Brain ventricular volume changes induced by long-duration spaceflight.

Long-duration spaceflight induces detrimental changes in human physiology. Its residual effects and mechanisms remain unclear. We prospectively investigated the changes in cerebrospinal fluid (CSF) volume of the brain ventricular regions in space crew by means of a region of interest analysis on structural brain scans. Cosmonaut MRI data were investigated preflight (n = 11), postflight (n = 11), and at long-term follow-up 7 mo after landing (n = 7). Post hoc analyses revealed a significant difference between preflight and postflight values for all supratentorial ventricular structures, i.e., lateral ventricle (mean % change ± SE = 13.3 ± 1.9), third ventricle (mean % change ± SE = 10.4 ± 1.1), and the total ventricular volume (mean % change ± SE = 11.6 ± 1.5) (all P < 0.0001), with higher volumes at postflight. At follow-up, these structures did not quite reach baseline levels, with still residual increases in volume for the lateral ventricle (mean % change ± SE = 7.7 ± 1.6; P = 0.0009), the third ventricle (mean % change ± SE = 4.7 ± 1.3; P = 0.0063), and the total ventricular volume (mean % change ± SE = 6.4 ± 1.3; P = 0.0008). This spatiotemporal pattern of CSF compartment enlargement and recovery points to a reduced CSF resorption in microgravity as the underlying cause. Our results warrant more detailed and longer longitudinal follow-up. The clinical impact of our findings on the long-term cosmonauts' health and their relation to ocular changes reported in space travelers requires further prospective studies.

Sebum lipids influence macrophage polarization and activation.

BACKGROUND: As lipids are known to regulate macrophage functions, it is reasonable to suppose that a sebocyte-macrophage axis mediated by sebum lipids may exist. OBJECTIVES: To investigate if sebocytes could contribute to the differentiation, polarization and function of macrophages with their secreted lipids. METHODS: Oil Red O lipid staining and Raman spectroscopy were used to assess the dermal lipid content and penetration. Immunohistochemistry was used to analyse the macrophage subsets. Human peripheral blood monocytes were differentiated in the presence of either supernatant from human SZ95 sebocytes or major sebum lipid components and activated with Propionibacterium acnes. Macrophage surface markers and their capacity to uptake fluorescein isothiocyanate-conjugated P. acnes were detected by fluorescence-activated cell sorting measurements. Cytokine protein levels were evaluated by enzyme-linked immunosorbent assay and Western blot analysis. RESULTS: Sebaceous gland-rich skin had an increased dermal lipid content vs. sebaceous gland-poor skin to which all the tested sebum component lipids could contribute by penetrating the dermoepidermal barrier. Of the lipids, oleic acid and linoleic acid promoted monocyte differentiation into alternatively activated macrophages. Moreover, linoleic acid also had an anti-inflammatory effect in P. acnes-activated macrophages, inhibiting the secretion of interleukin (IL)-1ß, IL-6 and tumour necrosis factor (TNF)-α. Squalene, palmitic acid, stearic acid and oleic acid augmented the secretion of IL-1ß, even in the absence of P. acnes, whereas oleic acid had a selective effect of inducing IL-1ß but downregulating IL-6 and TNF-α secretion. CONCLUSIONS: Our results suggest a role for sebaceous glands in modulating innate immune responses via their secreted lipids that are of possible pathological and therapeutic relevance.

Decreased peroxisome proliferator-activated receptor γ level and signalling in sebaceous glands of patients with acne vulgaris.

Little is known about the altered lipid metabolism-related transcriptional events occuring in sebaceous glands of patients with acne vulgaris. Peroxisome proliferator-activated receptor (PPAR)γ, a lipid-activated transcription factor, is implicated in differentiation and lipid metabolism of sebocytes. We have observed that PPARγ and its target genes, ADRP (adipose differentiation related protein) and PGAR (PPARγ angioprotein related protein) are expressed at lower levels in sebocytes from patients with acne than in those from healthy controls (HCs) Furthermore, endogenous PPARγ activator lipids such as arachidonic acid-derived keto-metabolites (e.g. 5KETE, 12KETE) are increased in acne-involved and nonacne-involved skin of patients with acne, compared with skin from healthy individuals. Our findings highlight the possible anti-inflammatory role of endogenous ligand-activated PPARγ signaling in human sebocyte biology, and suggest that modulating PPARγ- expression and thereby signaling might be a promising strategy for the clinical management of acne vulgaris.

Dietary regulation of adiponectin by direct and indirect lipid activators of nuclear hormone receptors.

Adiponectin is an adipokine mainly secreted by adipocytes that presents antidiabetic, anti-inflammatory, and antiatherogenic functions. Therefore, modulation of adiponectin expression represents a promising target for prevention or treatment of several diseases including insulin resistance and type II diabetes. Pharmacological agents such as the nuclear hormone receptor synthetic agonists like peroxisome proliferator activated receptor γ agonists are of particular interest in therapeutic strategies due to their ability to increase the plasma adiponectin concentration. Nutritional approaches are also of particular interest, especially in primary prevention, since some active compounds of our diet (notably vitamins, carotenoids, or other essential nutrients) are direct or indirect lipid-activators of nuclear hormone receptors and are modifiers of adiponectin expression and secretion. The aim of the present review is to summarize current knowledge about the nutritional regulation of adiponectin by derivatives of active compounds naturally present in the diet acting as indirect or direct activators of nuclear hormone receptors.

Leptin promotes a proinflammatory lipid profile and induces inflammatory pathways in human SZ95 sebocytes.

BACKGROUND: Leptin, the adipocyte-secreted hormone that regulates weight, is known to link lipid metabolism with inflammation in various cell types. However, its role in human sebocytes has not yet been investigated. OBJECTIVES: The purpose of this study was to investigate the effects of leptin in human sebaceous gland biology. METHODS: Expression of the long form of the leptin receptor (Ob-Rb) was detected by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and immunochemistry. Lipid analysis was by high-performance thin-layer chromatography, gas chromatography-mass spectrometry and time-of-flight mass spectrometer mass detection. Lipid bodies were visualized by BODIPY staining using fluorescent microscopy and measured by flow cytometry. Interleukin (IL)-6 and IL-8 mRNA levels were assessed by real-time qRT-PCR and their release was evaluated by enzyme-linked immunosorbent assay. Cyclooxygenase (COX)-2 and 5-lipooxygenase (LOX) protein expression and phosphorylation of p65 and signal transducer and activator of transcription (STAT)-3 were determined by Western blot analysis. RESULTS: Expression of Ob-Rb was detected in human sebaceous glands and in cultured human SZ95 sebocytes. The treatment of SZ95 sebocytes with leptin led to enlarged intracellular lipid bodies, increased ratios of unsaturated/saturated fatty acids and decreased vitamin E levels. Further supporting a proinflammatory role, leptin induced COX-2 and 5-LOX expression in SZ95 sebocytes and augmented the production of IL-6 and IL-8 cytokines. On leptin treatment, the STAT-3 and nuclear factor-κB pathways were activated, indicating that these known leptin signalling pathways are active in human sebocytes. CONCLUSIONS: Our findings suggest that leptin signalling may be involved in the proinflammatory regulation of sebaceous lipid metabolism and the induction of inflammatory enzymes and cytokines.

Non-pro-vitamin A and pro-vitamin A carotenoids in atopy development.

Carotenoids are important derivatives of the human diet and occur in high concentrations in the human organism. Various carotenoids are also present in human breast milk and are transferred to breast-fed children. The alternative to breastfeeding is supplementation with an infant milk formula, but these formulas contain only a limited variety of carotenoids. Our question is: 'What is the function of various carotenoids in human nutrition with a special emphasis on child development and the development of atopy?' In this review, the mechanisms of action of the most important non-pro-vitamin A and pro-vitamin A carotenoids: α-carotene, ß-carotene, ß-cryptoxanthin, lutein, zeaxanthin, lycopene and retinoids are discussed. In summary, the combination of carotenoids, especially lycopene, seems to be of great importance, and exclusive usage of ß-carotene in infant formula may yield in an increased atopy prevalence mediated in various target organs like the skin, lungs and immune competent cells. We conclude that the determination of novel bioactive metabolites of various carotenoids, at various stages in different organs during atopy development, might be the key to understanding the potential importance of carotenoids on atopy development.

Apo-10'-lycopenoic acid impacts adipose tissue biology via the retinoic acid receptors.

Apo-10'-lycopenoic acid (apo-10-lycac), a metabolite of lycopene, has been shown to possess potent biological activities, notably via the retinoic acid receptors (RAR). In the current study, its impact on adipose tissue and adipocytes was studied. In microarray experiments, the set of genes regulated by apo-10-lycac treatments was compared to the set of genes regulated by all-trans retinoic acid (ATRA), the natural ligand of RAR, in adipocytes. Approximately 27.5% of the genes regulated by apo-10-lycac treatments were also regulated by ATRA, suggesting a common ability in terms of gene expression modulation, possibly via RAR transactivation. The physiological impact of apo-10-lycac on adipose tissue biology was evaluated. If it had no effect on adipogenesis in the 3T3-L1 cell model, this metabolite may have a preventative effect against inflammation, by preventing the increase in the inflammatory markers, interleukin 6 and interleukin 1ß in various dedicated models. The ability of apo-10-lycac to transactivate the RAR and to modulate the transcription of RAR target gene was brought in vivo in adipose tissue. While apo-10-lycac was not detected in adipose tissue, a metabolite with a molecular weight with 2Da larger mass was detected, suggesting that a dihydro-apo-10'-lycopenoic acid, may be present in adipose tissue and that this compound could active or may lead to further active RAR-activating apo-10-lycac metabolites. Since apo-10-lycac treatments induce anti-inflammatory effects in adipose tissue but do not inhibit adipogenesis, we propose that apo-10-lycac treatments and its potential active metabolites in WAT may be considered for prevention strategies relevant for obesity-associated pathologies.

Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids.

AIMS/HYPOTHESIS: Calorie restriction is an essential component in the treatment of obesity and associated diseases. Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) act as natural hypolipidaemics, reduce the risk of cardiovascular disease and could prevent the development of obesity and insulin resistance. We aimed to characterise the effectiveness and underlying mechanisms of the combination treatment with LC n-3 PUFA and 10% calorie restriction in the prevention of obesity and associated disorders in mice. METHODS: Male mice (C57BL/6J) were habituated to a corn-oil-based high-fat diet (cHF) for 2 weeks and then randomly assigned to various dietary treatments for 5 weeks or 15 weeks: (1) cHF, ad libitum; (2) cHF with LC n-3 PUFA concentrate replacing 15% (wt/wt) of dietary lipids (cHF + F), ad libitum; (3) cHF with calorie restriction (CR; cHF + CR); and (4) cHF + F + CR. Mice fed a chow diet were also studied. RESULTS: We show that white adipose tissue plays an active role in the amelioration of obesity and the improvement of glucose homeostasis by combining LC n-3 PUFA intake and calorie restriction in cHF-fed mice. Specifically in the epididymal fat in the abdomen, but not in other fat depots, synergistic induction of mitochondrial oxidative capacity and lipid catabolism was observed, resulting in increased oxidation of metabolic fuels in the absence of mitochondrial uncoupling, while low-grade inflammation was suppressed, reflecting changes in tissue levels of anti-inflammatory lipid mediators, namely 15-deoxy-Δ(12,15)-prostaglandin J(2) and protectin D1. CONCLUSIONS/INTERPRETATION: White adipose tissue metabolism linked to its inflammatory status in obesity could be modulated by combination treatment using calorie restriction and dietary LC n-3 PUFA to improve therapeutic strategies for metabolic syndrome.

Docosahexaenoic acid (DHA) supplementation in atopic eczema: a randomized, double-blind, controlled trial.

BACKGROUND: The increasing prevalence of atopic eczema has been linked to the alteration of the Western diet, namely the reduced consumption of omega-3 (n-3) polyunsaturated fatty acids (PUFA) and an increased omega-6 (n-6) PUFA intake. OBJECTIVES: The aim of the pilot study was to determine the efficacy of dietary n-3 PUFA docosahexaenoic acid (DHA) in patients with atopic eczema. METHODS: Fifty-three patients suffering from atopic eczema aged 18-40 years were recruited into this randomized, double-blind, controlled trial and received either DHA 5.4 g daily (n = 21) or an isoenergetic control of saturated fatty acids (n = 23) for 8 weeks. At weeks 0, 4, 8 and 20 the clinical outcome was assessed by the SCORAD (severity scoring of atopic dermatitis) index. IgE production and activation of peripheral blood mononuclear cells (PBMC) were analysed. Plasma fatty acids were measured by gas chromatography. RESULTS: DHA, but not the control treatment, resulted in a significant clinical improvement of atopic eczema in terms of a decreased SCORAD [DHA: baseline 37.0 (17.9-48.0), week 8 28.5 (17.6-51.0); control: baseline 35.4 (17.2-63.0), week 8 33.4 (10.7-56.2)]. A significant reduction of anti-CD40/interleukin 4-mediated IgE synthesis of PBMC was detected in the DHA group only. Supplementation led to a modulated activation status of PBMC in both groups. The DHA group showed an increase of plasma n-3 PUFA and a decrease in the n-6/n-3 PUFA ratio. CONCLUSIONS: Our data suggest that dietary DHA could be bioactive and might have a beneficial impact on the outcome of atopic eczema, but our results need to be confirmed in a larger study.

Assessment of local control after laser-induced thermotherapy of liver metastases from colorectal cancer: contribution of FDG-PET in patients with clinical suspicion of progressive disease.

BACKGROUND: Management of patients after locally ablative treatment of liver metastases requires exact information about local control and systemic disease status. To fulfill these requirements, whole-body imaging using positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET) is a promising alternative to morphologic imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI). PURPOSE: To evaluate FDG-PET for the assessment of local control and systemic disease in patients with clinical suspicion of tumor progression after laser-induced thermotherapy (LITT) of colorectal liver metastases. MATERIAL AND METHODS: In 21 patients with suspicion of progressive disease after LITT, whole-body FDG-PET was performed. The presence of viable tumor within treated lesions, new liver metastases, and extrahepatic disease was evaluated visually and semiquantitatively (maximal standard uptake value [SUV(max)], tumor-to-normal ratio [T/N]). The standard of reference was histopathology (n = 25 lesions) and/or clinical follow-up (>12 months) including contrast-enhanced MRI of the liver. RESULTS: Among 54 metastases treated with LITT, 29 had residual tumor. Receiver operating characteristic (ROC) analysis of SUV(max) (area under the curve (AUC) 0.990) and T/N (AUC 0.968) showed a significant discrimination level of negative or positive lesion status with an equal accuracy of 94% (51/54). The overall accuracy of visual FDG-PET was 96% (52/54), with one false-negative lesion among six examined within 3 days after LITT, and one false-positive lesion examined 54 days after LITT. In the detection of new intra- and extrahepatic lesions, FDG-PET resulted in correct alteration of treatment strategy in 43% of patients (P = 0.007). CONCLUSION: FDG-PET is a promising tool for the assessment of local control and whole-body restaging in patients with clinical suspicion of tumor progression after locally ablative treatment of colorectal liver metastases with LITT.

Astroglia-derived retinoic acid is a key factor in glia-induced neurogenesis.

Astroglial cells are essential components of the neurogenic niches within the central nervous system. Emerging evidence suggests that they are among the key regulators of postnatal neurogenesis. Although astrocytes have been demonstrated to possess the potential to instruct stem cells to adopt a neuronal fate, little is known about the nature of the glia-derived instructive signals. Here we propose that all-trans retinoic acid, one of the most powerful morphogenic molecules regulating neuronal cell fate commitment, may be one of the glia-derived factors directing astroglia-induced neurogenesis. According to data obtained from several complementary approaches, we show that cultured astrocytes express the key enzyme mRNAs of retinoic acid biosynthesis and actively produce all-trans retinoic acid. We show that blockage of retinoic acid signaling by the pan-RAR antagonist AGN193109 prevents glia-induced neuron formation by noncommitted stem cells. Therefore, we provide strong in vitro evidence for retinoic acid action in astroglia-induced neuronal differentiation.

Evaluation of patients with liver metastases from colorectal cancer for locally ablative treatment with laser induced thermotherapy. Impact of PET with 18F-fluorodeoxyglucose on therapeutic decisions.

PURPOSE: Before locally ablative treatment of colorectal liver metastases, patients have to be carefully evaluated to decide whether this is the adequate therapy. In this study we determined the value of FDG-PET in comparison to conventional staging procedures. PATIENTS, METHODS: In 68 consecutive patients referred for laser induced thermotherapy (LITT) of liver metastases from colorectal cancer, pretherapeutic staging with conventional imaging (thoracic and abdominal CT, liver MRI, chest X-ray) and FDG-PET was performed. The examinations were analysed separately and blinded. Based on the staging information, therapeutic decisions were made by an interdisciplinary review board according to a standardized algorithm. The results were compared between conventional imaging and FDG-PET, and were validated by clinical follow up data and histopathology, respectively. RESULTS: On FDG-PET 210 lesions were interpreted as tumour manifestations. 48 of these were not seen on conventional imaging (true positive, n = 46). In contrast, 24 lesions were visualized by conventional imaging only (true positive, n = 12). Compared to conventional imaging, discrepant findings on FDG-PET led to treatment modifications in 25 patients (37%); these were correct in 20/25 patients. According to the actual treatment course, the inadequate treatment modifications in the remaining 5 patients were avoided by further diagnostic procedures (i.e. biopsies). CONCLUSION: In the evaluation of patients with known liver metastases from colorectal cancer before LITT, FDG-PET depicts relevant findings subsidiary to conventional imaging and thus is of high value for therapeutic decision making.

Effects of an enhanced vitamin A intake during the dry period on retinoids, lactoferrin, IGF system, mammary gland epithelial cell apoptosis, and subsequent lactation in dairy cows.

Studies in vitro show important interactions among vitamin A, lactoferrin, and insulin-like growth factor (IGF) binding proteins (IGFBP) and, thus, the IGF system. As a consequence, mammary gland epithelial cell proliferation and apoptosis during the bovine dry period and potential milk yield may be affected. We have studied effects of feeding vitamin A (550,000 IU/ d) that exceed daily requirements about 8-fold for up to 2 mo to dairy cows during the dry period on concentrations of retinol and its metabolites in plasma and milk, milk lactoferrin, plasma and milk IGF-I and IGFBP-3, lactoferrin and IGF-I mRNA levels in mammary gland tissue, mammary gland apoptosis, and 100-d milk yield in the ensuing lactation. In the group supplemented with vitamin A, the peripartal decrease of plasma retinol was delayed and attenuated, and colostral retinol plus retinylester concentration was enhanced, but colostral beta-carotene concentration decreased. The retinoic acid isomer 9,13-dicis retinoic acid that coeluted with 13-cis retinoic acid, was the predominant circulating retinoic acid and was higher in GrA than the control group. Plasma IGFBP-3 concentrations were positively correlated with plasma retinol concentrations (r = 0.51), but there were no group differences. Numbers of apoptotic epithelial cells in mammary epithelium were higher at drying off and parturition than in the middle of the dry period, coinciding with high concentrations of IGF-I and lactoferrin in mammary secretions. At parturition, numbers of apoptotic cells in mammary gland biopsies in cows supplemented with vitamin A were higher than in control cows. In conclusion, supplementation of dairy cows during the dry period with high amounts of vitamin A did not significantly modify concentrations of lactoferrin, IGFBP-3, and IGF-I in plasma and in mammary secretions, but slightly decreased energy-corrected 100-d milk yield and milk fat yield, possibly because of enhanced apoptic rates of mammary cells.

[Optical coherence tomography in geographic atrophy--a clinicopathologic correlation]. / Optische Kohärenztomographie bei geographischer Atrophie--eine klinisch-pathologische Korrelation.

BACKGROUND: Optical coherence tomography was used for the examination of patients with geographic atrophy in different stages of age-related macular degeneration. Always compared with biomicroscopy and fluorescein angiography [4,7,8,10]. PATIENTS AND METHODS: 37 patients with geographic atrophy (n = 55 eyes) out of 150 with AMD (n = 169 eyes) were examined. The results of biomicroscopy, fluorescein angiography, optical coherence tomography and histological knowledge in age-related macular degeneration were studied. RESULTS: Fluorescein angiography always identified geographic atrophy and in 13.5% the findings additionally were similar to an occult choroidal neovascularisation with circular hyperpigmentation. Geographic atrophy shows a significant thinning of the neurosensory retina of 135 microns as an average in optical coherence tomography (p < 0.0005) which did not correlate to visual acuity. Typically an enhanced vertically sharp demarcated reflectivity of the choroid is found because of the lacking pigment epithelium. 43% of the geographic atrophies were identified by optical coherence tomography. 3 out of 55 eyes (5%) in optical coherence tomography only show macular holes additionally to geographic atrophy. CONCLUSION: A typical pattern of reflectivity is found by optical coherence tomography with enhanced reflectivity of the choroid because of lacking pigment epithelium and significant thinning of the fovea. Atypical macular holes moreover are found in 5% neither appearing in biomicroscopy nor in fluorescein angiography. An occult choroidal neovascularisation can be differentiated by optical coherence tomography from geographic atrophy because there is no spindle-like thickening of the pigment epithelium and no enhanced choroidal reflectivity. In borderline cases optical coherence tomography may be helpful and therapeutically decisive in differentiating geographic atrophy and occult choroidal neovascularisation and in detecting atypical macular holes.

Embryonic subcellular distribution of 13-cis- and all-trans-retinoic acid indicates differential cytosolic/nuclear localization.

Isotretinoin (13-cis-retinoic acid [13CRA], Accutane) is used for the treatment of dermatological diseases. Isotretinoin is, however, teratogenic in animals and humans. The mechanism of action of its teratogenicity is still not clearly identified. It has little or no binding properties to cytosolic retinoid-binding proteins or nuclear retinoid receptors (RAR, RXR). One hypothesis is that the teratogenicity of 2 approximately equipotent teratogenic doses of 13CRA and all-trans-retinoic acids (ATRA) could mainly be correlated to ATRA in the nuclei, where the retinoic acid receptors (RARs) are located. To test this hypothesis, female mice at gestational day 11 were treated with approximately equipotent teratogenic doses of 13-cis-retinoic acid (100 mg/kg orally) or all-trans-retinoic acid (10 mg/kg orally) and sacrificed 1 h and 4 h after administration. Embryos were homogenized and centrifuged into 4 fractions, and the purity of the fractions was tested by quantification of marker constituents for various cell compartments. We analyzed, by RP-HPLC, nuclear, mitochondrial, microsomal, and cytosolic fractions, as well as embryo homogenate and maternal plasma. After treatment with 13-cis-retinoic acid, this substance was mainly located in the nuclear fraction of the embryo (approximately 82%), whereas all-trans-retinoic acid, after ATRA treatment, was mainly located in the cytosolic supernatant (approximately 64%). The binding to cellular retinoid-binding protein (CRABP) may limit the access of ATRA to the nucleus, in contrast to 13CRA, which does not bind to CRABP. The concentration of ATRA in the nuclear fraction was similar after administration of either 13CRA or ATRA. The teratogenic activity of 13-cis-retinoic acid could therefore be explained by its access to the nucleus and its possible conversion to all-trans-retinoic acids, which will interact with the nuclear retinoid receptors.

Synthesis, high-performance liquid chromatography-nuclear magnetic resonance characterization and pharmacokinetics in mice of CD271 glucuronide.

Retinoic acid-glucuronides are known as retinoids with activity in acne therapy, limited placental transfer and reduced retinoid adverse effects. We synthesized the glucuronide of a novel retinoid, CD271 (adapalene), used for the treatment of moderate acne. The synthesis product ("CD271 glucuronide", CD271G) was purified by preparative HPLC. It undergoes in aqueous solution, like other glucuronides, rapid acyl-migration of the bound aglycone leading to position isomers. Thus characterization of purified CD271G could be only achieved by HPLC-NMR coupling. A subfraction ("CD271GB") consisting essentially of 2'- and 3'-CD271G was used for pharmacokinetic studies. After a single subcutaneous injection at a dosage of 30 mg/kg the substance showed considerable uptake and metabolism to CD271 indicating that CD271GB could serve as a prodrug for CD271.

Synergistic teratogenic effects induced by retinoids in mice by coadministration of a RARalpha- or RARgamma-selective agonist with a RXR-selective agonist.

To study the interaction of retinoid-induced limb defects and cleft palate on day 11 of gestation, a RXR-selective agonist (AGN191701, an arylpropenyl-thiophene-carboxylic acid derivative, 20 mg/kg orally) was coadministered with a RARalpha-agonist (Am580, an arylcarboxamidobenzoic acid derivative, 5 mg/kg orally) to NMRI mice. AGN191701 was neither fetotoxic nor teratogenic at the dose used but potentiated Am580-induced limb defects and cleft palate and prevented Am580-induced fetal weight retardation. These results suggest that Am580-induced limb defects and probably cleft palate on day 11 of gestation may be mediated via RARalpha-RXR heterodimerization, particularly in the absence of toxicokinetic interactions. AGN191701 was also coadministered with a RARgamma-agonist (CD437, an adamantyl-hydroxyphenyl naphthoic acid derivative, 15 mg/kg orally) on days 8 and 11 of gestation to investigate which CD437-induced defects are mediated via RARgamma-RXR heterodimerization. On day 8 of gestation, AGN191701 potentiated CD437-induced embryolethality, exencephaly, spina bifida aperta, cleft palate, and tail defects, as well as visceral and skeletal defects, but not micrognathia. On day 11 of gestation, the incidence of CD437-induced cleft palate and limb defects was also potentiated when coadministered with the RXR agonist. These results suggest that synergistic teratogenic effects can be induced by coadministration of two receptor-selective retinoids, indicating the importance of RARalpha-RXR and RARgamma-RXR heterodimers in producing structural defects during organogenesis.