Systematic review of the receptor tyrosine kinase superfamily in neuroblastoma pathophysiology.

BACKGROUND: Neuroblastoma is a devastating disease accounting for 15% of all childhood cancer deaths. Yet, our understanding of key molecular drivers such as receptor tyrosine kinases (RTKs) in this pathology remains poorly clarified. Here, we provide a systematic analysis of the RTK superfamily in the context of neuroblastoma pathogenesis. METHODS: Statistical correlations for all RTK family members' expression to neuroblastoma patient survival across 10 independent patient cohorts were annotated, synthesized, and ranked using the R2: Genomics Analysis and Visualization Platform. Gene expression of selected members across different cancer cell lines was further analyzed in the Cancer Cell Line Encyclopedia, part of the Cancer Dependency Map portal (depmap portal ( http://depmap.org )). Finally, we provide a detailed literature review for highly ranked candidates. RESULTS: Our analysis defined two subsets of RTKs showing robust associations with either better or worse survival, constituting potential novel players in neuroblastoma pathophysiology, diagnosis, and therapy. We review the available literature regarding the oncogenic functions of these RTKs, their roles in neuroblastoma pathophysiology, and potential utility as therapeutic targets. CONCLUSIONS: Our systematic analysis and review of the RTK superfamily in neuroblastoma pathogenesis provides a new resource to guide the research community towards focused efforts investigating signaling pathways that contribute to neuroblastoma tumor establishment, growth, and/or aggressiveness and targeting these druggable molecules in novel therapeutic strategies.

AR visualizations in laparoscopy: surgeon preferences and depth assessment of vascular anatomy.

Introduction: This study compares five augmented reality (AR) vasculature visualization techniques in a mixed-reality laparoscopy simulator with 50 medical professionals and analyzes their impact on the surgeon. Material and methods: ​​The different visualization techniques' abilities to convey depth were measured using the participant's accuracy in an objective depth sorting task. Demographic data and subjective measures, such as the preference of each AR visualization technique and potential application areas, were collected with questionnaires. Results: Despite measuring differences in objective measurements across the visualization techniques, they were not statistically significant. In the subjective measures, however, 55% of the participants rated visualization technique II, 'Opaque with single-color Fresnel highlights', as their favorite. Participants felt that AR could be useful for various surgeries, especially complex surgeries (100%). Almost all participants agreed that AR could potentially improve surgical parameters, such as patient safety (88%), complication rate (84%), and identifying risk structures (96%). Conclusions: More studies are needed on the effect of different visualizations on task performance, as well as more sophisticated and effective visualization techniques for the operating room. With the findings of this study, we encourage the development of new study setups to advance surgical AR.

Prevalence of intestinal parasitism in preschool and school children in Colombia: Systematic review and meta-analysis.

OBJECTIVE: Intestinal parasitic infections (IPIs) are a public health challenge in developing countries such as Colombia, causing anaemia and delayed growth and development in children. We aimed to estimate the geographical and prevalence trend of IPIs in the last 30 years in school and preschool children in Colombia. METHODS: We conducted a systematic review and meta-analysis. We identified potential manuscripts through PubMed, EMBASE, Web of Science, LILACS, Scielo and Google Scholar on the IPIs prevalence in school and preschool children in Colombia. Articles included in the qualitative analysis were published between 1990 and 2020 in English or Spanish and met the inclusion criteria. Subsequently, a random-effects meta-analysis, a meta-regression and a trend analysis were performed. RESULTS: We identified 2292 articles; 109 were included in the qualitative review, and 79 articles were included in the meta-analysis. The estimated IPI prevalence was 55% (95% CI: 48-63). By age group, the prevalence in preschool children was 37% (95% CI: 26-49) and 66% (95% CI: 52-78) in schoolchildren. The prevalence by region was heterogeneous, with the Amazon being the highest (69%) and the Santanderes the lowest (28%). In the last 20 years, the prevalence of helminthiasis has decreased (from 64.66% in 1990-1995 to 22.09% in 2016-2020). CONCLUSION: The prevalence of IPIs is high (>30%) in three of the seven regions in Colombia. Biannual administration of mass deworming in schoolchildren is recommended in the Amazon region. Public policies aiming to control IPIs should be reinforced. Further prevalence studies should include Cesar, Guaviare, Vichada and Vaupés, where the epidemiology of IPIs is unknown. SUSTAINABLE DEVELOPMENT GOALS: Good health and wellbeing, clean water and sanitation, sustainable cities and communities.

Associations of persistent organic pollutants in human adipose tissue with retinoid levels and their relevance to the redox microenvironment.

Humans are exposed to a myriad of chemical substances in both occupational and environmental settings. Persistent organic pollutants (POPs) have drawn attention for their adverse effects including cancer and endocrine disruption. Herein, the objectives were 1) to describe serum and adipose tissue retinol levels, along with serum retinol binding protein 4 (RBP4) concentrations, and 2) to assess the associations of adipose tissue POP levels with these retinoid parameters, as well as their potential interaction with the previously-observed POP-related disruption of redox microenvironment. Retinol was measured in both serum and adipose tissue along with RBP4 levels in serum samples of 236 participants of the GraMo adult cohort. Associations were explored by multivariable linear regression analyses and Weighted Quantile Sum regression. Polychlorinated biphenyls (PCBs) 180, 153 and 138 were related to decreased adipose tissue retinol levels and increased serum RBP4/retinol ratio. Dicofol concentrations > limit of detection were associated with decreased retinol levels in serum and adipose tissue. Additionally, increased adipose tissue retinol levels were linked to an attenuation in previously-reported associations of adipose tissue PCB-153 with in situ superoxide dismutase activity. Our results revealed a suggestive link between retinoids, PCBs and redox microenvironment, potentially relevant for both mechanistic and public health purposes.

A multicenter retrospective study on cryopreserved amniotic membrane transplantation for the treatment of complicated corneal ulcers in the dog.

OBJECTIVE: To describe the surgical technique and outcome of amniotic membrane transplantation (AMT) for treatment of complicated corneal ulcers in dogs. ANIMALS STUDIED: One hundred and eleven dogs. PROCEDURE: Medical records (2010-2017) were reviewed to identify canine patients that underwent AMT for the treatment of complicated corneal ulcers. Quantitative and ordinal variables were analyzed using Mann-Whitney U test and Fisher's Exact test. RESULTS: Brachycephalic breeds were overrepresented (74/111; 66.6%). Three dogs were bilaterally affected. Fifty-one had melting ulcers (51/114; 44.7%), 33 stromal ulcers (33/63; 52.4%), 17 descemetoceles (17/63; 27%), and 13 perforations (13/63;20.6%). Mean defect size was 6.2 mm (2-18 mm). Human (32/114; 28.1%) or bovine (82/114; 71.9%) (AmnioVet(R)) cryopreserved amniotic membranes were used. Monolayer (31/114; 27.2%), bilayer (44/114; 38.6%) or multilayer technique (39/114; 34.2%) was performed, being anchored to the limbus (52/114; 45.6%), to the defect (48/114; 42.1%) or both (14/114; 12.3%). Mean epithelial healing and follow-up times were 25.6 days (15-45) and 98.7 days (21-400), respectively. Most common postsurgical complications included pigmentation (10/114; 8.8%) and graft failure (5/114; 4.4%). Depth and size of corneal lesions, human amniotic membrane (AM) and concurrent ocular diseases were associated with more complications (P < 0.05). Good cosmetic and visual outcomes were achieved in 99.1% (113/114) and 97.4% (111/114) of cases, respectively. Zero to low graft opacity was seen in 23.9% of the eyes (27/113), mild to moderate in 64.6% (73/113) and complete in 11.5% (13/113). CONCLUSIONS: Cryopreserved AMT is an effective surgical technique for the treatment of complicated corneal ulcers in the dog, with highly satisfactory visual and cosmetic outcomes.

Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats.

The aryl hydrocarbon receptor (AHR) mediates the toxicity of dioxins, but also plays important physiological roles. Selective AHR modulators, which elicit some effects imparted by this receptor without causing the marked toxicity of dioxins, are presently under intense scrutiny. Two novel such compounds are IMA-08401 (N-acetyl-N-phenyl-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide) and IMA-07101 (N-acetyl-N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide). They represent, as diacetyl prodrugs, AHR-active metabolites of the drug compounds laquinimod and tasquinimod, respectively, which are intended for the treatment of autoimmune diseases and cancer. Here, we toxicologically assessed the novel compounds in Sprague-Dawley rats, after a single dose (8.75-92.5mg/kg) and 5-day repeated dosing at the highest doses achievable (IMA-08401: 100mg/kg/day; and IMA-07101: 75mg/kg/day). There were no overt clinical signs of toxicity, but body weight gain was marginally retarded, and the treatments induced minimal hepatic extramedullary haematopoiesis. Further, both the absolute and relative weights of the thymus were significantly decreased. Cyp1a1 gene expression was substantially increased in all tissues examined. The hepatic induction profile of other AHR battery genes was distinct from that caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The only marked alterations in serum clinical chemistry variables were a reduction in triglycerides and an increase in 3-hydroxybutyrate. Liver and kidney retinol and retinyl palmitate concentrations were affected largely in the same manner as reported for TCDD. In vitro, the novel compounds activated CYP1A1 effectively in H4IIE cells. Altogether, these novel compounds appear to act as potent activators of the AHR, but lack some major characteristic toxicities of dioxins. They therefore represent promising new selective AHR modulators.

Ocular lesions produced by pine processionary caterpillar setae (Thaumetopoea pityocampa) in dogs: a descriptive study.

OBJECTIVE: To describe, for the first time in dogs, the ocular lesions induced by the pine processionary caterpillar (PPC) setae, and the associated corneal histopathology, medical treatment, and outcome. ANIMAL STUDIED: One hundred and forty client-owned dogs from Spain were studied. One hundred and twenty dogs came from the central area of Spain, 13 from the southern area, six from the northern area, and one dog came from the Mediterranean area. PROCEDURE: Medical records from four veterinary ophthalmology practices were reviewed. Dogs that were presented from endemic areas and that had PPC setae identified during their ophthalmic examination were included in the study. RESULTS: The following ocular lesions were identified: keratitis with crescent- or circular-shaped white stromal cellular infiltrates (98.57% [n = 138]), anterior uveitis (78.57% [n = 110]), conjunctival hyperemia and chemosis (33.57% [n = 47]), blepharitis (8.57% [n = 12]), and corneal ulcers (2.86% [n = 4]). Removal of the hairs by saline hydropulsion and medical treatment was successful in 99.29% (n = 139) of the cases. A single case healed following additional corneal reconstructive surgery to remove the deep corneal lesion and subsequent histopathology revealed an acute lesion with necrotic neutrophilic infiltrate and corneal edema. All ocular lesions resolved completely within 15 and 30 days after presentation, with the exception of one case that developed endophthalmitis. CONCLUSION: Pine processionary caterpillar should be included in the differential diagnosis of acute ocular lesions, especially if keratitis with corneal cellular infiltrate and anterior uveitis are present, in dogs from endemic areas during the months of spring and summer. In the majority of cases, irrigation and removal of the hairs together with medical treatment leads to a good outcome.

In utero and lactational exposure to a mixture of environmental contaminants detected in Canadian Arctic human populations alters retinoid levels in rat offspring with low margins of exposure.

Arctic inhabitants are highly exposed to persistent organic pollutants (POP), which may produce adverse health effects. This study characterized alterations in tissue retinoid (vitamin A) levels in rat offspring and their dams following in utero and lactational exposure to the Northern Contaminant Mixture (NCM), a mixture of 27 contaminants including polychlorinated biphenyls (PCB), organochlorine (OC) pesticides, and methylmercury (MeHg), present in maternal blood of the Canadian Arctic Inuit population. Further, effect levels for retinoid system alterations and other endpoints were compared to the Arctic Inuit population exposure and their interrelationships were assessed. Sprague-Dawley rat dams were dosed with NCM from gestational day 1 to postnatal day (PND) 23. Livers, kidneys and serum were obtained from offspring on PND35, PND77, and PND350 and their dams on PND30 for analysis of tissue retinoid levels, hepatic cytochrome P-450 (CYP) enzymes, and serum thyroid hormones. Benchmark doses were established for all endpoints, and a partial least-squares regression analysis was performed for NCM treatment, hepatic retinoid levels, CYP enzyme induction, and thyroid hormone levels, as well as body and liver weights. Hepatic retinoid levels were sensitive endpoints, with the most pronounced effects at PND35 though still apparent at PND350. The effects on tissue retinoid levels and changes in CYP enzyme activities, body and liver weights, and thyroid hormone levels were associated and likely driven by dioxin-like compounds in the mixture. Low margins of exposure were observed for all retinoid endpoints at PND35. These findings are important for health risk assessment of Canadian Arctic populations and further support the use of retinoid system analyses in testing of endocrine-system-modulating compounds.

Antiviral, Antibacterial, Antifungal, and Anticancer Activity of Plant Materials Derived from Cymbopogon citratus (DC.) Stapf Species.

The importance of natural plant materials in modern medicine is considerable, and raw materials with antiviral, antibacterial, antifungal, and anticancer properties are still sought because of microbe resistance and difficulties in anticancer therapy. This review focuses on the lemongrass Cymbopogon citratus (DC.) Stapf. and on the lemongrass oil properties and applications. Multiple applications of this plant were described in different latitudes and cultures, including cases of digestive disorders and anti-inflammatory, antipyretic, diaphoretic, stimulating, and antispasmodic conditions. Data from the literature on the composition of essential oil and extracts from C. citratus were analyzed, and the results of research on the antifungal, antibacterial, and antiviral effects were quoted. Essential oil inhibits the growth of fungi (Aspergillus niger, A. fumigatus, Candida spp.) and has an antibacterial effect (Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa). It also shows antiviral activity and deters insects. Lemongrass contains active substances with potential anticancer effects. This plant has apoptosis-stimulating properties, mainly through the activity of apigenin, which is the main active flavonoid in this plant. This active substance helps inhibit cell proliferation by stopping the cell cycle and directing cancer cells toward apoptosis.

Bioremediation of petroleum hydrocarbons polluted soil by spent mushroom substrates: Microbiological structure and functionality.

Spent mushroom substrate (SMS) holds valuable microbiota that can be useful in remediating polluted soils with hydrocarbons. However, the microorganisms behind the bioremediation process remain uncertain. In this work, a bioremediation assay of total petroleum hydrocarbons (TPHs) polluted soil by SMS application was performed to elucidate the microorganisms and consortia involved in biodegradation by a metabarcoding analysis. Untreated polluted soil was compared to seven bioremediation treatments by adding SMS of Agaricus bisporus, Pleurotus eryngii, Pleurotus ostreatus, and combinations. Soil microbial activity, TPH biodegradation, taxonomic classification, and predictive functional analysis were evaluated in the microbiopiles at 60 days. Different metagenomics approaches were performed to understand the impact of each SMS on native soil microbiota and TPHs biodegradation. All SMSs enhanced the degradation of aliphatic and aromatic hydrocarbons, being A. bisporus the most effective, promoting an efficient consortium constituted by the bacterial families Alcanivoraceae, Alcaligenaceae, and Dietziaceae along with the fungal genera Scedosporium and Aspergillus. The predictive 16 S rRNA gene study partially explained the decontamination efficacy by observing changes in the taxonomic structure of bacteria and fungi, and changes in the potential profiles of estimated degradative genes across the different treatments. This work provides new insights into TPHs bioremediation.

Potential protective role of let-7d-5p in atherosclerosis progression reducing the inflammatory pathway regulated by NF-κB and vascular smooth muscle cells proliferation.

The prevalence of cardiovascular diseases (CVDs) is increasing in the last decades, even is the main cause of death in first world countries being atherosclerosis one of the principal triggers. Therefore, there is an urgent need to decipher the underlying mechanisms involved in atherosclerosis progression. In this respect, microRNAs dysregulation is frequently involved in the progression of multiple diseases including CVDs. Our aim was to demonstrate that let-7d-5p unbalance could contribute to the pathophysiology of atherosclerosis and serve as a potential diagnostic biomarker. We evaluated let-7d-5p levels in vascular biopsies and exosome-enriched extracellular vesicles (EVs) from patients with carotid atherosclerosis and healthy donors. Moreover, we overexpressed let-7d-5p in vitro in vascular smooth muscle cells (VSMCs) to decipher the targets and the underlying mechanisms regulated by let-7d-5p in atherosclerosis. Our results demonstrate that let-7d-5p was significantly upregulated in carotid plaques from overweight patients with carotid atherosclerosis. Moreover, in EVs isolated from plasma, we found that let-7d-5p levels were increased in carotid atherosclerosis patients compared to control subjects specially in overweight patients. Receiver Operating Characteristic (ROC) analyses confirmed its utility as a diagnostic biomarker for atherosclerosis. In VSMCs, we demonstrated that increased let-7d-5p levels impairs cell proliferation and could serve as a protective mechanism against inflammation by impairing NF-κB pathway without affecting insulin resistance. In summary, our results highlight the role of let-7d-5p as a potential therapeutic target for atherosclerosis since its overexpression induce a decrease in inflammation and VSMCs proliferation, and also, as a novel non-invasive diagnostic biomarker for atherosclerosis in overweight patients.

Phantom study on surgical performance in augmented reality laparoscopy.

PURPOSE: Only a few studies have evaluated Augmented Reality (AR) in in vivo simulations compared to traditional laparoscopy; further research is especially needed regarding the most effective AR visualization technique. This pilot study aims to determine, under controlled conditions on a 3D-printed phantom, whether an AR laparoscope improves surgical outcomes over conventional laparoscopy without augmentation. METHODS: We selected six surgical residents at a similar level of training and had them perform a laparoscopic task. The participants repeated the experiment three times, using different 3D phantoms and visualizations: Floating AR, Occlusion AR, and without any AR visualization (Control). Surgical performance was determined using objective measurements. Subjective measures, such as task load and potential application areas, were collected with questionnaires. RESULTS: Differences in operative time, total touching time, and SurgTLX scores showed no statistical significance ([Formula: see text]). However, when assessing the invasiveness of the simulated intervention, the comparison revealed a statistically significant difference ([Formula: see text]). Participants felt AR could be useful for various surgeries, especially for liver, sigmoid, and pancreatic resections (100%). Almost all participants agreed that AR could potentially lead to improved surgical parameters, such as operative time (83%), complication rate (83%), and identifying risk structures (83%). CONCLUSION: According to our results, AR may have great potential in visceral surgery and based on the objective measures of the study, may improve surgeons' performance in terms of an atraumatic approach. In this pilot study, participants consistently took more time to complete the task, had more contact with the vascular tree, were significantly more invasive, and scored higher on the SurgTLX survey than with AR.

Discrimination of seasonality in cheeses by near-infrared technology.

BACKGROUND: Owing to the importance of the season of collection of milk for cheese quality, a study was made of the usefulness of near-infrared spectroscopy (NIRS) for discriminating the seasonal origin (winter or summer) of milk and quantifying the fat content of cheeses, since fat is one of the components most affected by the season of collection of milk for the elaboration of cheeses. RESULTS: In the internal validation, 96% of samples from winter milk and 97% of samples from summer milk were correctly classified, while in the external validation the prediction rate of samples correctly classified was 92%. Moreover, quantitative models allowed the determination of fat in winter, summer and winter + summer cheeses. CONCLUSION: Rapid prediction of the fat content of cheeses and the seasonal origin (winter or summer) of milk was achieved using NIRS without previous destruction or treatment of samples.

Pose-Dependent Weights and Domain Randomization for Fully Automatic X-Ray to CT Registration.

Fully automatic X-ray to CT registration requires a solid initialization to provide an initial alignment within the capture range of existing intensity-based registrations. This work addresses that need by providing a novel automatic initialization, which enables end to end registration. First, a neural network is trained once to detect a set of anatomical landmarks on simulated X-rays. A domain randomization scheme is proposed to enable the network to overcome the challenge of being trained purely on simulated data and run inference on real X-rays. Then, for each patient CT, a fully-automatic patient-specific landmark extraction scheme is used. It is based on backprojecting and clustering the previously trained network's predictions on a set of simulated X-rays. Next, the network is retrained to detect the new landmarks. Finally the combination of network and 3D landmark locations is used to compute the initialization using a perspective-n-point algorithm. During the computation of the pose, a weighting scheme is introduced to incorporate the confidence of the network in detecting the landmarks. The algorithm is evaluated on the pelvis using both real and simulated x-rays. The mean (± standard deviation) target registration error in millimetres is 4.1 ± 4.3 for simulated X-rays with a success rate of 92% and 4.2 ± 3.9 for real X-rays with a success rate of 86.8%, where a success is defined as a translation error of less than 30 mm .

Usability of Graphical Visualizations on a Tool-Mounted Interface for Spine Surgery.

Screw placement in the correct angular trajectory is one of the most intricate tasks during spinal fusion surgery. Due to the crucial role of pedicle screw placement for the outcome of the operation, spinal navigation has been introduced into the clinical routine. Despite its positive effects on the precision and safety of the surgical procedure, local separation of the navigation information and the surgical site, combined with intricate visualizations, limit the benefits of the navigation systems. Instead of a tech-driven design, a focus on usability is required in new research approaches to enable advanced and effective visualizations. This work presents a new tool-mounted interface (TMI) for pedicle screw placement. By fixing a TMI onto the surgical instrument, physical de-coupling of the anatomical target and navigation information is resolved. A total of 18 surgeons participated in a usability study comparing the TMI to the state-of-the-art visualization on an external screen. With the usage of the TMI, significant improvements in system usability (Kruskal-Wallis test p < 0.05) were achieved. A significant reduction in mental demand and overall cognitive load, measured using a NASA-TLX (p < 0.05), were observed. Moreover, a general improvement in performance was shown by means of the surgical task time (one-way ANOVA p < 0.001).

Effects of a high-fat diet and global aryl hydrocarbon receptor deficiency on energy balance and liver retinoid status in male Sprague-Dawley rats.

The physiological functions of the aryl hydrocarbon receptor (AHR) are only beginning to unfold. Studies in wildtype and AHR knockout (AHRKO) mice have recently disclosed that AHR activity is required for obesity and steatohepatitis to develop when mice are fed with a high-fat diet (HFD). In addition, a line of AHRKO mouse has been reported to accumulate retinoids in the liver. Whether these are universal manifestations across species related to AHR activity level is not known yet. Therefore, we here subjected wildtype and AHRKO male rats (on Sprague-Dawley background) to HFD feeding coupled with free access to 10% sucrose solution and water; controls received a standard diet and water. Although the HFD-fed rats consumed more energy throughout the 24-week feeding regimen, they did not get overweight. However, relative weights of the brown and epididymal adipose tissues were elevated in HFD-fed rats, while that of the liver was lower in AHRKO than wildtype rats. Moreover, the four groups exhibited diet- or genotype-dependent differences in biochemical variables, some of which suggested marked dissimilarities from AHRKO mice. Expression of pro- and anti-inflammatory genes was induced in livers of HFD-fed AHRKO rats, but histologically they did not differ from others. HFD reduced the hepatic concentrations of retinyl palmitate, 9-cis-4-oxo-13,14-dihydroretinoic acid and (suggestively) retinol, whereas AHR status had no effect. Hence, the background strain/line of AHRKO rat is resistant to diet-induced obesity, and AHR does not modulate this or liver retinoid concentrations. Yet, subtle AHR-dependent differences in energy balance-related factors exist despite similar weight development.

Role of aryl hydrocarbon receptor (AHR) in overall retinoid metabolism: Response comparisons to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure between wild-type and AHR knockout mice.

Young adult wild-type and aryl hydrocarbon receptor knockout (AHRKO) mice of both sexes and the C57BL/6J background were exposed to 10 weekly oral doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; total dose of 200 µg/kg bw) to further characterize the observed impacts of AHR as well as TCDD on the retinoid system. Unexposed AHRKO mice harboured heavier kidneys, lighter livers and lower serum all-trans retinoic acid (ATRA) and retinol (REOH) concentrations than wild-type mice. Results from the present study also point to a role for the murine AHR in the control of circulating REOH and ATRA concentrations. In wild-type mice, TCDD elevated liver weight and reduced thymus weight, and drastically reduced the hepatic concentrations of 9-cis-4-oxo-13,14-dihydro-retinoic acid (CORA) and retinyl palmitate (REPA). In female wild-type mice, TCDD increased the hepatic concentration of ATRA as well as the renal and circulating REOH concentrations. Renal CORA concentrations were substantially diminished in wild-type male mice exclusively following TCDD-exposure, with a similar tendency in serum. In contrast, TCDD did not affect any of these toxicity or retinoid system parameters in AHRKO mice. Finally, a distinct sex difference occurred in kidney concentrations of all the analysed retinoid forms. Together, these results strengthen the evidence of a mandatory role of AHR in TCDD-induced retinoid disruption, and suggest that the previously reported accumulation of several retinoid forms in the liver of AHRKO mice is a line-specific phenomenon. Our data further support participation of AHR in the control of liver and kidney development in mice.

Bone toxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the retinoid system: A causality analysis anchored in osteoblast gene expression and mouse data.

Dioxin exposures impact on bone quality and osteoblast differentiation, as well as retinoic acid metabolism and signaling. In this study we analyzed associations between increased circulating retinol concentrations and altered bone mineral density in a mouse model following oral exposure to 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD). Additionally, effects of TCDD on differentiation marker genes and genes involved with retinoic acid metabolism were analysed in an osteoblast cell model followed by benchmark dose-response analyses of the gene expression data. Study results show that the increased trabecular and decreased cortical bone mineral density in the mouse model following TCDD exposure are associated with increased circulating retinol concentrations. Also, TCDD disrupted the expression of genes involved in osteoblast differentiation and retinoic acid synthesis, degradation, and nuclear translocation in directions compatible with increasing cellular retinoic acid levels. Further evaluation of the obtained results in relation to previously published data by the use of mode-of-action and weight-of-evidence inspired analytical approaches strengthened the evidence that TCDD-induced bone and retinoid system changes are causally related and compatible with an endocrine disruption mode of action.

Endocrine, metabolic and apical effects of in utero and lactational exposure to non-dioxin-like 2,2',3,4,4',5,5'-heptachlorobiphenyl (PCB 180): A postnatal follow-up study in rats.

PCB 180 is a persistent and abundant non-dioxin-like PCB (NDL-PCB). We determined the developmental toxicity profile of ultrapure PCB 180 in developing offspring following in utero and lactational exposure with the focus on endocrine, metabolic and retinoid system alterations. Pregnant rats were given total doses of 0, 10, 30, 100, 300 or 1000 mg PCB 180/kg bw on gestational days 7-10 by oral gavage, and the offspring were sampled on postnatal days (PND) 7, 35 and 84. Decreased serum testosterone and triiodothyronine concentrations on PND 84, altered liver retinoid levels, increased liver weights and induced 7-pentoxyresorufin O-dealkylase (PROD) activity were the sensitive effects used for margin of exposure (MoE) calculations. Liver weights were increased together with induction of the metabolizing enzymes cytochrome P450 (CYP) 2B1, CYP3A1, and CYP1A1. Less sensitive effects included decreased serum estradiol and increased luteinizing hormone levels in females, decreased prostate and seminal vesicle weight and increased pituitary weight in males, increased cortical bone area and thickness of tibial diaphysis in females and decreased cortical bone mineral density in males. Developmental toxicity profiles were partly different in male and female offspring, males being more sensitive to increased liver weight, PROD induction and decreased thyroxine concentrations. MoE assessment indicated that the 95th percentile of current maternal PCB 180 concentrations do not exceed the estimated tolerable human lipid-based PCB 180 concentration. Although PCB 180 is much less potent than dioxin-like compounds, it shares several toxicological targets suggesting a potential for interactions.