the different benefits and costs of investments in sons and daughters, females should adjust the brood sex ratio according to their own quality to maximize their fitness. In the barn swallow Hirundo rustica, as in many other passerines, females should increase the proportion of sons in their broods with increasing maternal body size, because rearing sons is particularly costly to small females with low feeding capacity, and because reproductive success in the barn swallow, which may depend on rearing conditions, varies more in males. However, evidence supporting this prediction is lacking, even in this model species of sex allocation. Using the Asian subspecies of the barn swallow H. r. gutturalis, we confirmed this prediction. Larger mothers with a longer keel had more sons in their brood. We found that male nestlings invested more in pheomelanin pigmentation compared with female nestlings, while they had shorter wing lengths, indicating that male nestlings are costly to rear compared with female nestlings. Smaller mothers that are at a disadvantage in provisioning may not retard the nestling period by producing daughters, which reduces their parental investment and thus saves their residual reproductive value. This breeding strategy might be particularly beneficial to Japanese barn swallows that breed in environments with high nest predation.
The diversity of pigmentation in the skin, hair, and eyes of humans has been largely attributed t... more The diversity of pigmentation in the skin, hair, and eyes of humans has been largely attributed to the diversity of pH in melanosomes with an acidic pH being proposed to suppress melanin production, especially eumelanogenesis. We previously showed that an acidic pH greatly suppresses the late stage of eumelanogenesis after the dopachrome stage. The oxidation of tyrosine by tyrosinase in the presence of cysteine forms cysteinyldopa isomers, which are further oxidized to give rise to pheomelanin via benzothiazine intermediates. However, how those steps are controlled by pH has not been characterized. We therefore examined whether pheomelanin synthesis is chemically promoted at an acidic pH. We found that pheomelanin production either from dopa or tyrosine in the presence of cysteine by tyrosinase was greatest at pH values of 5.8-6.3, while eumelanin production was suppressed at pH 5.8. This suggests that mixed melanogenesis is chemically shifted to more pheomelanic states at a weakly ...
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Papers by Shosuke Ito