High doses of cobalt inhibited hair follicle development in Rex Rabbits

L. Liu, Q. Gao, C. Wang, Z. H. Fu, K. Wang, F. C. Li


An experiment was conducted to investigate the effect of cobalt supplementation on hair follicle development in rabbits. Rex rabbits (30-d-old, n=180) were divided randomly into five equal treatment groups: rabbits fed a basal diet (control, measured cobalt content of 0.27 mg/kg) or rabbits fed a basal diet with an additional 0.1, 0.4, 1.6 or 6.4 mg/kg cobalt (in the form of cobalt sulfate) supplementation (measured cobalt contents of 0.35, 0.60, 1.83 and 6.62 mg/kg, respectively). Treatment with 6.4 mg/kg cobalt significantly decreased hair follicle density (P<0.05), while low levels of cobalt (0.1-1.6 mg/kg) had no effect on hair follicle density (P>0.05). The addition of dietary cobalt at the highest level examined (6.4 mg/kg) significantly increased the gene expression of bone morphogenetic protein (BMP) 2 and BMP4 in skin tissue (P<0.05), while the mRNA levels of versican, alkaline phosphatase, hepatocyte growth factor, and noggin remained unchanged (P>0.05). Compared with their levels in the control group, dietary cobalt treatment significantly suppressed the protein levels of p-mechanistic target of rapamycin (mTOR) and p-ribosomal protein S6 protein kinase (P<0.05) but did not alter the protein levels of p-AMP-activated protein kinase, Wnt10b or p-β-catenin (P>0.05). In conclusion, cobalt at the highest concentration examined inhibited hair follicle development, which may have involved the mTOR-BMP signalling pathway.


cobalt; hair follicle development; mTOR-BMP signalling pathway; rabbits

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Blessing M., Nanney L.B., King L.E., Jones C.M., Hogan, B.L.M. 1993. Transgenic mice as a model to study the role of TGF-β-related molecules in hair follicles. Genes Dev., 7: 204-215. https://doi.org/10.1101/gad.7.2.204

Chong H.W. 2016. Metformin, an activator of AMPK, promotes the growth of hair follicles via AMPK/β-catenin signaling pathway. Program, 68: 112-113.

De Blas C., Mateos G.G. 1998. Feed formulation. In: Nutrition of the Rabbit. CAB International Press. Wallingford (UK).

Deng Z., Lei X., Zhang X., Zhang H., Liu S., Chen Q., Hu H., Wang X., Ning L., Cao Y., Zhao T., Zhou J., Chen T., Duan E. 2015. mTOR signaling promotes stem cell activation via counterbalancing BMP-mediated suppression during hair regeneration. J. Mol. Cell Biol., 7: 62-72. https://doi.org/10.1093/jmcb/mjv005

Fuchs E., Merrill B.J., Jamora C., DasGupta R. 2001. At the roots of a never-ending cycle. Dev. Cell, 1: 13-25. https://doi.org/10.1016/s1534-5807(01)00022-3

Fu C., Liu L., Li F. 2018. Acetate alters the process of lipid metabolism in rabbits. Animal, 12: 1895-1902. https://doi.org/10.1017/S1751731117003275

Gallo S., Gatti S., Sala V., Albano R., Costelli P., Casanova E., Comoglio P.M., Crepaldi T. 2014. Agonist antibodies activating the Met receptor protect cardiomyoblasts from cobalt chlorideinduced apoptosis and autophagy. Cell Death Dis., 5: e1185. https://doi.org/10.1038/cddis.2014.155

Ghaedi M., Ahmadi F., Shokrollahi A. 2007. Simultaneous preconcentration and determination of copper, nickel, cobalt and lead ions content by flame atomic absorption spectrometry. J. Hazard. Mater., 142: 272-278. https://doi.org/10.1016/j.jhazmat.2006.08.012

Huelsken J., Vogel R., Erdmann B., Cotsarelis G., Birchmeier W. 2001. Birchmeier β-catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell, 105: 533-545. https://doi.org/10.1016/s0092-8674(01)00336-1

Hynd P.I. 2000. The nutritional biochemistry of wool and hair follicles. Anim. Sci., 70: 181-195. https://doi.org/10.1017/s1357729800054655

John F.T., Gordon H.E. 1947. Is cobalt a dietary essential for the rabbit. J. Nutr., 34: 121-127. https://doi.org/10.1093/jn/34.1.121

Kawakami T., Hanao N., Nishiyama K., Kadota Y, Inoue M., Sato M., Suzuki S. 2012. Differential effects of cobalt and mercury on lipid metabolism in the white adipose tissue of high-fat diet-induced obesity mice. Toxicol. Appl. Pharmacol., 258: 32-42. https://doi.org/10.1016/j.taap.2011.10.004

Kellenberger A.J., Tauchi M. 2013. Mammalian target of rapamycin complex 1 (mTORC1) may modulate the timing of anagen entry in mouse hair follicles. Exp. Dermatol., 22: 77-80. https://doi.org/10.1111/exd.12062

Krugluger W., Stiefsohn K., Laciak K., Moser K., Moser C. 2011. Vitamin B12 activates the Wnt-pathway in human hair follicle cells by induction of betacatenin and inhibition of glycogensynthase kinase-3 transcription. J. Cosmet. Dermatol. Sci. App., 11: 25-29. https://doi.org/10.4236/jcdsa.2011.12004

Li C.T., Liu J.X., Yu B., Liu R., Dong C., Li S.J. 2016. Notch signaling represses hypoxia-inducible factor-1α-induced activation of Wnt/β-catenin signaling in osteoblasts under cobalt-mimicked hypoxia. Mol. Med. Rep., 14: 689-696. https://doi.org/10.3892/mmr.2016.5324

Li K.R., Zhang Z.Q., Yao J., Zhao Y.X., Duan J., Cao C., Jiang Q. 2013. Ginsenoside Rg-1 protects retinal pigment epithelium (RPE) cells from cobalt chloride (CoCl2) and hypoxia assaults. PLoS One, 8: e84171. https://doi.org/10.1371/journal.pone.0084171

Li Y.H., Zhang K., Ye J.X., Lian X.H., Yang T. 2011. Wnt10b promotes growth of hair follicles via a canonical Wnt signalling pathway. Clin. Exp. Dermatol., 36: 534-540. https://doi.org/10.1111/j.1365-2230.2011.04019.x

Liu L., Liu H., Fu C., Li C., Li F. 2017. Acetate induces anorexia via up-regulating the hypothalamic pro-opiomelanocortin (POMC) gene expression in rabbits. J. Anim. Feed Sci., 26: 266-273. http://doi.org/10.22358/jafs/75979/2017

Liu L., Liu H., Ning L., Li F. 2019. Rabbit SLC15A1, SLC7A1 and SLC1A1 genes are affected by site of digestion stage of development and dietary protein content. Animal, 13: 326-332. https://doi.org/10.1017/S1751731118001404

Livak K.J., Schmittgen T.D. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2 (-Delta Delta C (T)) method. Methods, 25: 402-408. https://doi.org/10.1006/meth.2001.1262

Madaan A., Verma R., Singh A.T., Jaggi M. 2018. Review of hair follicle dermal papilla cells as in vitro screening model for hair growth. Int. J. Cosmet. Sci., 40: 429-450. https://doi.org/10.1111/ics.12489

Marlon R.S., Ruth S.U., Ralf P. 2009. The hair follicle as a dynamic miniorgan. Curr. Biol., 19: 132-142. https://doi.org/10.1016/j.cub.2008.12.005

McDowell L.R. 1992. Minerals in animal and human nutrition. Academic Press, Inc., San Diego, CA. Paus R., Cotsarelis G. 1999. The biology of hair follicles. N. Engl. J. Med., 341: 491-497. https://doi.org/10.1056/NEJM199908123410706

Poeggeler B., Schulz C., Pappolla M.A., Bodó E., Tiede S., Lehnert H., Paus R. 2010. Leptin and the skin: a new frontier. Exp. Dermatol., 19: 12-28. https://doi.org/10.1111/j.1600-0625.2009.00930.x

Reddy S., Andl T.H., Bagasra A., Lu M.M., Epstein D.J., Morrisey E.E., Millar S.E. 2001. Characterization of Wnt gene expression in developing and postnatal hair follicles and identification of Wnt5a as a target of Sonic hedgehog in hair follicle morphogenesis. Mech. Dev., 107: 69-82. https://doi.org/10.1016/s0925-4773(01)00452-x

Rendl M., Polak L., Fuchs E. 2008. BMP signaling in dermal papilla cells is required for their hair follicle-inductive properties. Genes Dev., 22: 543-557. https://doi.org/10.1101/gad.1614408

Roges G.E. 2004. Hair follicle differentiation and regulation. Int. J. Biol. Sci., 48: 163-170.

Schwarz F.J., Kirchgessner M., Stangl G.I. 2000. Cobalt requirement of beef cattle feed intake and growth at different levels of cobalt supply. J. Anim. Physiol. Anim. Nutr., 83: 121-131. https://doi.org/10.1046/j.1439-0396.2000.00258.x

Stenn K.S., Paus R. 2001. Controls of hair follicle cycling. Physiol. Rev., 81: 449-494. https://doi.org/10.1152/physrev.2001.81.1.449

Wang L.C., Liu Z.Y., Gambardella L., Delacour A., Shapiro R., Yang J., Sizing I., Rayhorn P., Garber E.A., Benjamin C.D., Williams K.P., Taylor F.R., Barrandon Y., Ling L., Burkly L.C. 2000. Regular articles: conditional disrupt ion of hedgehog signaling pathway defines its critical role in hair development and regeneration. J. Invest. Dermatol., 114: 901-908. https://doi.org/10.1046/j.1523-1747.2000.00951.x

Weinberg W.C., Goodman L.V., George C., Morgan D.L., Ledbetter S., Yuspa S.H., Lichti U. 1993. Reconstitution of hair follicle development in vivo: determination of follicle formation, hair growth, and hair quality by dermal cells. J. Invest. Dermatol., 100: 229-236. https://doi.org/10.1111/1523-1747.ep12468971

Wilson N., Hynd P.I., Powell B.C. 1999. The role of BMP-2 and BMP-4 in follicle initiation and the murine hair cycle. Exp. Dermatol., 8: 367-368.

Wolff G.L., Kodell R.L., Moore S.R., Cooney C.A. 1998. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/A mice. FASEB J., 11: 949-957. https://doi.org/10.1096/fasebj.12.11.949

Zhong X., Lin R., Li Z., Mao J., Chen L. 2014. Effects of Salidroside on cobalt chloride-induced hypoxia damage and mTOR signaling repression in PC12 cells. Biol. Pharm. Bull., 37: 1199-1206. https://doi.org/10.1248/bpb.b14-00100

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 Universitat Politècnica de València


Official journal of the World Rabbit Science Association (WRSA)


e-ISSN: 1989-8886     ISSN: 1257-5011   https://doi.org/10.4995/wrs