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PubMed1993

Regulation of the human HOXD4 gene by retinoids.

Hox genes are developmentally regulated in mammalian embryogenesis, according to temporally and spatially restricted patterns which are affected by retinoids, vitamin A derivatives which have a function as, or at least mimic the action of, axis-specifying morphogens. In the human embryonal carcinoma cell line NT2/D1, HOX gene clusters are activated by at least two retinoids, all-trans- and 9-cis-retinoic acid (RA), in a 3' to 5' sequential cascade which reproduces the activation pattern observed in early embryogenesis. We have studied the regulation of the early activated HOXD4 gene, which is expressed in human embryogenesis in multiple transcripts generated by the developmentally controlled use of alternative transcription start sites and polyadenylation signals. Transfection of a 2.9 kb HOXD4 upstream genomic region linked to a reporter gene in NT2/D1 cells, allowed the identification of two different promoters and a distal enhancer element necessary for RA-dependent gene activation. This element confers to a heterologous promoter the ability to be induced by RA in NT2/D1 cells, and transactivated by alpha, beta and gamma retinoic acid receptors (RARs), but not retinoid X receptor (RXR), in COS-7 cells. DNase I footprinting analysis allowed the identification of four sequences which bind nuclear factors from both RA-induced NT2/D1 cells and embryonic tissues with similar patterns. The use of specific antibodies allowed the identification of at least RAR beta in some of the DNA-protein complexes, although the four sequences bind single RARs transfected in COS cells much less efficiently, or not at all, when compared to a canonical RAR responsive element. Induction of the HOXD4 promoter-enhancer in the presence of a selective RAR alpha antagonist indicated that the RAR alpha-dependent RAR beta activation is nevertheless a necessary step in HOX gene activation. Our results indicate that the ligand-dependent activity of RARs upon specific, cis-acting regulatory elements may have a key role in the induction of early activated HOX genes in response to retinoids. However, RARs represent only a fraction of the transcription factors interacting with the RA-responsive HOXD4 enhancer, which appears to be a complex element requiring specific combinations of nuclear factors for its proper function.

Amino Acid Sequence↗

PubMed2006

Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells.

High dose beta-carotene supplementation of smokers was associated with increased lung cancer risk in two intervention trials. It was proposed that generation of apocarotenals in smoke-exposed lungs impaired retinoic acid (RA) signaling, leading to squamous metaplasia and cell proliferation. To test this, we compared RA target gene regulation by retinoids, apocarotenals or beta-carotene by transcriptomics in BEAS-2B cells cultured to promote squamous differentiation. Retinoids, beta-carotene as well as apocarotenals induced known RA target genes. Retinoids upregulated involucrin, indicating that retinoids did not rescue BEAS-2B cells from squamous differentiation. Muc5AC, a marker for mucous differentiation, was transiently induced. beta-Carotene and apocarotenals less strongly induced involucrin and did not induce muc5AC. In summary, apocarotenals or beta-carotene upregulated RA target genes suggesting promotion, not inhibition, of RA signaling in BEAS-2B cells. Furthermore, apocarotenals and beta-carotene regulated gene expression independently of RA signaling. Squamous differentiation is not unequivocally linked to RA deficiency in BEAS-2B cells.

Bronchi↗

PubMed2004

Activation by retinoids of the uncoupling protein UCP1.

The uncoupling protein from brown adipose tissue (UCP1) is a transporter that catalyzes a regulated discharged of the mitochondrial proton gradient. The proton conductance in UCP1 is inhibited by nucleotides and activated by fatty acids. We have recently shown that all-trans-retinoic acid (ATRA) is a high-affinity activator of UCP1. In the present report, we have set to analyze the structural requirements for the ligands that activate UCP1 and particularly the specificity for different retinoids. For this purpose, we have developed a new protocol to determine the activity of UCP1 in respiring yeast mitochondria that can be adapted for high-throughput screenings. Our results evidence differences between the structural requirements for the activation by fatty acids and retinoids. Thus, although all active retinoids must possess a carboxylate, the introduction of additional polar groups renders them inactive. The linear and rigid structure of these molecules suggests the existence of a long hydrophobic binding pocket. We postulate that the access to the retinoid binding site must occur from the lipid bilayer and this could be at the interface between two transmembrane alpha-helices.

Carrier Proteins↗

PubMed2004

Gene expression profiling identifies retinoids as potent inducers of macrophage lipid efflux.

Vitamin A and its naturally occurring derivatives 9-cis retinoic acid (9-cis RA) and all-trans retinoic acid (ATRA) exert a variety of biological effects including immunomodulation, growth, differentiation, and apoptosis of normal and neoblastic cells. In order to directly study the effects of these retinoids on macrophage gene expression and lipid metabolism, primary human monocytes and in vitro differentiated macrophages were stimulated with beta-carotene, 9-cis RA, and ATRA and global gene expression profiles were analyzed by Affymetrix DNA-microarrays and differentially regulated genes were verified by quantitative TaqMan RT-PCR. Among others, we have identified a strong up-regulation of a cluster of genes involved in cholesterol metabolism including apolipoproteins (apoC-I, apoC-II, apoC-IV, apoE), the scavenger receptor CD36, steroid-27-hydroxylase (CYP27A1), liver X receptor alpha (LXRalpha), and ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). Since the CYP27A1 gene displayed the strongest up-regulation on the mRNA level, we cloned various deletion constructs of the promoter region and analyzed the response to retinoids in macrophages. Thereby, a novel retinoic acid-responsive element could be located within 191 bp of the proximal CYP27A1 promoter. To further assess the functional consequences of retinoid receptor action, we carried out phospholipid and cholesterol efflux assays. We observed a strong induction of apoA-I-dependent lipid efflux in stimulated macrophages, implicating an important role for retinoids in cellular functions of macrophages.

ATP-Binding Cassette Transporters↗

PubMed2006

Identification and characterization of the human retinoid X receptor alpha gene promoter.

Retinoid X receptors (RXRs) comprise a family of nuclear retinoid activated transcription factors that are members of the steroid hormone receptor superfamily. RXRs are obligate heterodimerization partners with several other hormone receptor family members, making them critical mediators of a wide range of signaling pathways. Retinoids have been used successfully for the prevention of a number of epithelial cancers, including skin squamous cell carcinoma (SCC). The reduced expression levels of retinoid receptors including RXRalpha, the predominant RXR expressed in skin, is associated with malignancy in skin SCC. In order to study the regulation of RXRalpha in skin SCC carcinogenesis we have previously mapped the majority of the human RXRalpha gene. In the present study we have identified its first exon and promoter region. Exon 1, which contains the translation start site, is located in a highly G+C rich region of the genome at least 58 kb centromeric from exon 2. The promoter region itself is unusually G+C rich (75% G+C in 1200 bp of upstream sequence), has 17 putative SP1 transcription factor binding sites and no TATA or CAAT boxes. Transient transfection experiments with RXRalpha promoter-luciferase reporter constructs in SRB12-p9 skin SCC cells, as well as with PC3 prostate carcinoma cells, revealed that RXRalpha transcription is relatively weak compared to the positive control thymidine kinase (TK) promoter and is stimulated by treatment with all-trans retinoic acid (ATRA), the biologically active form of vitamin A. These results indicate that the RXRalpha gene is transcribed at stable levels, similar to most housekeeping genes, and its transcription is regulated by ATRA. In addition, the 5' untranslated region of RXRalpha is highly G+C rich, resulting in a potentially stable folding pattern, that would place RXRalpha amongst a group of genes that are subject to regulation at the translational level.

Animals↗

PubMed2004

A comparison of the effectiveness of soy protein isolate and fish oil for reducing the severity of retinoid-induced hypertriglyceridemia.

The effectiveness of soy protein isolate (SPI) to reduce the severity of retinoid-induced hypertriglyceridemia has been demonstrated in the rat, but not in human subjects. Because fish oil has been demonstrated to be effective at lowering serum triglyceride concentration in human subjects undergoing retinoid therapy, a study was conducted to compare the ability of SPI with that of fish oil to reduce the severity of retinoid-induced hypertriglyceridemia in the rat. Male Fischer 344 rats, n=8/group, were fed one of four isonitrogenous, isoenergetic diets, consisting of a control diet containing 24% casein +20% corn oil (C), and three 13-cis retinoic acid (13cRA)-supplemented diets containing 24% casein +20% corn oil (R), 24% SPI +20% corn oil (SR), and 24% casein +15% fish oil and 5% corn oil (FR). There was no effect of diet on food intake or final body weight. Serum triglyceride concentration for group R was higher (P<0.001) than for groups C, SR, and FR (7.20 vs. 2.50, 2.84, and 2.02 mmol/L, respectively); values for groups SR and FR did not differ for this parameter. The serum concentration of 13cRA for group R did not differ from that for groups SR and FR. Thus, SPI was as effective as fish oil in reducing the severity of retinoid-induced hypertriglyceridemia in an animal model, suggesting that it may be effective for this purpose in human subjects.

Animals↗

PubMed2005

Retinoid receptor cross-talk in respiratory epithelium cancer chemoprevention.

The rationale for using retinoids in the prevention of respiratory epithelium cancers is based on their ability to coordinately regulate differentiation, proliferation and apoptosis. The complex retinoid signaling pathways and their cross-reactions are modulated by multiple mechanisms that are gradually being elucidated. It is possible that significant molecular changes take place during the very early stages of respiratory epithelial carcinogenesis, which enable cancer cells to escape apoptosis and result in unimpeded proliferation. Here, we propose that a "switch on/off" model dictates the cross-talk between retinoid receptors and other signal transducing pathways during respiratory epithelium carcinogenesis. This model might contribute to the development of novel selective retinoids and their clinical evaluation in combinatorial chemopreventive strategies.

Animals↗

PubMed2005

Regulation of multiple dopamine signal transduction molecules by retinoids in the developing striatum.

Increasing evidence based on pharmacological and genetic studies suggests that retinoid signaling plays an important role in developmental control of striatal neurons. In the present report, we screened for genes that might be regulated by retinoids in the developing striatum. We cultured tissue explants from the lateral ganglionic eminence (striatal primordium), and for regional comparison, its adjacent structures of the cerebral cortex and the medial ganglionic eminence in embryonic day 15 rat telencephalon. Using the ribonuclease protection assay, we found that both all-trans retinoic acid and 9-cis retinoic acid significantly up-regulated dopamine D1 receptor, heterotrimeric G protein olfactory, adenylyl cyclase type V and dopamine- and cyclic adenosine 3':5'-monophosphate-regulated phosphoprotein mRNAs in the lateral ganglionic eminence culture. By contrast, neither all-trans retinoic acid nor 9-cis retinoic acid significantly altered D1 receptor, heterotrimeric G protein olfactory, adenylyl cyclase type V and dopamine- and cyclic adenosine 3':5'-monophosphate-regulated phosphoprotein mRNAs in the cortical and the medial ganglionic eminence cultures except that D1 receptor mRNA was dramatically induced in the medial ganglionic eminence by retinoic acid treatments. To test whether the induction of multiple dopamine signaling molecules in the lateral ganglionic eminence was due to a general enhancement of neuronal differentiation by retinoic acid, we assayed the effects of retinoic acid on other differentiation markers, including glutamate decarboxylase 65, NR1 subunit of glutamate NMDA receptor and microtubule-associated protein-2. None of these genes were significantly altered by retinoic acid treatments in the lateral ganglionic eminence culture, indicating the specificity of gene regulation by retinoic acid signaling. As D1 receptor, heterotrimeric G protein olfactory, adenylyl cyclase type V and dopamine- and cyclic adenosine 3':5'-monophosphate-regulated phosphoprotein are important molecules involved in propagation of striatal dopamine neurotransmission, our study raises the hypothesis that retinoid signaling may coordinately activate the transcriptional program that is associated with the dopamine signaling pathway in developing striatal neurons. Such coordinate regulation by retinoids may be part of the mechanisms by which the complex yet highly organized neurochemical constituents of the striatum are established during development.

Adenylyl Cyclases↗

PubMed2006

Retinoids control anterior and dorsal properties in the developing forebrain.

We have previously shown that retinoic acid (RA) synthesized by the retinaldehyde dehydrogenase 2 (RALDH2) is required in forebrain development. Deficiency in RA due to inactivation of the mouse Raldh2 gene or to complete absence of retinoids in vitamin-A-deficient (VAD) quails, leads to abnormal morphogenesis of various forebrain derivatives. In this study we show that double Raldh2/Raldh3 mouse mutants have a more severe phenotype in the craniofacial region than single null mutants. In particular, the nasal processes are truncated and the eye abnormalities are exacerbated. It has been previously shown that retinoids act mainly on cell proliferation and survival in the ventral forebrain by regulating SHH and FGF8 signaling. Using the VAD quail model, which survives longer than the Raldh-deficient mouse embryos, we found that retinoids act in maintaining the correct position of anterior and dorsal boundaries in the forebrain by modulating FGF8 anteriorly and WNT signaling dorsally. Furthermore, BMP4 and FGF8 signaling are affected in the nasal region and BMP4 is ventrally expanded in the optic vesicle. At the optic cup stage, Pax6, Tbx5 and Bmp4 are ectopically expressed in the presumptive retinal pigmented epithelium (RPE), while Otx2 and Mitf are not induced, leading to a dorsal transdifferentiation of RPE to neural retina. Therefore, besides being required for survival of ventral structures, retinoids are involved in restricting anterior identity in the telencephalon and dorsal identity in the diencephalon and the retina.

Aldehyde Oxidoreductases↗

PubMed2002

Activation and induction of glycine N-methyltransferase by retinoids are tissue- and gender-specific.

Glycine N-methyltransferase (GNMT) is a key protein in the liver that functions to regulate S-adenosylmethionine (SAM) and the SAM/S-adenosylhomocysteine ratio. Significant GNMT expression is also present in the kidney and pancreas. Inappropriate regulation of GNMT may have negative consequences on methyl group and folate metabolism. We have demonstrated that retinoid compounds significantly elevated hepatic GNMT activity and abundance (approximately 2-fold) in male rats. However, pancreatic GNMT activity and abundance were not altered by retinoid treatment. Likewise, retinoid administration was without effect on renal GNMT activity. Hepatic GNMT activity was also elevated in female rats treated with all-trans-retinoic acid, but to a lesser extent compared to males. Collectively, these results indicate that the modulation of methyl group metabolism by retinoids is tissue- and gender-specific, and may compromise the availability of methyl groups for SAM-dependent transmethylation reactions. In support of this, SAM-dependent synthesis of creatinine was significantly reduced 21% following all-trans-retinoic acid treatment.

Animals↗

PubMed2000

In vitro effect of retinoids on calcineurin activity.

Calcineurin was shown previously to be inhibited by members of the tyrphostin family of tyrosine kinase inhibitors, with the most effective inhibition suggested to be caused by the presence of a conjugated side chain (Martin BL, Biochem Pharmacol 56: 483-488, 1998). Retinoids are a family of naturally occurring biomolecules having non-aromatic ring structures and conjugated side chains as substituents on the ring. Three oxidation states of the all-trans configuration of retinoids (retinol, retinal, and retinoic acid) were tested as effectors of calcineurin. Only retinoic acid was found to inhibit calcineurin effectively, with an IC(50) value of approximately 50 microM. Retinol and retinal caused less than 30% inhibition at concentrations up to 100 microM. All three retinoids caused some precipitation of reaction components: retinoic acid and retinal above 50 microM, and retinol above 250 microM. Bacterial alkaline phosphatase was not inhibited by the retinoids, indicating that metal centers alone are insufficient for significant inhibition by retinoic acid. An aromatic ring was not required for inhibition and may not provide additional inhibition, inasmuch as an aromatic analog of retinoic acid (acitretin) showed less effective inhibition. These data are consistent with the presence of conjugated, unsaturated groups enhancing the inhibition of calcineurin.

Animals↗

PubMed2001

Retinoid X receptor agonist elevation of serum triglycerides in rats by potentiation of retinoic acid receptor agonist induction or by action as single agents.

Hypertriglyceridemia is a major side-effect of retinoid therapy in humans. We previously reported that agonists for the retinoic acid receptors (RARs), but not the retinoid X receptors (RXRs), elevate serum triglycerides in male Fischer rats, and that, surprisingly, the RAR/RXR pan-agonists 9-cis-retinoic acid and AGN 191659 [(E)-5-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)propen-1-yl]-2-thiophenecarboxylic acid] induce 2- to 3-fold higher levels of serum triglycerides than the RAR-selective agonists alone. We have now demonstrated that hypertriglyceridemia induced by an RAR agonist, AGN 190121 [4-[4-(2',6',6'-trimethylcyclohex-1-enyl)-but-1-yne-3-enyl]benzoic acid], is substantially potentiated by the RXR-selective agonists AGN 191701 [(E) 2-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)propen-1-yl]-4-thiophene-carboxylic acid] and AGN 192849 [(3,5,5,8,8,-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) (5 carboxypyrid-2-yl)sulfide] in a dose-dependent manner. RXR-specific retinoids, as previously reported, had no independent effect on serum triglycerides when tested at 24 hr after final dosing, but did elicit a reversible hypertriglyceridemia at 2.5 and 5 hr. This induction of serum triglycerides could not be blocked by the potent RAR-specific antagonist AGN 193109 [4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)-ethynyl] benzoic acid]. The RXR ligand-induced hypertriglyceridemia was independent of the effect of feeding or fasting. The relative potencies of RXR-specific retinoids for acute triglyceride elevation (AGN 194204 [3,7-dimethyl-6S,7S-methano-7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl] 2(E),4(E) heptadienoic acid] > AGN 192849 approximately AGN 191701) approximately correlated with potencies in the activation of the RXR receptors. The RAR/RXR pan-agonist effect included >50% inhibition of total heparin-releasable lipase activity in serum, consistent with inhibition of lipase-mediated triglyceride disposal. These data also indicate that RAR and RXR ligands can act synergistically to induce hypertriglyceridemia through distinct mechanisms of action.

Animals↗

PubMed2000

Retinoids inhibit bradykinin B1 receptor-sensitized responses in human umbilical vein.

Bradykinin B1 receptors are not expressed under physiological conditions but are induced under inflammatory conditions. In isolated human umbilical vein, a spontaneous bradykinin B1 receptor sensitization process has been demonstrated. On the other hand, retinoids have been shown to exert anti-inflammatory and immunomodulatory actions. We have now examined the effects of all-trans-retinoic acid and 9-cis-retinoic acid on the bradykinin B1 receptor-sensitized responses in human umbilical vein. Both retinoids produced a concentration-dependent rightward shift of the concentration-response curves for the bradykinin B1 receptor agonist, des-Arg(9)-bradykinin. Retinoid treatment did not modify the responses to bradykinin B1 receptor-unrelated agonists, bradykinin or serotonin. In conclusion, retinoids inhibit bradykinin B1 receptor-sensitized responses and this action could participate in their anti-inflammatory and immunomodulatory effects.

Alitretinoin↗

PubMed1999

Fra-1: a novel target for retinoid action.

Using a cDNA gene expression array system, we identified fra-1 as a novel target molecule for retinoid action in the human pancreatic carcinoma cell line Dan-G. Retinoid treatment resulted in a significant and time-dependent induction of the fra-1 expression on the post-transcriptional level. Supershift assays revealed that fra-1 participates in the activator protein 1 complex together with c-fos, c-jun and junB. Transient transfection experiments using a reporter plasmid containing an activator protein site upstream of the CAT reporter gene revealed that the phorbolester-induced CAT activity was suppressed by retinoids. Since fra-1 lacks a transactivation function, we therefore suggest that the retinoid-mediated induction of fra-1 might function as a negative regulator of the activator protein 1 activity in human pancreatic carcinoma cells.

Gene Expression Regulation↗

PubMed2001

Qualitative and quantitative liquid chromatographic determination of natural retinoids in biological samples.

Liquid chromatography continues to be the preferred method for determining retinoids in biological samples. The highly unstable nature of retinoids and the real possibility of artifacts or erroneous results have led to the development of rapid and highly automated protocols for retinoid extraction, separation and detection. Due to strong light absorbance in the ultraviolet region, UV detectors still predominate although mass spectrometric detection is gaining increased popularity. This paper reviews recent advances and provides major guidelines for using liquid chromatography to identify and quantify retinoids in biological samples.

Chromatography, Liquid↗

PubMed1985

Rapid analysis of the major classes of retinoids by step gradient reversed-phase high-performance liquid chromatography using retinal (O-ethyl) oxime derivatives.

A rapid step-gradient reversed-phase high-performance liquid chromatography (HPLC) method is presented for analysis of the major classes of retinoids in tissues. Retinal was converted into a new derivative, retinal (O-ethyl) oxime, since the standard derivative, retinaloxime, co-elutes with retinol on reversed-phase HPLC. The most abundant naturally occurring retinyl esters, retinyl palmitate and retinyl stearate, were eluted within 12 min to complete the separation. Retinoids were extracted in the presence of an antioxidant, butylated hydroxytoluene, and a lipid carrier, cholesterol. Recoveries of 98-100% were obtained from tissue samples by internal addition for the retinoids tested (retinol, retinal and retinyl palmitate); and the absolute recovery of endogenous retinal from rat eyecups was confirmed by spectrophotometric measurements of rhodopsin. Extraction was carried out in an air atmosphere and under subdued incandescent light rather than requiring inert atmosphere and safe-light conditions used in most methods. Cis-trans isomers were not separated under the reversed-phase HPLC conditions employed. Quantitation was carried out using retinyl acetate as internal standard and the day to day precision was better than 3.5%. A sensitivity of about 1 ng is obtained for all retinoids using absorbance monitoring at 325 nm and a C18 5 micrometers column with 12% reversed-phase loading. The tocopherols can also be separated and detected simultaneously with similar sensitivity by this method using a fluorescence detector in series [G. J. Handelman, L. J. Machlin, K. Fitch, J. J. Weiter and E. A. Dratz, J. Nutr., 115 (1985) 807].

Animals↗

PubMed1987

Detection of some retinoid radicals using high-performance liquid chromatography with electron spin resonance spectroscopy or electrochemical detection.

Radical species were detected in the incubation mixtures of some retinoids (retinoic acid, retinal, retinol and retinyl acetate) by using the spin-trapping technique. The spin-adducts were resolved by high-performance liquid chromatography on a reversed-phase column with isocratic elution and detected by electron spin resonance spectroscopy and electrochemical detection. The spin-adducts were eluted in the order retinoic acid, retinol, retinyl acetate, in a similar manner to the retinoids themselves. These results suggest that the spin-adducts are products of nitrosobenzene with retinoid radicals in which the retinoid radicals retain their original chemical structures.

Chromatography, High Pressure Liquid↗

PubMed1998

Quantitative determination of endogenous retinoids in mouse embryos by high-performance liquid chromatography with on-line solid-phase extraction, column switching and electrochemical detection.

An isocratic high-performance liquid chromatographic method for the determination of 9-cis-retinoic acid, 13-cis-retinoic acid, all-trans-retinoic acid and all-trans-retinol in mouse embryos using on-line solid-phase extraction and column switching in combination with electrochemical detection has been developed. The method was validated using retinoids in albumin solutions and 13-cis-acitretin was used as internal standard. About 370 microliters of albumin solution was injected on a 10 x 2.1-mm I.D. pre-column packed with Bondapak C18, 37-53-micron particles. The proteins were washed to waste within 5 min using as mobile phase, a 1:3 dilution of mobile phase 2, which consisted of acetonitrile-methanol-2% ammonium acetate-glacial acetic acid (79:2:16:3, v/v). Components retained on the pre-column were back-flushed to and separated on the 250 x 4.6-mm I.D. Suplex pKb-100 analytical column using mobile phase 2. The retinoids were detected electrochemically at +750 mV using a coulometric electrochemical detector. The total analysis time was about 20 min. Recoveries were in the range of 86-103%. The mass limits of detection were about 10 pg and 25 pg for the retinoic acids and all-trans-retinol, respectively. The intra-assay precision, reported as relative standard deviation, was in general better than 4% (n = 6) for the four retinoids. Inter-assay precision was in the range 3-4% (n = 10). The method was applied for determination of endogenous retinoids in 9.5 day-old mouse embryos. A 340-microliter solution containing 100 microliters of embryo homogenate (1.64 embryos) was analyzed. The concentrations of all-trans-retinol and all-trans-retinoic acid were found to be 279 pg per embryo and 75.8 pg per embryo, respectively. The amount of 13-cis-retinoic acid and 9-cis-retinoic acid was below the detection limit.

Animals↗