臺灣博碩士論文加值系統

先前本實驗室已觀察到母鼠孕期攝食氧化炸油(oxidized frying oil; OFO)會造成子代畸形，由於OFO已知可活化PPARα，環境汙染物塑化劑 (DEHP)和鐵弗龍成分全氟辛酸(PFOA)與OFO一樣都是PPARα的活化劑，懷孕期間暴露於這些環境汙染物，也會造成子代的發育毒性，這些環境汙染物已證實部分與PPARα活化有關，但PPARα活化如何影響胎胚發育，其中機制有待釐清。

文獻指出PPARα活化劑clofibrate，會顯著影響參與維生素A酸(retinoic acid, RA)代謝相關基因表現。RA是胚胎發育時期重要的型態原(morphogen)，RA表現量過多或過少均會造成畸胎。胚胎發育期間RA的表現需要精確的時空 (Spatial-temporal) 調節，本研究假設母鼠孕期攝取OFO可能透過PPARα活化，影響母鼠與胚胎體內的RA合成及代謝，進而導致子代畸形，實驗分為二部份:1.探討孕期攝取OFO並添加RA是否可以降低畸胎率。若孕期攝食OFO使RA生成量減少而致畸胎，則補充RA應能成功降低其畸胎率; 反之則可能是RA生成過多。2.探討炸油畸胎性與PPARα活化及維生素A代謝干擾之關係。將炸油區分為極性(OFO-polar fraction；PO)與非極性區分物(OFO-nonpolar fraction；NP)，先前研究已知OFO的PPARα活化物存在於PO，若能證實PO不但放大PPARα活化，也放大其畸胎性及干擾RA代謝效應，則間接支持我們假說。

結果: 1. OFO補充RA顯著增加母鼠full-litter resorptions (FLR)、胎兒死亡及畸胎率、骨骼異常機率更甚於未補充RA組，可見補充RA不能挽救炸油致畸胎。2.分離自OFO的PO更加劇胎兒死亡率、畸胎率、骨骼發育不良機率，與PPARα活化，且不論母親或胚胎均發現PO組RA合成與分解相關酵素基因表現偏離正常對照組。結論: OFO畸胎性並非母鼠RA缺乏所造成，但OFO飲食的確在PPARα活化的同時，也干擾了RA合成與分解，至於畸胎性是否與PPARα活化有關則有待進一步研究證實。

In our previous study, we had observed a higher incidence of malformations in fetuses of dams receiving oxidized frying oil (OFO) during pregnancy. It has been reported that OFO can activate the peroxisome proliferator-activated receptor alpha (PPARα). Clofibrate, as a PPARα activator, has been shown to affect expression of genes participating in retinoic acid (RA) catabolism. Being regarded as a morphogen, excess or deficiency of RA during fetus development, both result in teratogenesis. Environmental contaminants such as plasticizer (di(2-ethylhexyl)
phthalate; DEHP), teflon components (perfluorooctanoic acid ; PFOA) activate PPARα as well. Exposure to these Environmental contaminants has been shown to cause developmental toxicity in the offspring during pregnancy, which is partly attributed to PPARα activation. However, the underlying mechanisms remain to be clarified.
RA is indispensible for the precisely spatial and temporal regulation during embryonic development. In this study, we hypothesized that the maternal ingestion of OFO during pregnancy, via PPARα activation, results in teratogenesis by interfering with maternal and embryonic RA synthesis/catabolism. To test this hypothesis, two experiments were included: in Expt. 1, we sought to investigate whether the OFO-mediated teratogenesis can be rescued by RA supplementation. If OFO-mediated teratogenesis is associated with RA deficiency in dams and their fetuses, supplementation of RA would successfully rescue the defects; otherwise, an exaggerated effect would be seen. In Expt. 2, the relevance of OFO teratogenic effect, PPARα activation and the interference of RA metabolism were explored. The OFO was fractionated into OFO-polar fraction (PO) and OFO-nonpolar fraction (NP). It is known that the PPARα activators in OFO are present in the PO fraction, rather than NP fraction. We expected our hypothesis would be supported indirectly if we could see the teratogenic effect of OFO, along with PPARα activation and RA metabolic interference was amplified in dams and their fetuses receiving PO during gestational period compared with their counterparts receiving NP or OFO.
As results of Expt. 1, supplementation of RA in OFO group significantly increased maternal full-litter resorptions (FLR), incidences of fetal death, birth defects, and skeletal abnormalities as compared to the OFO group without RA supplementation. It suggests that supplementation of RA did not rescue, but aggravate, the teratogenesis caused by OFO. In Expt. 2, the fetus mortality, incidences of birth defects and skeletal abnomalities, and PPARα activation consistently showed an order of PO>NP>SO (fresh soybean oil control) groups. In addition, the expression levels of genes encoding enzymes related with RA synthesis/catabolism in the liver of dams and their fetuses receiving PO diet were significantly different from those of their normal counterparts. Based on above results, we concluded that the OFO-mediated teratogenesis is not attributable to RA deficiency. However, dietary OFO does interfere with RA metabolism in accordance with PPARα activation. The role of PPARα in the OFO-mediated teratogengesis will be investigated in the future studies.

目錄 i
圖目錄 iv
表目錄 v
縮寫對照表 vi
中文摘要 ix
Abstract xi
第一章 前言 1
第二章 文獻回顧 3
一、發育毒理(Developmental toxicology) 3
(一) 歷史背景 3
(二) 孕期因營養素缺乏致畸胎： 4
(三) 維生素A與致畸胎 5
二、 氧化炸油 (Oxidized frying oil, OFO) 9
(一) 炸油之化學組成 9
(二) 炸油對動物生理影響 9
(三) 炸油與脂質代謝 11
(四) 炸油與維生素A 11
三、環境汙染物的發育毒性與PPARα活化關係 13
(一) 塑化劑 di(2-ethylhexyl)phthalate (DEHP) 13
(二) 鐵弗龍成分全氟辛酸perfluorooctanoic acid (PFOA) 16
第三章 材料與方法 17
一、實驗設計與假說 17
二、氧化炸油製備 19
三、將炸油分離成極性與非極性區分物 19
四、薄片層析法 TLC 21
五、試驗飼料配製 22
六、炸油飼料-添加維生素A 24
七、動物飼養 24
八、檢體收集 25
九、胚胎骨骼染色 (Skeletal Staining in Fetal mouse) 25
十、抽取RNA及cDNA的製備 28
十一、 Real time polymerase chain reaction(同步定量PCR；qRT-PCR) 34
十二、 統計分析 37
第四章 結果 38
一、 探討孕期攝取炸油並添加Retinoic acid是否可以降低畸胎率。 38
(一) 母鼠孕期間體重變化與飼料攝取量 38
(二) 胚胎毒性 38
(三) 母鼠生殖性狀 39
(四) 胚胎存活率與外觀異常 39
(五) 胚胎骨骼發育 40
二、探討炸油畸胎性與PPARα活化及維生素A代謝干擾關係 51
(一) 炸油極性與非極性物之分離區分結果 51
(二) 母鼠孕期間體重變化與飼料攝取量 52
(三) 母鼠與胚胎肝臟PPARα活化效應 52
(四) 胚胎毒性 52
(五) 母鼠生殖性狀 52
(六) 胚胎存活率與外觀異常 53
(七) 胚胎骨骼發育 53
(八) 母鼠與胚胎肝臟維生素A代謝 54
第五章 討論 63
一、 探討孕期攝取炸油並添加Retinoic acid是否可以降低畸胎率。 63
二、 探討炸油的畸胎性與PPARα活化及維生素A代謝干擾之關係。 65
第六章 結論 71
一、 探討孕期攝取炸油並添加Retinoic acid是否可以降低畸胎率。 71
二、 探討炸油的畸胎性與PPARα活化及維生素A代謝干擾之關係。 71
第七章 附件 72
胚胎骨骼染色 72
第八章 參考文獻 77

1.Issemann, I. and S. Green, Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature, 1990. 347(6294): p. 645-50.
2.Chao, P.M., et al., Oxidized frying oil up-regulates hepatic acyl-CoA oxidase and cytochrome P450 4 A1 genes in rats and activates PPARalpha. J Nutr, 2001. 131(12): p. 3166-74.
3.趙蓓敏, 氧化炸油活化PPARα之探討. 國立台灣大學農業化學研究所博士論文, 2002.
4.莊蕙璟, 孕期攝食炸油飲食對子代的代謝程式化效應. 中國醫藥大學營養學系碩士班碩士論文, 2011.
5.Warkany, J.a.S., E., Congenital malformations induced in rats by maternal vitamin A deficiency. Arch. Ophthalmol., 1946. 35: p. 150-169.
6.Kochhar, D.M., Teratogenic activity of retinoic acid. . Acta Pathol Microbiol Immuno Scand 1967. 70: p. 398-404.
7.Tay, S., et al., A comparison of the roles of peroxisome proliferator-activated receptor and retinoic acid receptor on CYP26 regulation. Molecular Pharmacology, 2010. 77(2): p. 218-27.
8.Lei, Z., et al., Reduction of all-trans-retinal in the mouse liver peroxisome fraction by the short-chain dehydrogenase/reductase RRD: induction by the PPAR alpha ligand clofibrate. Biochemistry, 2003. 42(14): p. 4190-6.
9.Hayashi, Y., et al., Hepatic peroxisome proliferator-activated receptor alpha may have an important role in the toxic effects of di(2-ethylhexyl)phthalate on offspring of mice. Toxicology, 2011. 289(1): p. 1-10.
10.Abbott, B.D., et al., Perfluorooctanoic acid induced developmental toxicity in the mouse is dependent on expression of peroxisome proliferator activated receptor-alpha. Toxicol Sci, 2007. 98(2): p. 571-81.
11.Wilson, J.G., Evironment and birth defects. New York: Academic Press, 1973.
12.Warkany, J. and H. Kalter, Congenital malformations. New England Journal of Medicine, 1961. 265: p. 265-993.
13.Schardein, J.L. and K.a. Keller, Potential human developmental toxicants and the role of animal testing in their identification and chacterization. CRC Crit Rev Toxicol 1989. 19: p. 251-339.
14.Hale, F., Pigs born without eyeballs. J Hered, 1935. 27: p. 105-106.
15.Warkany, J., Manifestations of Prenatal Nutritional Deficiency. Vitamins & Hormones, 1945. 3: p. 73-103.
16.Warkany, J. and R.C. Nelson, Appearance of skeletal abnormalities in offspring of rats reared on deficient diet. Science, 1940. 92: p. 383-384.
17.Warkany, J. and R.C. Nelson, Skeletal abnormalities induced in rats by maternal nutritional deficiency: histological studies. Arch. Path., 1942. 34: p. 375-384.
18.Warkany, J. and E. Schraffenberger, Congenital malformations induced in rats by maternal nutritional deficiency:VI. preventive factor. Journal of nutrition, 1944. 27: p. 477-484
19.Gagne, A., et al., Absorption, transport, and bioavailability of vitamin e and its role in pregnant women. J Obstet Gynaecol Can, 2009. 31: p. 210-217.
20.Hozyasz, K., J. Mazur, and M. Chelchowska, Alpha-tocopherol levels in mothers of children with cleft lip or with cleft lip and palate. Ginekologia Polska, 2006. 77(4): p. 255-62.
21.Cheng, D.W. and B.H. Thomas, Relationship of time of therapy to teratogeny in maternal avitaminosis E. Proc. Iowa Acad. Sc, 1953. 60: p. 290-299.
22.Nelson, M.M., C.W. Asling, and H.M. Evans, Production of congenital abnormalities in young by maternal pteroylglutamic acid deficiency during gestation. Journal of nutrition, 1952. 48: p. 61-79.
23.Nelson, M.M., et al., Multiple congenital abnormalities resulting from transitory deficiency of pteroylglutamic acid during gestation in rat. Journal of nutrition 1955. 56: p. 349-369.
24.Smithells, R.W., S. Sheppard, and C.J. Schorah, Vitamin deficiencies and neural tube defects. Arch. Dis. Child., 1976. 51: p. 944-950.
25.Beaudin, A.E. and P.J. Stover, Folate-mediated one-carbon metabolism and neural tube defects: balancing genome synthesis and gene expression. Birth Defects Res C Embryo Today, 2007. 81(3): p. 183-203.
26.Mason, K., Foetal death, prolonged gestation, and difficult parturition in the rat as a result of vitamin A-deficiency. Am. J. Anat., 1935. 57: p. 303-349.
27.Napoli, J.L., Physiological insights into all-trans-retinoic acid biosynthesis. Biochimica et Biophysica Acta, 2012. 1821(1): p. 152-67.
28.Rhinn, M. and P. Dolle, Retinoic acid signalling during development. Development, 2012. 139(5): p. 843-58.
29.Warkany, J. and E. Schraffenberger, Congenital malformations induced in rats by maternal vitamin A deficiency. Arch. Ophthalmol., 1946. 35: p. 150-169.
30.Jackson, B. and V.E. Kinsey, The relation between maternal vitamin-A intake,blood level, and ocular abnormalities in the offspring of the rat. Am. J. Ophthalmol., 1946. 29: p. 1234-1242.
31.Wilson, J.G., C.B. Roth, and J. Warkany, An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. Am. J. Anat. , 1953. 92: p. 189-217.
32.Wilson, J.G. and J. Warkany, Malformations in the genito-urinary tract induced by maternal vitamin A deficiency in therat Am. J. Anat., 1948. 83: p. 357-407.
33.Wilson, J.G. and J. Warkany, Aorticarch and cardiac anomalies in the offspring of vitamin A deficient rats. Am. J. Anat., 1949. 85: p. 113-155.
34.Cohlan, S.Q., Congenital anomalies in the rat produced by excessive intake of vitamin A during pregnancy. Pediatrics 1954. 13: p. 556-567.
35.Kochhar, D.M., Teratogenic activity of retinoic acid. Acta Pathol Microbiol Immuno Scand, 1967. 70: p. 398-404.
36.Shenefelt, R.E., Morphogenesis of malformations in hamsters caused by retinoic acid: Relation to dose and stage of treatment Teratology, 1972. 5: p. 103-118.
37.Rosa, F.W., Teratogenicity of isotretinoin. Lancet, 1983. 2: p. 513.
38.Lammer, E.J., et al., Retinoic acid embryopathy. N Engl J Med 1985. 313: p. 837-841.
39.Niederreither, K. and P. Dolle, Retinoic acid in development: towards an integrated view. Nature Reviews Genetics, 2008. 9(7): p. 541-553.
40.Ashique, A.M., et al., Morphological defects in a novel Rdh10 mutant that has reduced retinoic acid biosynthesis and signaling. Genesis, 2012. 50(5): p. 415-23.
41.Artman, N.R., The chemical and biological properties of heated and oxidized fats. Adv. Lipid Res., 1969. 7: p. 245-330.
42.Liu, J.F. and C.J. Huang, Tissue alpha-tocopherol retention in male rats is compromised by feeding diets containing oxidized frying oil. journal of Nutrition, 1995. 125: p. 3071-3080.
43.Chao, P.M., et al., Oxidized frying oil up-regulates hepatic acyl-CoA oxidase and cytochrome P450 4 A1 genes in rats and activates PPARalpha. JoURNAL OF NUTrition, 2001. 131: p. 3166-3174.
44.Liao, C.H., H.M. Shaw, and P.M. Chao, Impairment of glucose metabolism in mice induced by dietary oxidized frying oil is different from that induced by conjugated linoleic acid. Nutrition, 2008. 24(7-8): p. 744-52.
45.Crampton, J.M. and E. Voss, An investigation of the chronic toxicity and acceptability of Castrix. J Am Pharm Assoc Am Pharm Assoc, 1952. 41(3): p. 135-8.
46.Combe, N., M.J. Constantin, and B. Entressangles, Lymphatic absorption of nonvolatile oxidation products of heated oils in the rat. Lipids, 1981. 16(1): p. 8-14.
47.Chang, S.S., R.J. Peterson, and C.T. Ho, Chemical reactions involved in the deep-fat frying of foods. Journal of the American Oil Chemists Society, 1978. 55(10): p. 718-27.
48.Siu, G.M. and H.H. Draper, Metabolism of malonaldehyde in vivo and in vitro. Lipids, 1982. 17(5): p. 349-55.
49.Huang, C.J., Cheung, N. S., and Lu, V. R., Effects of deteriorated frying oil and dietary protein levels on liver microsomal enzymes in rats. Journal of the American Oil Chemists'' Society, 1988. 65: p. 1796-1803.
50.吳映蓉, 膳食炸油對乳腺腫瘤之促進作用與雌性素之角色. 國立臺灣大學農業化學研究所博士論文, 1996.
51.湯雅理, 炸油餵食對老鼠肝中維生素A含量及肝微粒體Cytochrome P-450酵素活性之影響. 國立臺灣大學農業化學研究所碩士論文, 1994.
52.Chao, P.M., et al., The up-regulation of hepatic acyl-CoA oxidase and cytochrome P450 4A1 mRNA expression by dietary oxidized frying oil is comparable between male and female rats. Lipids, 2004. 39(3): p. 233-8.
53.Sulzle, A., F. Hirche, and K. Eder, Thermally oxidized dietary fat upregulates the expression of target genes of PPAR alpha in rat liver. Journal of Nutrition, 2004. 134(6): p. 1375-83.
54.Koch, A., et al., Thermally oxidized oil increases the expression of insulin-induced genes and inhibits activation of sterol regulatory element-binding protein-2 in rat liver. Journal of Nutrition, 2007. 137(9): p. 2018-23.
55.Chao, P.M., et al., A high oxidised frying oil content diet is less adipogenic, but induces glucose intolerance in rodents. British Journal of Nutrition, 2007. 98(1): p. 63-71.
56.Muindi, J.F. and C.W. Young, Lipid hydroperoxides greatly increase the rate of oxidative catabolism of all-trans-retinoic acid by human cell culture microsomes genetically enriched in specified cytochrome P-450 isoforms. Cancer Research, 1993. 53(6): p. 1226-9.
57.Alnouti, Y. and C.D. Klaassen, Tissue distribution, ontogeny, and regulation of aldehyde dehydrogenase (Aldh) enzymes mRNA by prototypical microsomal enzyme inducers in mice. Toxicological Sciences, 2008. 101(1): p. 51-64.
58.Lei, Z., et al., Reduction of all-trans-retinal in the mouse liver peroxisome fraction by the short-chain dehydrogenase/reductase RRD: induction by the PPARa ligand clofibrate. Biochemistry and Cell Biology, 2003. 42: p. 4190-4196.
59.劉致昕、黃秀美, 天然尚好　更要拒買劣質品. 商業周刊, 2011年. 1228: p. 56,58.
60.Pelley, J., Plasticizer may make boys less masculine. Environ Sci Technol., 2008.
61.Lamb, J.C.t., et al., Reproductive effects of four phthalic acid esters in the mouse. Toxicol Appl Pharmacol, 1987. 88(2): p. 255-69.
62.Tyl, R.W., et al., Developmental toxicity evaluation of dietary di(2-ethylhexyl)phthalate in Fischer 344 rats and CD-1 mice. Fundam Appl Toxicol, 1988. 10(3): p. 395-412.
63.Jarfelt, K., et al., Antiandrogenic effects in male rats perinatally exposed to a mixture of di(2-ethylhexyl) phthalate and di(2-ethylhexyl) adipate. Reprod Toxicol, 2005. 19(4): p. 505-15.
64.Xu, Y., et al., Maternal di-(2-ethylhexyl)-phthalate exposure influences essential fatty acid homeostasis in rat placenta. Placenta, 2008. 29(11): p. 962-9.
65.Lau, C., Thibodeaux, J. R., Hanson, R. G., Narotsky, M. G., Rogers, J. M., Lindstrom, A. B., and Strynar,M. J., Effects of perfluorooctanoic acid exposure during pregnancy in the mouse. Toxicol. Sci., 2006. 90: p. 510–518.
66.黃勤方, 孕期攝食炸油飲食對子代的代謝程式化效應. 中國醫藥大學營養學系碩士班碩士論文, 2011.
67.Liu, J.F. and C.J. Huang, Dietary oxidized frying oil enhances tissue alpha-tocopherol depletion and radioisotope tracer excretion in vitamin E-deficient rats. J. Nutr, 1996. 126: p. 2227-2235.
68.El-Sayyad, H.I., et al., Effects of fried potato chip supplementation on mouse pregnancy and fetal development. Nutrition, 2011. 27(3): p. 343-50.
69.Chao, P.M., et al., Peroxisome proliferation in liver of rats fed oxidized frying oil. Journal of Nutritional Science and Vitaminology, 2005. 51(5): p. 361-8.
70.Palkar, P.S., et al., Effect of prenatal peroxisome proliferator-activated receptor alpha (PPARalpha) agonism on postnatal development. Toxicology, 2010. 276(1): p. 79-84.
71.Nishimura, N., et al., Altered thyroxin and retinoid metabolic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin in aryl hydrocarbon receptor-null mice. Arch Toxicol, 2005. 79(5): p. 260-7.
72.Du, L., et al., Differentiation-specific factors modulate epidermal CYP1-4 gene expression in human skin in response to retinoic acid and classic aryl hydrocarbon receptor ligands. J Pharmacol Exp Ther, 2006. 319(3): p. 1162-71.
73.Gerbal-Chaloin, S., et al., Role of CYP3A4 in the regulation of the aryl hydrocarbon receptor by omeprazole sulphide. Cell Signal, 2006. 18(5): p. 740-50.
74.Fan, X., et al., Targeted disruption of Aldh1a1 (Raldh1) provides evidence for a complex mechanism of retinoic acid synthesis in the developing retina. Mol Cell Biol, 2003. 23(13): p. 4637-48.
75.Niederreither, K., et al., Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet, 1999. 21(4): p. 444-8.
76.Niederreither, K., et al., Retinoic acid synthesis and hindbrain patterning in the mouse embryo. Development, 2000. 127(1): p. 75-85.
77.Vermot, J., et al., Retinoic acid controls the bilateral symmetry of somite formation in the mouse embryo. Science, 2005. 308(5721): p. 563-6.
78.Dobbs-McAuliffe, B., Q. Zhao, and E. Linney, Feedback mechanisms regulate retinoic acid production and degradation in the zebrafish embryo. Mech Dev, 2004. 121(4): p. 339-50.
79.Molotkova, N., A. Molotkov, and G. Duester, Role of retinoic acid during forebrain development begins late when Raldh3 generates retinoic acid in the ventral subventricular zone. Dev Biol, 2007. 303(2): p. 601-10.
80.Dupe, V., et al., A newborn lethal defect due to inactivation of retinaldehyde dehydrogenase type 3 is prevented by maternal retinoic acid treatment. Proc Natl Acad Sci U S A, 2003. 100(24): p. 14036-41.
81.Meng, X.Y., Q.C. Zheng, and H.X. Zhang, A comparative analysis of binding sites between mouse CYP2C38 and CYP2C39 based on homology modeling, molecular dynamics simulation and docking studies. Biochim Biophys Acta, 2009. 1794(7): p. 1066-72.
82.White, J.A., et al., Identification of the retinoic acid-inducible all-trans-retinoic acid 4-hydroxylase. J Biol Chem, 1996. 271(47): p. 29922-7.
83.Gaemers, I.C., et al., All-trans-4-oxo-retinoic acid: a potent inducer of in vivo proliferation of growth-arrested A spermatogonia in the vitamin A-deficient mouse testis. Endocrinology, 1996. 137(2): p. 479-85.
84.Niederreither, K., et al., Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development. Nat Genet, 2002. 31(1): p. 84-8.
85.Taimi, M., et al., A novel human cytochrome P450, CYP26C1, involved in metabolism of 9-cis and all-trans isomers of retinoic acid. J Biol Chem, 2004. 279(1): p. 77-85.
86.White, J.A., et al., Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all-trans-retinoic acid metabolism. Proc Natl Acad Sci U S A, 2000. 97(12): p. 6403-8.
87.Fujii, H., et al., Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos. EMBO J, 1997. 16(14): p. 4163-73.
88.MacLean, G., et al., Cloning of a novel retinoic-acid metabolizing cytochrome P450, Cyp26B1, and comparative expression analysis with Cyp26A1 during early murine development. Mech Dev, 2001. 107(1-2): p. 195-201.
89.Tahayato, A., P. Dolle, and M. Petkovich, Cyp26C1 encodes a novel retinoic acid-metabolizing enzyme expressed in the hindbrain, inner ear, first branchial arch and tooth buds during murine development. Gene Expr Patterns, 2003. 3(4): p. 449-54.
90.Zhang, Y., R. Zolfaghari, and A.C. Ross, Multiple retinoic acid response elements cooperate to enhance the inducibility of CYP26A1 gene expression in liver. Gene, 2010. 464(1-2): p. 32-43.
91.Ross, A.C., et al., Multiple cytochrome P-450 genes are concomitantly regulated by vitamin A under steady-state conditions and by retinoic acid during hepatic first-pass metabolism. Physiol Genomics, 2011. 43(1): p. 57-67.
92.Ray, W.J., et al., CYP26, a novel mammalian cytochrome P450, is induced by retinoic acid and defines a new family. J Biol Chem, 1997. 272(30): p. 18702-8.
93.Thatcher, J.E., A. Zelter, and N. Isoherranen, The relative importance of CYP26A1 in hepatic clearance of all-trans retinoic acid. Biochem Pharmacol, 2010. 80(6): p. 903-12.
94.Loudig, O., et al., Transcriptional co-operativity between distant retinoic acid response elements in regulation of Cyp26A1 inducibility. Biochem J, 2005. 392(Pt 1): p. 241-8.
95.Bowles, J. and P. Koopman, Retinoic acid, meiosis and germ cell fate in mammals. Development, 2007. 134(19): p. 3401-11.
96.MacLean, G., et al., Apoptotic extinction of germ cells in testes of Cyp26b1 knockout mice. Endocrinology, 2007. 148(10): p. 4560-7.
97.Pennimpede, T., et al., The role of CYP26 enzymes in defining appropriate retinoic acid exposure during embryogenesis. Birth Defects Res A Clin Mol Teratol, 2010. 88(10): p. 883-94.
98.http://en.wikipedia.org/wiki/ALDH1A2.
99.Duester, G., Retinoic Acid Synthesis and Signaling during Early Organogenesis. 2008. 134(6): p. 921-931.
100.Andreola, F., et al., Mouse liver CYP2C39 is a novel retinoic acid 4-hydroxylase. Its down-regulation offers a molecular basis for liver retinoid accumulation and fibrosis in aryl hydrocarbon receptor-null mice. J Biol Chem, 2004. 279(5): p. 3434-8.
101.Hollemann, T., et al., Regionalized metabolic activity establishes boundaries of retinoic acid signalling. EMBO J, 1998. 17(24): p. 7361-72.
102.Chen, Y., et al., Increased XRALDH2 activity has a posteriorizing effect on the central nervous system of Xenopus embryos. Mech Dev, 2001. 101(1-2): p. 91-103.
103.Strate, I., et al., Retinol dehydrogenase 10 is a feedback regulator of retinoic acid signalling during axis formation and patterning of the central nervous system. Development, 2009. 136(3): p. 461-72.
104.Astrom, A., U. Pettersson, and J.J. Voorhees, Structure of the human cellular retinoic acid-binding protein II gene. Early transcriptional regulation by retinoic acid. J Biol Chem, 1992. 267(35): p. 25251-5.
105.Menegola, E., M.L. Broccia, and E. Giavini, Atlas of rat fetal skeleton double stained for bone and cartilage. Teratology, 2001. 64(3): p. 125-33.