Prenatal Exposure to Per- and Polyfluoroalkyl Substances and ASD-Related Symptoms in Early Childhood: Mediation Role of Steroids.

Previous studies regarding the associations between perfluoroalkyl and polyfluoroalkyl substances (PFAS) and autism spectrum disorder (ASD) have yielded inconsistent results, with the underlying mechanisms remaining unknown. In this study, we quantified 13 PFAS in cord serum samples from 396 neonates and followed the children at age 4 to assess ASD-related symptoms. Our findings revealed associations between certain PFAS and ASD-related symptoms, with a doubling of perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) concentrations associated with respective increases of 1.79, 1.62, and 1.45 units in language-related symptoms and PFDA exhibiting an association with higher score of sensory stimuli. Nonlinear associations were observed in the associations of 6:2 chlorinated polyfluorinated ether sulfonate (Cl-PFAES) and 8:2 Cl-PFAES with ASD-related symptoms. Employing weighted quantile sum (WQS) regression, we observed significant mixture effects of multiple PFAS on all domains of ASD-related symptoms, with PFNA emerging as the most substantial contributor. Assuming causality, we found that 39-40% of the estimated effect of long-chain PFAS (PFUnDA and PFDoDA) exposure on sensory stimuli was mediated by androstenedione. This study provides novel epidemiological data about prenatal PFAS mixture exposure and ASD-related symptoms.

Caprylic Acid Inhibits High Mobility Group Box-1-Induced Mitochondrial Damage in Myocardial Tubes.

Myocardial damage significantly impacts the prognosis of patients with cancer; however, the mechanisms of myocardial damage induced by cancer and its treatment remain unknown. We previously reported that medium-chain fatty acids (MCFAs) improve cancer-induced myocardial damage but did not evaluate the differences in effect according to MCFA type. Therefore, this study investigated the role of inflammatory cytokines in cancer-induced myocardial damage and the effects of three types of MCFAs (caprylic acid [C8], capric acid [C10], and lauric acid [C12]). In a mouse model, the C8 diet showed a greater effect on improving myocardial damage compared with C10 and C12 diets. Myocardial tubes differentiated from H9C2 cardiomyoblasts demonstrated increased mitochondrial oxidative stress, decreased membrane potential and mitochondrial volume, and inhibited myocardial tube differentiation following treatment with high-mobility group box-1 (HMGB1) but not interleukin-6 and tumor necrosis factor-α cytokines. However, HMGB1 treatment combined with C8 improved HMGB1-induced mitochondrial damage, enhanced autophagy, and increased mitochondrial biogenesis and maturation. However, these effects were only partial when combined with beta-hydroxybutyrate, a C8 metabolite. Thus, HMGB1 may play an important role in cancer-related myocardial damage. C8 counteracts HMGB1's effects and improves cancer-related myocardial damage. Further clinical studies are required to investigate the effects of C8.

Comparative toxicity assessment of alternative versus legacy PFAS: Implications for two primary trophic levels in freshwater ecosystems.

Perfluoroalkyl substances (PFAS) are common environmental pollutants, but their toxicity framework remains elusive. This research focused on ten PFAS, evaluating their impacts on two ecotoxicologically relevant model organisms from distinct trophic levels: the crustacean Daphnia magna and the unicellular green alga Raphidocelis subcapitata. The results showed a greater sensitivity of R. subcapitata compared to D. magna. However, a 10-day follow-up to the 48 h immobilisation test in D. magna showed delayed mortality, underlining the limitations of relying on EC50 s from standard acute toxicity tests. Among the compounds scrutinized, Perfluorodecanoic acid (PFDA) was the most toxic to R. subcapitata, succeeded by Perfluorooctane sulfonate (PFOS), Perfluorobutanoic acid (PFBA), and Perfluorononanoic acid (PFNA), with the latter being the only one to show an algicidal effect. In the same species, assessment of binary mixtures of the compounds that demonstrated high toxicity in the single evaluation revealed either additive or antagonistic interactions. Remarkably, with an EC50 of 31 mg L-1, the short-chain compound PFBA, tested individually, exhibited toxicity levels akin to the notorious long-chain PFOS, and its harm to freshwater ecosystems cannot be ruled out. Despite mounting toxicological evidence and escalating environmental concentrations, PFBA has received little scientific attention and regulatory stewardship. It is strongly advisable that regulators re-evaluate its use to mitigate potential risks to the environmental and human health.

Associations between prenatal exposure to per- and polyfluoroalkyl substances and plasma immune molecules in three-year-old children in China.

BACKGROUND: Many studies have reported that prenatal exposure to Per- and Polyfluoroalkyl Substances (PFASs) can disrupt immune function. However, little is known about the effects of PFASs on immune molecules. The study analyzed the association between prenatal exposure to mixed and single PFASs and plasma immune molecules in three-year-old children. METHODS: Ten PFASs were measured in umbilical cord serum, while peripheral blood samples were collected at age three to measure immune molecules. Associations between exposure to individual and combined PFASs and immune molecules were analyzed using Generalized Linear Models and Weighted Quantile Sum (WQS) regression. RESULTS: (1) Interleukin-4 (IL-4) increased by 23.85% (95% CI:2.99,48.94) with each doubling of Perfluorooctanoic Acid (PFOA), and Interleukin-6 (IL-6) increased by 39.07% (95%CI:4.06,85.86) with Perfluorotridecanoic Acid (PFTrDA). Elevated PFOA and Perfluorononanoic Acid (PFNA) were correlated with increases of 34.06% (95% CI: 6.41, 70.28) and 24.41% (95% CI: 0.99, 53.27) in Eotaxin-3, respectively. Additionally, the doubling of Perfluorohexane Sulfonic Acid (PFHxS) was associated with a 9.51% decrease in Periostin (95% CI: -17.84, -0.33). (2) The WQS analysis revealed that mixed PFASs were associated with increased IL-6 (ß = 0.37, 95%CI:0.04,0.69), mainly driven by PFTrDA, PFNA, and 8:2 Chlorinated Perfluoroethyl Sulfonamide (8:2 Cl-PFESA). Moreover, mixed PFASs were linked to an increase in Eotaxin-3 (ß = 0.32, 95% CI: 0.09,0.55), primarily influenced by PFOA, PFTrDA, and Perfluorododecanoic Acid (PFDoDA). CONCLUSIONS: Prenatal PFASs exposure significantly alters the levels of immune molecules in three-year-old children, highlighting the importance of understanding environmental impacts on early immune development.

The Protective Effect of Uridine in a Rotenone-Induced Model of Parkinson's Disease: The Role of the Mitochondrial ATP-Dependent Potassium Channel.

The effect of the modulators of the mitochondrial ATP-dependent potassium channel (mitoKATP) on the structural and biochemical alterations in the substantia nigra and brain tissues was studied in a rat model of Parkinson's disease induced by rotenone. It was found that, in experimental parkinsonism accompanied by characteristic motor deficits, both neurons and the myelin sheath of nerve fibers in the substantia nigra were affected. Changes in energy and ion exchange in brain mitochondria were also revealed. The nucleoside uridine, which is a source for the synthesis of the mitoKATP channel opener uridine diphosphate, was able to dose-dependently decrease behavioral disorders and prevent the death of animals, which occurred for about 50% of animals in the model. Uridine prevented disturbances in redox, energy, and ion exchanges in brain mitochondria, and eliminated alterations in their structure and the myelin sheath in the substantia nigra. Cytochemical examination showed that uridine restored the indicators of oxidative phosphorylation and glycolysis in peripheral blood lymphocytes. The specific blocker of the mitoKATP channel, 5-hydroxydecanoate, eliminated the positive effects of uridine, suggesting that this channel is involved in neuroprotection. Taken together, these findings indicate the promise of using the natural metabolite uridine as a new drug to prevent and, possibly, stop the progression of Parkinson's disease.

Preparation and Application of Decanoic Acid/Arginine Hydrogels to a Transdermal Formulation.

We prepared a supramolecular hydrogel composed of decanoic acid and arginine (C10/Arg gel) and evaluated its application to a transdermal formulation. C10/Arg gel adjusted to pH 7 with 1 M NaOH aq or 1 M HCl aq provided a translucent hydrogel with a lamellar liquid crystal structure in the concentration region of decanoic acid ≥12% and arginine ≤9%. Rheological measurements showed that C10/Arg gel is a viscoelastic material with both solid and liquid properties, with elasticity being dominant over viscosity in the low shear stress region. The skin permeability of hydrocortisone (HC) and indomethacin (IM) from C10/Arg gels was investigated in vitro using hairless mouse skin and compared to control formulation drug suspensions (IM or HC) in water. The cumulative permeation amount of HC and IM from the C10/Arg gel at 10 h after application was approximately 16 and 11 times higher than that of the control, respectively. On the other hand, the flux of IM decreased with increasing arginine concentration, likely due to the acid-base interaction between Arg and IM in C10/Arg gel. Adequate drug skin permeation enhancement by C10/Arg gel requires optimizing the gel composition for each specific drug.

Head-to-Head Comparison of Caco-2 Transwell and Gut-on-a-Chip Models for Assessing Oral Peptide Formulations.

Oral delivery of potent peptide drugs provides key formulation challenges in the pharmaceutical industry: stability, solubility, and permeability. Intestinal permeation enhancers (PEs) can overcome the low oral bioavailability by improving the drug permeability. Conventional in vitro and ex vivo models for assessing PEs fail to predict efficacy in vivo. Here, we compared Caco-2 cells cultured in the conventional static Transwell model to a commercially available continuous flow microfluidic Gut-on-a-Chip model. We determined baseline permeability of FITC-Dextan 3 kDa (FD3) in Transwell (5.3 ± 0.8 × 10-8 cm/s) vs Chip (3.2 ± 1.8 × 10-7 cm/s). We screened the concentration impact of two established PEs sodium caprate and sucrose monolaurate and indicated a requirement for higher enhancer concentration in the Chip model to elicit equivalent efficacy e.g., 10 mM sodium caprate in Transwells vs 25 mM in Chips. Fasted and fed state simulated intestinal fluids (FaSSIF/FeSSIF) were introduced into the Chip and increased basal FD3 permeability by 3-fold and 20-fold, respectively, compared to 4-fold and 4000-fold in Transwells. We assessed the utility of this model to peptides (Insulin and Octreotide) with PEs and observed much more modest permeability enhancement in the Chip model in line with observations in ex vivo and in vivo preclinical models. These data indicate that microfluidic Chip models are well suited to bridge the gap between conventional in vitro and in vivo models.

Construction of injectable micron-sized polymorphic vesicles for prolonged local anesthesia with weekly sustained release of ropivacaine.

Currently, to overcome the short half-life of the local anesthetic ropivacaine, drug delivery systems such as nanoparticles and liposomes have been used to prolong the analgesic effect, but they are prone to abrupt release from the site of administration or have poor slow-release effects, which increases the risk of cardiotoxicity. In this study, injectable lipid suspensions based on ropivacaine-docusate sodium hydrophobic ion pairing (HIP) were designed to significantly prolong the duration of analgesia. The resulting ion-paired lipid suspension (HIP/LIPO) had a micrometer scale and a high zeta potential, which facilitates stable in situ retention. The strong interaction between docusate sodium and ropivacaine was verified using thermal and spectroscopic analyses, and the formation of micron-sized polymorphic vesicles was attributed to the mutual stabilizing interactions between ropivacaine-docusate sodium HIP, docusate sodium and lecithin. The HIP/LIPO delivery system could maintain drug release for more than 5 days in vitro and achieve high analgesic efficacy for more than 10 days in vivo, reducing the side effects associated with high drug doses. The stable HIP/LIPO delivery system is a promising strategy that offers a clinically beneficial alternative for postoperative pain management and other diseases.

Association of serum fatty acid pattern with depression in U.S. adults: analysis of NHANES 2011-2012.

BACKGROUND: Exposure to different concentration levels of fatty acids (FAs) may have an impact on depression. However, previous studies using individual FAs may not reflect the performance of mixtures of various FAs, and the associations of FA patterns with depression remain unclear. METHODS: We conducted the cross-sectional analysis in 792 adults aged 18 and older with available serum FAs and depression screening data in the National Health and Nutrition Examination Survey (NHANES) 2011-2012. The serum concentrations of thirty FAs were measured using gas chromatography-mass spectrometry and their percentage compositions were subsequently calculated. Depression was defined as the Patient Health Questionnaire-9 score ≥ 10. We employed principal component analysis to derive serum FA patterns. We examined the association between these patterns and depression in the overall population and various subgroups through survey-weighted logistic regression. RESULTS: Four distinct patterns of serum FAs were identified: 'high eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); low docosatetraenoic acid (DTA) and docosapentaenoic acid (DPA) n-6', 'high long-chain saturated FA and long chain FA', 'low median-chain saturated FA and myristoleic acid' and 'low capric acid and lauric acid; high gamma-linolenic acid (GLA) and stearidonic acid (SDA)' pattern. Individuals in the high tertile of 'high EPA and DHA; low DTA and DPA n-6' pattern score had 0.46 (95% CI: 0.22, 0.93) lower odds of developing depression compared to individuals in the lowest tertile after adjusting for confounders such as age, sex, physical activity and total energy intake, etc. The odds ratio (OR) of depression was increased in the population with the highest tertile of 'low capric acid and lauric acid; high GLA and SDA' pattern (OR: 2.45, 95% CI: 1.24, 4.83). In subgroup analyses, we observed that the association between 'high EPA and DHA; low DTA and DPA n-6' and depression persisted among specific demographic and lifestyle subgroups, including females, non-Mexican Americans, non-obese, those aged over 60 years, smokers and drinkers. Similarly, 'low capric acid and lauric acid; high GLA and SDA' showed stable associations in female, non-Mexican Americans and smokers. CONCLUSIONS: Serum FA patterns are associated with depression, and their relationships vary across sex, race, BMI, age, smoking and drinking subgroups, highlighting the importance of considering specific FA patterns within these demographic and lifestyle categories. Utilization of combined FA administration may serve as a mitigation measure against depression in these specific populations.

10-hydroxy decanoic acid, trans-10-hydroxy-2-decanoic acid, and sebacic acid: Source, metabolism, and potential health functionalities and nutraceutical applications.

The popularity of royal jelly (RJ) as a functional food has attracted attention from various industries, especially nutraceuticals, due to the increasing demand from health enthusiasts. Sebacic acid, 10-hydroxy decanoic acid, and trans-10-hydroxy-2-decanoic acid are the primary medium-chain fatty acids (MCFAs) within RJ responsible for their health benefits. This review aims to consolidate information on these MCFAs' metabolic relationship and health functionalities in nutraceutical applications. We also investigated the natural characteristics mediated by these MCFAs and their metabolism in organisms. Finally, the production of these MCFAs using conventional (from castor oil) and alternative (from RJ) pathways was also discussed. This review can be a reference for using them as functional ingredients in nutraceutical industries.

Positive Associations of Perfluoroalkyl and Polyfluoroalkyl Substances With Hypertension May Be Attenuated by Endogenous Sex Hormones: A Nationally Representative Cross-Sectional Study.

BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substance (PFAS) has endocrine-disrupting properties and may affect blood pressure. Endogenous hormones also play a crucial role in the progression of hypertension. However, their interaction with hypertension remains to be explored. METHODS: This study included 10 794 adults aged ≥18 years from the China National Human Biomonitoring program. Weighted multiple logistic regression and linear regression were used to examine the associations of serum PFAS with hypertension, diastolic blood pressure, and systolic blood pressure. Joint effects of PFAS mixtures on hypertension, diastolic blood pressure, and systolic blood pressure were evaluated using quantile-based g-computation. Additive and multiplicative interactions were used to assess the role of PFAS with testosterone and estradiol on hypertension. RESULTS: The prevalence of hypertension in Chinese adults was 35.50%. Comparing the fourth quartile with the first quartile, odds ratio (95% CI) of hypertension were 1.53 (1.13-2.09) for perfluorononanoic acid, 1.40 (1.03-1.91) for perfluorodecanoic acid, 1.34 (1.02-1.78) for perfluoroheptane sulfonic acid, and 1.46 (1.07-1.99) for perfluorooctane sulfonic acid. Moreover, PFAS mixtures, with perfluorononanoic acid contributing the most, were positively associated with hypertension, diastolic blood pressure, and systolic blood pressure. PFAS and endogenous hormones had an antagonistic interaction in hypertension. For example, the relative excess risk ratio, attributable proportion, and synergy index for perfluorononanoic acid and estradiol were -3.61 (-4.68 to -2.53), -1.65 (-2.59 to -0.71), and 0.25 (0.13-0.47), respectively. CONCLUSIONS: Perfluorononanoic acid, perfluorodecanoic acid, perfluoroheptane sulfonic acid, perfluorooctane sulfonic acid, and PFAS mixtures showed positive associations with hypertension, systolic blood pressure, and diastolic blood pressure. Positive associations of PFAS with hypertension might be attenuated by increased levels of endogenous sex hormones.

Enzymatic Synthesis and Characterization of MLM-type Structured Lipid Using Grapeseed Oil and Capric Acid.

The objectives were to optimize the reaction conditions for C10:0 incorporation into grapeseed (GS) oil, characterize the structured lipid (SL) product, and study the changes in antioxidant activity of the SL. Taguchi method was used to optimize C10:0 incorporation by combining parameters in a total of 9 experiments. Lipozyme ® RM IM (Rhizomucor miehei immobilized lipase) and Lipozyme ® 435 (Candida antarctica recombinant immobilized lipase) were used as biocatalysts for the acidolysis reactions. C10:0 incorporation and triacylglycerol (TAG) species of the SL were analyzed to determine optimal conditions and enzyme type that gave higher incorporation. The optimal conditions were the same for both enzymes as follows: substrate molar ratio 1:3 (GS oil: C10:0), enzyme load 5% (w/w) of substrates, temperature 65℃, and time 12 h. HPLC analysis of SL gave MLM-type TAG species of 11.51±0.11 mol% and 12.68±0.34 mol% for Lipozyme ® RM IM and Lipozyme ® 435, respectively. GC analysis indicated that C10:0 incorporated at the sn-1,3 positions of the SL were 46.03±0.55 mol% and 47.28±1.22 mol%, respectively, for Lipozyme ® RM IM and Lipozyme ® 435. However, the total C10:0 incorporated into TAG species with Lipozyme ® RM IM was significantly higher (60.08±0.04 mol%) compared to 50.78±0.44 mol% for Lipozyme ® 435. Scaled-up (300 g) acidolysis reaction and characterization were done on SL synthesized using Lipozyme ® RM IM. SL reaction product was purified using short path distillation and fully characterized in terms of lipid classes, tocopherol, thermal behavior, and oxidative stability. The yield of purified scaled-up SL after short path distillation (SPD) was 72.96 wt%. The antioxidant in SL was reduced after SPD due to loss of tocopherols. This MLM-type-SL synthesized within 12 h using Lipozyme ® RM IM had a high content of C10:0 and may have functional and health benefits.

Association of diet with per- and polyfluoroalkyl substances in plasma and human milk in the New Hampshire Birth Cohort Study.

Per- and polyfluoroalkyl substances (PFAS) are related to various adverse health outcomes, and food is a common source of PFAS exposure. Dietary sources of PFAS have not been adequately explored among U.S. pregnant individuals. We examined associations of dietary factors during pregnancy with PFAS concentrations in maternal plasma and human milk in the New Hampshire Birth Cohort Study. PFAS concentrations, including perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), and perfluorodecanoate (PFDA), were measured in maternal plasma collected at ∼28 gestational weeks and human milk collected at ∼6 postpartum weeks. Sociodemographic, lifestyle and reproductive factors were collected from prenatal questionnaires and diet from food frequency questionnaires at ∼28 gestational weeks. We used adaptive elastic net (AENET) to identify important dietary variables for PFAS concentrations. We used multivariable linear regression to assess associations of dietary variables selected by AENET models with PFAS concentrations. Models were adjusted for sociodemographic, lifestyle, and reproductive factors, as well as gestational week of blood sample collection (plasma PFAS), postpartum week of milk sample collection (milk PFAS), and enrollment year. A higher intake of fish/seafood, eggs, coffee, or white rice during pregnancy was associated with higher plasma or milk PFAS concentrations. For example, every 1 standard deviation (SD) servings/day increase in egg intake during pregnancy was associated with 4.4 % (95 % CI: 0.6, 8.4), 3.3 % (0.1, 6.7), and 10.3 % (5.6, 15.2) higher plasma PFOS, PFOA, and PFDA concentrations respectively. Similarly, every 1 SD servings/day increase in white rice intake during pregnancy was associated with 7.5 % (95 % CI: -0.2, 15.8) and 12.4 % (4.8, 20.5) greater milk PFOS and PFOA concentrations, respectively. Our study suggests that certain dietary factors during pregnancy may contribute to higher PFAS concentrations in maternal plasma and human milk, which could inform interventions to reduce PFAS exposure for both birthing people and offspring.

Study on multiscale structures and digestibility of cassava starch and medium-chain fatty acids complexes using molecular simulation techniques.

Effect of complexation of three medium-chain fatty acids (octanoic, decylic and lauric acid, OA, DA and LA, respectively) on structural characteristics, physicochemical properties and digestion behaviors of cassava starch (CS) was investigated. Current study indicated that LA was more easily to combine with CS (complex index 88.9%), followed by DA (80.9%), which was also consistent with their corresponding complexed lipids content. Following the investigation of morphology, short-range ordered structure, helical structure, crystalline/amorphous region and fractal dimension of the various complexes, all cassava starch-fatty acids complexes (CS-FAs) were characterized with a flaked morphology rather than a round morphology in native starch (control CS). X-ray diffraction demonstrated that all CS-FAs had a V-type crystalline structure, and nuclear magnetic resonance spectroscopy confirmed that the complexes made from different fatty acids displayed similar V6 or V7 type polymorphs. Interestingly, small-angle X-ray scattering analysis revealed that α value became greater following increased carbon chain length of fatty acids, indicating the formation of a more ordered fractal structure in the aggregates. Changes in rheological parameters G' and G'' indicated that starch complexed with fatty acids was more likely to form a gel network, but difference among three CS-FAs complexes was significant, which might be contributed to their corresponding hydrophobicity and hydrophilicity raised from individual fatty acids. Importantly, digestion indicated that CS-LA complexes had the lowest hydrolysis degree, followed by the greatest RS content, indicating the importance of chain length of fatty acids for manipulating the fine structure and functionality of the complexes.

Unraveling the link between heavy metals, perfluoroalkyl substances and depression: Insights from epidemiological and bioinformatics strategies.

Heavy metals and per- and polyfluoroalkyl substances (PFASs) have become particularly important when studying the development of depression, a common illness that severely restricts psychosocial functioning and diminishes quality of life. Therefore, the potential joint effects of heavy metal and PFAS exposure on depression, as well as the underlying mechanisms involved, were investigated by using integrated epidemiological and bioinformatic approaches in the present study. A thorough analysis of 7301 samples from the National Health and Nutrition Examination Survey (NHANES) cycles that occurred between 2005 and 2018 was performed. Single-exposure studies have shown that cadmium exposure is positively associated with depression, whereas perfluorooctanesulfonic acid (PFOS) exposure and perfluorodecanoic acid (PFDE) exposure are negatively associated with depression. Furthermore, the Bayesian kernel machine regression (BKMR) and quantile g-computation (QGcomp) models were employed to investigate the collective impact of exposure to mixed metals on depression. Cadmium emerged as the principal contributor to depression. Moreover, the addition of PFAS to the metal mixture had an antagonistic effect on depression, with PFOS having the most prominent influence. Analysis of the effects of co-exposure to cadmium and PFOS confirmed the presence of an antagonistic effect. The inflection points of cadmium and PFOS were determined to be -1.11 and 2.27, respectively. Additionally, exposure to cadmium and PFOS had the opposite effects on two crucial pathways, namely, the rap1 and calcium signaling pathways, which involve core genes related to depression such as ADORA2A, FGF2, and FGFR1. These findings have significant implications for future studies and provide new strategies for exploring the mechanisms underlying co-exposure effects.

Evaluation of the protective effect of capric acid on behavioral and biochemical alterations in valproic acid-induced model of autism.

AIM AND OBJECTIVE: The purpose of the study is to determine the neuroprotective effect of capric acid on sodium valproate-induced model of autism. METHODS: In this study, the effect of CA was observed in animals with single dose of valproic acid (600 mg/kg, i. p.) where the disease condition was confirmed by developmental impairment in pups. Behavioral tests that assess anxiety, depression, stereotypical and repetitive behavior, social interaction, learning and memory, and other confounding variables were performed. Subsequently, oxidative stress parameters, pro-inflammatory cytokine levels and mitochondrial complex activities in the selected brain regions were analyzed. RESULTS: Valproic acid successfully produced autism-like symptoms from post-natal day 7 and also demonstrated impairment in social behavior, learning and memory, and anxiety and depression. Valproic acid was found to produce oxidative stress and neuro-inflammation in the hippocampus, prefrontal cortex, and cerebellum. Treatment with capric acid produced a positive effect on the alterations with maximum effects evident at 400 mg/kg, p. o. through amelioration of behavioral as well as biochemical changes. CONCLUSION: The current study concluded that capric acid could act as a likely candidate for the treatment and management of autism via significant modulation of neurobehavioral parameters, oxidative stress, mitochondrial dysfunction and inflammatory markers.

G-protein-coupled receptor 84 regulates acute inflammation in normal and diabetic skin wounds.

Lipids have emerged as potent regulators of immune cell function. In the skin, adipocyte lipolysis increases the local pool of free fatty acids and is essential for coordinating early macrophage inflammation following injury. Here, we investigate G-protein-coupled receptor 84 (GPR84), a medium-chain fatty acid (MCFA) receptor, for its potential to propagate pro-inflammatory signaling after skin injury. GPR84 signaling was identified as a key component of regulating myeloid cell numbers and subsequent tissue repair through in vivo administration of a pharmacological antagonist and the MCFA decanoic acid. We found that impaired injury-induced dermal adipocyte lipolysis is a hallmark of diabetes, and lipidomic analysis demonstrated that MCFAs are significantly reduced in diabetic murine wounds. Furthermore, local administration of decanoic acid rescued myeloid cell numbers and tissue repair during diabetic wound healing. Thus, GPR84 is a readily targetable lipid signaling pathway for manipulating injury-induced tissue inflammation with beneficial effects on acute diabetic healing.

Neonatal intestinal mucus barrier changes in response to maturity, inflammation, and sodium decanoate supplementation.

The integrity of the intestinal mucus barrier is crucial for human health, as it serves as the body's first line of defense against pathogens. However, postnatal development of the mucus barrier and interactions between maturity and its ability to adapt to external challenges in neonatal infants remain unclear. In this study, we unveil a distinct developmental trajectory of the mucus barrier in preterm piglets, leading to enhanced mucus microstructure and reduced mucus diffusivity compared to term piglets. Notably, we found that necrotizing enterocolitis (NEC) is associated with increased mucus diffusivity of our large pathogen model compound, establishing a direct link between the NEC condition and the mucus barrier. Furthermore, we observed that addition of sodium decanoate had varying effects on mucus diffusivity depending on maturity and health state of the piglets. These findings demonstrate that regulatory mechanisms governing the neonatal mucosal barrier are highly complex and are influenced by age, maturity, and health conditions. Therefore, our results highlight the need for specific therapeutic strategies tailored to each neonatal period to ensure optimal gut health.

Characterizing Important Dietary Exposure Sources of Perfluoroalkyl Acids in Inuit Youth and Adults in Nunavik Using a Feature Selection Tool.

BACKGROUND: Previous studies have identified the consumption of country foods (hunted/harvested foods from the land) as the primary exposure source of perfluoroalkyl acids (PFAA) in Arctic communities. However, identifying the specific foods associated with PFAA exposures is complicated due to correlation between country foods that are commonly consumed together. METHODS: We used venous blood sample data and food frequency questionnaire data from the Qanuilirpitaa? ("How are we now?") 2017 (Q2017) survey of Inuit individuals ≥16 y of age residing in Nunavik (n=1,193). Adaptive elastic net, a machine learning technique, identified the most important food items for predicting PFAA biomarker levels while accounting for the correlation among the food items. We used generalized linear regression models to quantify the association between the most predictive food items and six plasma PFAA biomarker levels. The estimates were converted to percent changes in a specific PFAA biomarker level per standard deviation increase in the consumption of a food item. Models were also stratified by food type (market or country foods). RESULTS: Perfluorooctanesulfonic acid (PFOS), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) were associated with frequent consumption of beluga misirak (rendered fat) [14.6%; 95% confidence interval (CI): 10.3%, 18.9%; 14.6% (95% CI: 10.1%, 19.0%)], seal liver [9.3% (95% CI: 5.0%, 13.7%); 8.1% (95% CI: 3.5%, 12.6%)], and suuvalik (fish roe mixed with berries and fat) [6.0% (95% CI: 1.3%, 10.7%); 7.5% (95% CI: 2.7%, 12.3%)]. Beluga misirak was also associated with higher concentrations of perfluorohexanesulphonic acid (PFHxS) and perfluorononanoic acid (PFNA), albeit with lower percentage changes. PFHxS, perfluorooctanoic acid (PFOA), and PFNA followed some similar patterns, with higher levels associated with frequent consumption of ptarmigan [6.1% (95% CI: 3.2%, 9.0%); 5.1% (95% CI: 1.1%, 9.1%); 5.4% (95% CI: 1.8%, 9.0%)]. Among market foods, frequent consumption of processed meat and popcorn was consistently associated with lower PFAA exposure. CONCLUSIONS: Our study identifies specific food items contributing to environmental contaminant exposure in Indigenous or small communities relying on local subsistence foods using adaptive elastic net to prioritize responses from a complex food frequency questionnaire. In Nunavik, higher PFAA biomarker levels were primarily related to increased consumption of country foods, particularly beluga misirak, seal liver, suuvalik, and ptarmigan. Our results support policies regulating PFAA production and use to limit the contamination of Arctic species through long-range transport. https://doi.org/10.1289/EHP13556.

Thyroid cancer and endocrine disruptive chemicals: a case-control study on per-fluoroalkyl substances and other persistent organic pollutants.

Objective: The aim was to evaluate the possible association between some endocrine disruptive chemicals and thyroid cancer (TC) in an Italian case-control cohort. Methods: We enrolled 112 TC patients and 112 sex- and age-matched controls without known thyroid diseases. Per- and poly-fluoroalkyl substances (PFAS), poly-chlorinated biphenyls (PCBs), and dichlorodiphenyltrichloroethane (4,4'-DDT and 4,4'-DDE) were measured in the serum by liquid or gas chromatography-mass spectrometry. Unconditional logistic regression, Bayesan kernel machine regression and weighted quantile sum models were used to estimate the association between TC and pollutants' levels, considered individually or as mixture. BRAFV600E mutation was assessed by standard methods. Results: The detection of perfluorodecanoic acid (PFDA) was positively correlated to TC (OR = 2.03, 95% CI: 1.10-3.75, P = 0.02), while a negative association was found with perfluorohexanesulfonic acid (PFHxS) levels (OR = 0.63, 95% CI: 0.41-0.98, P = 0.04). Moreover, perfluorononanoic acid (PFNA) was positively associated with the presence of thyroiditis, while PFHxS and perfluorooctane sulfonic acid (PFOS) with higher levels of presurgical thyroid-stimulating hormone (TSH). PFHxS, PFOS, PFNA, and PFDA were correlated with less aggressive TC, while poly-chlorinated biphenyls (PCB-105 and PCB-118) with larger and more aggressive tumors. Statistical models showed a negative association between pollutants' mixture and TC. BRAF V600E mutations were associated with PCB-153, PCB-138, and PCB-180. Conclusion: Our study suggests, for the first time in a case-control population, that exposure to some PFAS and PCBs associates with TC and some clinical and molecular features. On the contrary, an inverse correlation was found with both PFHxS and pollutants' mixture, likely due to a potential reverse causality.