Per- and polyfluoroalkyl substances alter innate immune function: evidence and data gaps.

Per- and polyfluoroalkyl substances (PFASs) are a large class of compounds used in a variety of processes and consumer products. Their unique chemical properties make them ubiquitous and persistent environmental contaminants while also making them economically viable and socially convenient. To date, several reviews have been published to synthesize information regarding the immunotoxic effects of PFASs on the adaptive immune system. However, these reviews often do not include data on the impact of these compounds on innate immunity. Here, current literature is reviewed to identify and incorporate data regarding the effects of PFASs on innate immunity in humans, experimental models, and wildlife. Known mechanisms by which PFASs modulate innate immune function are also reviewed, including disruption of cell signaling, metabolism, and tissue-level effects. For PFASs where innate immune data are available, results are equivocal, raising additional questions about common mechanisms or pathways of toxicity, but highlighting that the innate immune system within several species can be perturbed by exposure to PFASs. Recommendations are provided for future research to inform hazard identification, risk assessment, and risk management practices for PFASs to protect the immune systems of exposed organisms as well as environmental health.

Per- and Polyfluoroalkyl Substances in Food Packaging: Migration, Toxicity, and Management Strategies.

PFASs are linked to serious health and environmental concerns. Among their widespread applications, PFASs are known to be used in food packaging and directly contribute to human exposure. However, information about PFASs in food packaging is scattered. Therefore, we systematically map the evidence on PFASs detected in migrates and extracts of food contact materials and provide an overview of available hazard and biomonitoring data. Based on the FCCmigex database, 68 PFASs have been identified in various food contact materials, including paper, plastic, and coated metal, by targeted and untargeted analyses. 87% of these PFASs belong to the perfluorocarboxylic acids and fluorotelomer-based compounds. Trends in chain length demonstrate that long-chain perfluoroalkyl acids continue to be found, despite years of global efforts to reduce the use of these substances. We utilized ToxPi to illustrate that hazard data are available for only 57% of the PFASs that have been detected in food packaging. For those PFASs for which toxicity testing has been performed, many adverse outcomes have been reported. The data and knowledge gaps presented here support international proposals to restrict PFASs as a group, including their use in food contact materials, to protect human and environmental health.

VHL: Trends and Insight into a Multi-Modality, Interdisciplinary Approach for Management of Central Nervous System Hemangioblastoma.

Von Hippel-Lindau (VHL) is a multi-system disease which results in significant morbidity from central nervous system (CNS) involvement as well as ocular, renal and neuro-endocrine effects. Haemangioblastomas of the CNS present a number of challenges. The natural history of these lesions is varied, as is the size and location within the CNS. Whilst surgery is considered the mainstay of treatment and best chance at curing these lesions, this is also often associated with significant risks due to the anatomical location of these lesions, most commonly the posterior fossa and spinal cord.We review the literature and describe our experience across two separate European VHL referral centres. Alternative treatment options and combined modalities are increasingly being used in the context of managing CNS haemangioblastomas. We analyse the increasing use of stereotactic radiosurgery and the evolution of medical treatments as potential future adjuncts to surgery. The availability of multiple modalities in our armamentarium is essential in tailoring a personalised treatment approach to these patients. Owing to the multi-systemic nature of the disease, in our experience, managing the care of patients with VHL is best delivered using an interdisciplinary approach utilising multiple specialties and adopting an individually tailored holistic approach.

The maternal microbiome promotes placental development in mice.

The maternal microbiome is an important regulator of gestational health, but how it affects the placenta as the interface between mother and fetus remains unexplored. Here, we show that the maternal gut microbiota supports placental development in mice. Depletion of the maternal gut microbiota restricts placental growth and impairs feto-placental vascularization. The maternal gut microbiota modulates metabolites in the maternal and fetal circulation. Short-chain fatty acids (SCFAs) stimulate cultured endothelial cell tube formation and prevent abnormalities in placental vascularization in microbiota-deficient mice. Furthermore, in a model of maternal malnutrition, gestational supplementation with SCFAs prevents placental growth restriction and vascular insufficiency. These findings highlight the importance of host-microbial symbioses during pregnancy and reveal that the maternal gut microbiome promotes placental growth and vascularization in mice.

The maternal microbiome promotes placental development in mice.

The maternal microbiome is an important regulator of gestational health, but how it impacts the placenta as the interface between mother and fetus remains unexplored. Here we show that the maternal gut microbiota supports placental development in mice. Depletion of the maternal gut microbiota restricts placental growth and impairs feto-placental vascularization. The maternal gut microbiota modulates metabolites in the maternal and fetal circulation. Short-chain fatty acids (SCFAs) stimulate angiogenesis-related tube formation by endothelial cells and prevent abnormalities in placental vascularization in microbiota-deficient mice. Furthermore, in a model of maternal malnutrition, gestational supplementation with SCFAs prevents placental growth restriction and vascular insufficiency. These findings highlight the importance of host-microbial symbioses during pregnancy and reveal that the maternal gut microbiome promotes placental growth and vascularization in mice.

Legacy and emerging per- and polyfluoroalkyl substances suppress the neutrophil respiratory burst.

Per- and polyfluoroalkyl substances (PFASs) are used in a multitude of processes and products, including nonstick coatings, food wrappers, and fire-fighting foams. These chemicals are environmentally-persistent, ubiquitous, and can be detected in the serum of 98% of Americans. Despite evidence that PFASs alter adaptive immunity, few studies have investigated their effects on innate immunity. The report here presents results of studies that investigated the impact of nine environmentally-relevant PFASs [e.g. perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid potassium salt (PFOS-K), perfluorononanoic acid (PFNA), perfluorohexanoic acid (PFHxA), perfluorohexane sulfonic acid (PFHxS), perfluorobutane sulfonic acid (PFBS), ammonium perfluoro(2-methyl-3-oxahexanoate) (GenX), 7H-perfluoro-4-methyl-3,6-dioxa-octane sulfonic acid (Nafion byproduct 2), and perfluoromethoxyacetic acid sodium salt (PFMOAA-Na)] on one component of the innate immune response, the neutrophil respiratory burst. The respiratory burst is a key innate immune process by which microbicidal reactive oxygen species (ROS) are rapidly induced by neutrophils in response to pathogens; defects in the respiratory burst can increase susceptibility to infection. The study here utilized larval zebrafish, a human neutrophil-like cell line, and primary human neutrophils to ascertain whether PFAS exposure inhibits ROS production in the respiratory burst. It was observed that exposure to PFHxA and GenX suppresses the respiratory burst in zebrafish larvae and a human neutrophil-like cell line. GenX also suppressed the respiratory burst in primary human neutrophils. This report is the first to demonstrate that these PFASs suppress neutrophil function and support the utility of employing zebrafish larvae and a human cell line as screening tools to identify chemicals that may suppress human immune function.

Can Nutrition Play a Role in Ameliorating Digital Eye Strain?

Digital eye strain is a complex, multifactorial condition that can be caused by excessive screen time exposure to various electronic devices such as smartphones, tablets, e-readers, and computers. Current literature suggests oxidative damage concomitant with a chronic pro-inflammatory state represent significant etiopathogenic mechanisms. The present review aims to discuss the potential dietary role for micronutrients with nutraceutical properties to ameliorate various ocular and vision-related symptoms associated with digital eye strain. For ocular surface dysfunction, enhanced anti-inflammatory benefits with omega-3 polyunsaturated fatty acids have been well documented for treatment of dry eye disease. The anti-oxidative and immunosuppressive properties of anthocyanin phytochemicals may also confer protective effects against visually induced cognitive stress and digital asthenopia. Meanwhile, nutraceutical strategies involving xanthophyll macular carotenoids demonstrate enhanced cognitive functioning and overall visual performance that aids digital eye strain. Collectively, preliminary findings seem to offer a strong line of evidence to substantiate the need for additional randomized controlled trials aimed at treating digital eye strain with adjunctive nutraceutical strategies. Further RCT and comparisons on commercially available nutritional supplements are needed to quantify the clinical benefits.

The immune cell infiltrate in the tumour microenvironment of phaeochromocytomas and paragangliomas.

Emerging evidence suggests the composition of the tumour microenvironment (TME) correlates with clinical outcome and that each tumour type has a unique TME including a variable population of inflammatory cells. We performed immunohistochemistry on 65 phaeochromocytoma and paraganglioma (PPGL) tumour samples with 20 normal adrenal medulla samples for comparison. The immune cells assessed were macrophages, lymphocytes and neutrophils, and we compared the proportion of infiltration of these immune cells with clinical and histopathological factors. There was a higher proportion of immune cells in tumour tissue compared to non-neoplastic adrenal medulla tissue, with a predominance of macrophages. There was a higher proportion of M2:M1 macrophages and T-helper lymphocytes in aggressive tumours compared to indolent ones. For SDHB-associated tumours, there was a higher proportion of M2 macrophage infiltration, with higher M2:M1 in aggressive SDHB PPGLs compared to indolent tumours. These data demonstrate that immune cells do infiltrate the TME of PPGLs, confirming that PPGLs are immunologically active tumours. Differences in the TME of PPGLs were observed between aggressive and indolent tumours. These differences could potentially be exploited as an aid in predicting tumour behaviour.

Regional specification of oral mucosal immunity.

In this issue of Science Immunology, Barreto de Albuquerque et al. track immune responsiveness to the foodborne pathogen Listeria monocytogenes during oral infection. Their findings extend the notion of compartmentalized immunity within the gastrointestinal tract to the oral cavity and provide previously unkown insights into regional specialization of oral immunity.

Indigenous microbiota protects development of medication-related osteonecrosis induced by periapical disease in mice.

Bacterial infection is a common finding in patients, who develop medication-related osteonecrosis of the jaw (MRONJ) by the long-term and/or high-dose use of anti-resorptive agents such as bisphosphonate (BPs). However, pathological role of bacteria in MRONJ development at the early stage remains controversial. Here, we demonstrated that commensal microbiota protects against MRONJ development in the pulp-exposed periapical periodontitis mouse model. C57/BL6 female mice were treated with intragastric broad-spectrum antibiotics for 1 week. Zoledronic acid (ZOL) through intravenous injection and antibiotics in drinking water were administered for throughout the experiment. Pulp was exposed on the left maxillary first molar, then the mice were left for 5 weeks after which bilateral maxillary first molar was extracted and mice were left for additional 3 weeks to heal. All mice were harvested, and cecum, maxilla, and femurs were collected. ONJ development was assessed using µCT and histologic analyses. When antibiotic was treated in mice, these mice had no weight changes, but developed significantly enlarged ceca compared to the control group (CTL mice). Periapical bone resorption prior to the tooth extraction was similarly prevented when treated with antibiotics, which was confirmed by decreased osteoclasts and inflammation. ZOL treatment with pulp exposure significantly increased bone necrosis as determined by empty lacunae and necrotic bone amount. Furthermore, antibiotics treatment could further exacerbate bone necrosis, with increased osteoclast number. Our findings suggest that the commensal microbiome may play protective role, rather than pathological role, in the early stages of MRONJ development.

Indigenous microbiota protects development of medication-related osteonecrosis induced by periapical disease in mice / 国际口腔科学杂志·英文版

Bacterial infection is a common finding in patients, who develop medication-related osteonecrosis of the jaw (MRONJ) by the long-term and/or high-dose use of anti-resorptive agents such as bisphosphonate (BPs). However, pathological role of bacteria in MRONJ development at the early stage remains controversial. Here, we demonstrated that commensal microbiota protects against MRONJ development in the pulp-exposed periapical periodontitis mouse model. C57/BL6 female mice were treated with intragastric broad-spectrum antibiotics for 1 week. Zoledronic acid (ZOL) through intravenous injection and antibiotics in drinking water were administered for throughout the experiment. Pulp was exposed on the left maxillary first molar, then the mice were left for 5 weeks after which bilateral maxillary first molar was extracted and mice were left for additional 3 weeks to heal. All mice were harvested, and cecum, maxilla, and femurs were collected. ONJ development was assessed using μCT and histologic analyses. When antibiotic was treated in mice, these mice had no weight changes, but developed significantly enlarged ceca compared to the control group (CTL mice). Periapical bone resorption prior to the tooth extraction was similarly prevented when treated with antibiotics, which was confirmed by decreased osteoclasts and inflammation. ZOL treatment with pulp exposure significantly increased bone necrosis as determined by empty lacunae and necrotic bone amount. Furthermore, antibiotics treatment could further exacerbate bone necrosis, with increased osteoclast number. Our findings suggest that the commensal microbiome may play protective role, rather than pathological role, in the early stages of MRONJ development.

Response to Comments on "Aberrant type 1 immunity drives susceptibility to mucosal fungal infections".

Puel and Casanova and Kisand et al. challenge our conclusions that interferonopathy and not IL-17/IL-22 autoantibodies promote candidiasis in autoimmune polyendocrinopathy­candidiasis­ectodermal dystrophy. We acknowledge that conclusive evidence for causation is difficult to obtain in complex human diseases. However, our studies clearly document interferonopathy driving mucosal candidiasis with intact IL-17/IL-22 responses in Aire-deficient mice, with strong corroborative evidence in patients.

A Systematic Review of Carotenoids in the Management of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) remains a leading cause of modifiable vision loss in older adults. Chronic oxidative injury and compromised antioxidant defenses represent essential drivers in the development of retinal neurodegeneration. Overwhelming free radical species formation results in mitochondrial dysfunction, as well as cellular and metabolic imbalance, which becomes exacerbated with increasing age. Thus, the depletion of systemic antioxidant capacity further proliferates oxidative stress in AMD-affected eyes, resulting in loss of photoreceptors, neuroinflammation, and ultimately atrophy within the retinal tissue. The aim of this systematic review is to examine the neuroprotective potential of the xanthophyll carotenoids lutein, zeaxanthin, and meso-zeaxanthin on retinal neurodegeneration for the purpose of adjunctive nutraceutical strategy in the management of AMD. A comprehensive literature review was performed to retrieve 55 eligible publications, using four database searches from PubMed, Embase, Cochrane Library, and the Web of Science. Epidemiology studies indicated an enhanced risk reduction against late AMD with greater dietary consumption of carotenoids, meanwhile greater concentrations in macular pigment demonstrated significant improvements in visual function among AMD patients. Collectively, evidence strongly suggests that carotenoid vitamin therapies offer remarkable synergic protection in the neurosensory retina, with the potential to serve as adjunctive nutraceutical therapy in the management of established AMD, albeit these benefits may vary among different stages of disease.

A Systematic Review of Carotenoids in the Management of Diabetic Retinopathy.

Diabetic retinopathy, which was primarily regarded as a microvascular disease, is the leading cause of irreversible blindness worldwide. With obesity at epidemic proportions, diabetes-related ocular problems are exponentially increasing in the developed world. Oxidative stress due to hyperglycemic states and its associated inflammation is one of the pathological mechanisms which leads to depletion of endogenous antioxidants in retina in a diabetic patient. This contributes to a cascade of events that finally leads to retinal neurodegeneration and irreversible vision loss. The xanthophylls lutein and zeaxanthin are known to promote retinal health, improve visual function in retinal diseases such as age-related macular degeneration that has oxidative damage central in its etiopathogenesis. Thus, it can be hypothesized that dietary supplements with xanthophylls that are potent antioxidants may regenerate the compromised antioxidant capacity as a consequence of the diabetic state, therefore ultimately promoting retinal health and visual improvement. We performed a comprehensive literature review of the National Library of Medicine and Web of Science databases, resulting in 341 publications meeting search criteria, of which, 18 were found eligible for inclusion in this review. Lutein and zeaxanthin demonstrated significant protection against capillary cell degeneration and hyperglycemia-induced changes in retinal vasculature. Observational studies indicate that depletion of xanthophyll carotenoids in the macula may represent a novel feature of DR, specifically in patients with type 2 or poorly managed type 1 diabetes. Meanwhile, early interventional trials with dietary carotenoid supplementation show promise in improving their levels in serum and macular pigments concomitant with benefits in visual performance. These findings provide a strong molecular basis and a line of evidence that suggests carotenoid vitamin therapy may offer enhanced neuroprotective effects with therapeutic potential to function as an adjunct nutraceutical strategy for management of diabetic retinopathy.

Carotenoids in the Management of Glaucoma: A Systematic Review of the Evidence.

Primary open-angle glaucoma (POAG) remains a leading cause of irreversible blindness globally. Recent evidence further substantiates sustained oxidative stress, and compromised antioxidant defenses are key drivers in the onset of glaucomatous neurodegeneration. Overwhelming oxidative injury is likely attributed to compounding mitochondrial dysfunction that worsens with age-related processes, causing aberrant formation of free radical species. Thus, a compromised systemic antioxidant capacity exacerbates further oxidative insult in glaucoma, leading to apoptosis, neuroinflammation, and subsequent tissue injury. The purpose of this systematic review is to investigate the neuroprotective benefits of the macular carotenoids lutein, zeaxanthin, and meso-zeaxanthin on glaucomatous neurodegeneration for the purpose of adjunctive nutraceutical treatment in glaucoma. A comprehensive literature search was conducted in three databases (PubMed, Cochrane Library, and Web of Science) and 20 records were identified for screening. Lutein demonstrated enhanced neuroprotection on retinal ganglion cell survival and preserved synaptic activity. In clinical studies, a protective trend was seen with greater dietary consumption of carotenoids and risk of glaucoma, while greater carotenoid levels in macular pigment were largely associated with improved visual performance in glaucomatous eyes. The data suggest that carotenoid vitamin therapy exerts synergic neuroprotective benefits and has the capacity to serve adjunctive therapy in the management of glaucoma.

Aberrant type 1 immunity drives susceptibility to mucosal fungal infections.

Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)- and signal transducer and activator of transcription 1 (STAT1)-dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)-STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell-dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.

Monitoring patients receiving dopamine agonist therapy for hyperprolactinaemia.

The surveillance strategy for patients taking low dose cabergoline for hyperprolactinaemia is controversial. As more evidence has emerged that the risks of cardiac valvulopathy in this population of patients are low, fewer and fewer endocrinologists adhere strictly to the original medicines and healthcare products agency MHRA guidance of "at least" annual echocardiography. Strict adherence to this guidance would be costly in monetary terms (£5.76 million/year in the UK) and also in resource use (90,000 extra echocardiograms/year). This article reviews the proposed pathophysiological mechanism underlying the phenomenon of dopamine agonist valvulopathy, the characteristic echocardiographic changes seen, summarises the published literature on the incidence of valvulopathy with low dose cabergoline and examines the previous and current evidence-based screening guidelines.

Visual Function and Macular Carotenoid Changes in Eyes with Retinal Drusen-An Open Label Randomized Controlled Trial to Compare a Micronized Lipid-Based Carotenoid Liquid Supplementation and AREDS-2 Formula.

PURPOSE: To compare the changes in visual and ocular parameters in individuals with retinal drusen who were treated with two commercially available nutritional supplements. METHODS: An open-label, single-center, randomized, parallel-treatment with an observational control group design was utilized. The treatment groups included individuals with fine retinal drusen sub-clinical age-related macular degeneration (AMD), while the control group consisted of ocular normal individuals. The treatment groups were randomly assigned to the micronized lipid-based carotenoid supplement, Lumega-Z (LM), or the PreserVision Age-Related Eye Disease Study 2 (AREDS-2) soft gel (PV). Visual performance was evaluated using the techniques of visual acuity, dark adaptation recovery and contrast sensitivity, at baseline, three months, and six months. Additionally, the macular pigment optical density (MPOD) was measured. The control group was not assigned any carotenoid supplement. The right eye and left eye results were analyzed separately. RESULTS: Seventy-nine participants were recruited for this study, of which 68 qualified and 56 participants had useable reliable data. Of the individuals who completed this study, 25 participants belonged to the LM group, 16 belonged to the PV group, and 15 to the control group. The LM group demonstrated statistically significant improvements in contrast sensitivity function (CSF) in both eyes at six months (p < 0.001). The LM group displayed a positive linear trend with treatment time in CSF (p < 0.001), with benefits visible after just three months of supplementation. Although there was a trend showing improvement in CSF in the PV group, the change was not significant after a Bonferroni-corrected p-value of p < 0.00625. Visual acuity, dark adaptation recovery and MPOD did not significantly improve in either treatment groups. CONCLUSION: The LM group demonstrated greater and faster benefits in visual performance as measured by CSF when compared to the PV group. This trial has been registered at clinicaltrials.gov (NCT03946085).

The maternal microbiome modulates fetal neurodevelopment in mice.

'Dysbiosis' of the maternal gut microbiome, in response to challenges such as infection1, altered diet2 and stress3 during pregnancy, has been increasingly associated with abnormalities in brain function and behaviour of the offspring4. However, it is unclear whether the maternal gut microbiome influences neurodevelopment during critical prenatal periods and in the absence of environmental challenges. Here we investigate how depletion and selective reconstitution of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibited reduced brain expression of genes related to axonogenesis, deficient thalamocortical axons and impaired outgrowth of thalamic axons in response to cell-extrinsic factors. Gnotobiotic colonization of microbiome-depleted dams with a limited consortium of bacteria prevented abnormalities in fetal brain gene expression and thalamocortical axonogenesis. Metabolomic profiling revealed that the maternal microbiome regulates numerous small molecules in the maternal serum and the brains of fetal offspring. Select microbiota-dependent metabolites promoted axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with these metabolites abrogated deficiencies in fetal thalamocortical axons. Manipulation of the maternal microbiome and microbial metabolites during pregnancy yielded adult offspring with altered tactile sensitivity in two aversive somatosensory behavioural tasks, but no overt differences in many other sensorimotor behaviours. Together, our findings show that the maternal gut microbiome promotes fetal thalamocortical axonogenesis, probably through signalling by microbially modulated metabolites to neurons in the developing brain.

In vivo assessment of respiratory burst inhibition by xenobiotic exposure using larval zebrafish.

Currently, assessment of the potential immunotoxicity of a given agent involves a tiered approach for hazard identification and mechanistic studies, including observational studies, evaluation of immune function, and measurement of susceptibility to infectious and neoplastic diseases. These studies generally use costly low-throughput mammalian models. Zebrafish, however, offer an excellent alternative due to their rapid development, ease of maintenance, and homology to mammalian immune system function and development. Larval zebrafish also are a convenient model to study the innate immune system with no interference from the adaptive immune system. In this study, a respiratory burst assay (RBA) was utilized to measure reactive oxygen species (ROS) production after developmental xenobiotic exposure. Embryos were exposed to non-teratogenic doses of chemicals and at 96 h post-fertilization, the ability to produce ROS was measured. Using the RBA, 12 compounds with varying immune-suppressive properties were screened. Seven compounds neither suppressed nor enhanced the respiratory burst; five reproducibly suppressed global ROS production, but with varying potencies: benzo[a]pyrene, 17ß-estradiol, lead acetate, methoxychlor, and phenanthrene. These five compounds have all previously been reported as immunosuppressive in mammalian innate immunity assays. To evaluate whether the suppression of ROS by these compounds was a result of decreased immune cell numbers, flow cytometry with transgenic zebrafish larvae was used to count the numbers of neutrophils and macrophages after chemical exposure. With this assay, benzo[a]pyrene was found to be the only chemical that induced a change in the number of immune cells by increasing macrophage but not neutrophil numbers. Taken together, this work demonstrates the utility of zebrafish larvae as a vertebrate model for identifying compounds that impact innate immune function at non-teratogenic levels and validates measuring ROS production and phagocyte numbers as metrics for monitoring how xenobiotic exposure alters the innate immune system.