Increase In Liver Weight Research Articles

Histopathological features and metabolic disorders in Tunisian rodent Psammomys obesus fed high-caloric diets

This study aimed at investigating the alteration of lipid serum profile and histopathological damage in Psammomys obesus fed different high calorie diets. Animals were randomly assigned to four groups. P. obesus of the control group were fed with a Low-Calorie natural Diet, the Chenopodicae plant (0.42 kcal/g). The three other groups were fed high calorie diets rich in carbohydrates and protein or rich in carbohydrates and fat (~3.5 - 4.7 kcal/g). Lipid serum profile was assessed bimonthly during seven-month diets. The recorded energy intake was significantly high in the groups fed high calorie diets compared with the control group. Body weight was significantly increased in animal groups fed high calorie diets. All Psammomys obesus fed high-calorie diets developed dyslipidemia with the distinction of different sub-groups developing or not obesity and diabetes. High calorie diets rich in carbohydrates and fat induced a remarkable increase in lipid serum biomarkers indicating a fast induction of dyslipidemia from the first month of the experiment with a significant increase in transaminase activities after two months revealing pronounced hepatotoxicity and nephrotoxicity which were confirmed by a significant increase in liver and kidney relative weight and adiposity index. Severe histological alterations were recorded in obese, diabetic and dyslipidemic Psammomys obesus with a noticeable hypertrophy of the adipocytes, glomeruli and islets of Langerhans, as well as increased hepatic lipid droplet accumulation, apoptosis, necrosis and inflammation. A significant decrease in the thickness of the whole retinal layer was also observed after seven-months diet. Animals fed Low-calorie natural diet don’t show any signs of obesity, dyslipidemia or diabetes. The high calorie diets induced rapid and severe changes in body weight, severe metabolic syndrome and histopathological features causing organ structural and functional injuries. Psammomys obesus seems like an excellent model for studying nutritional pathophysiological-metabolic disorders including obesity, diabetes, dyslipidemia and their complications, particularly diabetic retinopathy, comparable to those of human metabolic processes.

Safety of Elixinol Hemp Extract: In Vitro Genetic Toxicity and Subchronic Toxicity in Rats.

The results of safety studies performed with Elixinol Hemp Extract, a blend of hemp extract, cannabidiol (CBD) isolate, and copaiba containing approximately 65% total CBD, are described in this paper. In a 15-day range-finding study in rats, there were no effects of treatment with up to 101.4 mg/kg bw/day of the extract by gavage on any safety parameter measured in the study, with the exception that centrilobular hepatocellular hypertrophy occurred in all treatment groups, which correlated with increases in absolute liver weight in high-dose females and liver to terminal body weight ratio in mid-dose and high-dose females. A GLP-compliant 90-day OECD Guideline 408 study in rats that included a behavioral battery and a 28-day recovery phase was also conducted with Elixinol Hemp Extract administered by gavage. The doses used in the 90-day study were 0 (vehicle), 28.94, 50.64, and 86.81 mg/kg bw/day. The findings were similar to those observed in the range-finding study. There were no effects of the test material on any test parameter in the 90-day study other than findings related to the liver (increased liver weight in high-dose main study males and mid-dose and high-dose main study females and low incidences of hepatocellular hypertrophy and vacuolation in main study high-dose males). Similar findings were not observed in the recovery animals, and there were no alterations in the clinical chemistry suggestive of liver toxicity in any of the main study or recovery animals. Therefore, the liver outcomes observed in the main study were not considered adverse. The test material also tested negative for mutagenicity in bacterial reverse mutation assays (plate incorporation and preincubation) in the absence and presence of metabolic activation. The results indicate that the oral 90-day no observed adverse effect level (NOAEL) of Elixinol Hemp Extract in rats is 86.81 mg/kg bw/day (highest dose administered), and that the extract is not mutagenic.

Tryptophan Prevents the Development of Non-Alcoholic Fatty Liver Disease.

The main aim of this research is to study the protective effects of tryptophan on the histomorphological and biochemical abnormalities in the liver caused by a high-calorie diet (HCD), as well as its ability to normalize mitochondrial functions in order to prevent the development of non-alcoholic fatty liver disease (NAFLD). The study was conducted in male Wistar rats aged 3 months at the start of the experiment. Control animals (group I) were fed a standard diet. Group II experimental animals were fed a diet with an excess of fat (45%) and carbohydrates (31%) for 12 weeks. Group III experimental animals also received L-tryptophan at a dose of 80 mg/kg body weight in addition to the HCD. The presence of NAFLD, functional activity, physiological regeneration, and the state of the liver parenchyma and connective tissue were assessed using physiological, morphological, histo-morphometric, biochemical, and biophysical research methods. HCD induced the development of NAFLD, which is characterized by an increase in liver weight, hypertrophy of hepatocytes and an increase in the concentration of lipids, cholesterol and triglycerides in liver tissue. Increased alanine aminotransferase activity in the liver of obese rats also confirm hepatocytes damage. Tryptophan added to the diet lowered the severity of NAFLD by reducing fat accumulation and violations of bioelectric properties, and prevented a decrease in mitochondrial ATP synthesis. The addition of tryptophan can have a potential positive effect on the liver, reducing the severity of structural, biochemical, mitochondrial and bioelectric damage caused by HCD.

Contamination of Polycyclic Aromatic Hydrocarbons (PAHs) on Processed Food: A Review

Polycyclic Aromatic Hydrocarbons (PAHs) are wide range of environmental pollutants that commonly contaminate processed food as combustion by-products and constitute a wide range of toxic, carcinogenic, mutagenic adverse health risk. PAHs as an endocrine disruptor can also interfere with the production, release, metabolism, and elimination of unwanted substance in the body or can mimic the occurrence of natural hormones. PAHs formed during food processing largely depends on a number of factors such as type of the food, heating and processing methods. The major sources of PAHs in the environment includes petrogenic, pyrogenic and biological sources. PAHs contamination on processed food via processes such as smoking, roasting, frying or grilling (barbecued) is a function of both the fat content in the food substance and its proximity to the heat source. Studies revealed that eating contaminated food substances can cause reduced pregnancy, foetal reabsorption, gastric neoplasms, increased liver weight, fibrosis, having neurological and carcinogenic risk. PAHs can be removed from the environment via the following processes of either Biodegradation, Photolysis degradation, Dry deposition and/or Wet deposition.

Toxicological Assessment of Higher Olefins in OECD TG 422 Repeated Dose and Reproductive /Developmental Toxicity Screening Tests in Han Wistar Rats.

Higher olefins (HO) are used primarily as intermediates in the production of other chemicals, such as polymers, fatty acids, plasticizer alcohols, surfactants, lubricants, amine oxides, and detergent alcohols. The potential toxicity of five HO (i.e., 1-Octene, Nonene, Decene, Hexadecene, and 1-Octadecene) with carbon ranging from C8 to C18 was examined in a combined repeated dose and reproduction/developmental toxicity screening study (OECD TG 422). These five HO were administered to Han Wistar rats by gavage at 0 (controls), 100, 300, and 1000mg/kg bw/day. As a group of substances, adaptive changes in the liver (liver weight increase without pathological evidence), as well as increased kidney weight in male rats, were observed in HO with carbon numbers from C8 to C10. The overall systemic no observed adverse effect level (NOAEL) for all HO was determined at 1000mg/kg bw/day. In the reproductive/developmental toxicity assessment, offspring viability, size, and weights were reduced in litters from females treated with Nonene at 1000mg/kg bw/day. The overall no observed effects level (NOEL) for reproductive toxicity was considered to be 300mg/kg bw/day for Nonene and 1000mg/kg bw/day for the other four HO, respectively. These data significantly enrich the database on the toxicity of linear and branched HO, allowing comparison with similar data published on a range of linear and branched HO. Comparisons between structural class and study outcome provide further supportive data in order to validate the read-across hypothesis as part of an overall holistic testing strategy.

Modulatory effects of extract of Heinsia crinita against fructose/streptozotocin-induced oxidative stress in diabetic rat models

Oxidative stress plays a crucial role in the development of type 2 diabetes and the associated microvascular and cardiovascular complications. In the study, we have investigated the effects of Heinsia crinita (H. crinita) extracts on lipid peroxidation and oxidative stress responses using diabetic rats. Type 2 diabetes was induced with 10 % fructose/40 mg/kg body weight streptozotocin (STZ). H. crinita extract was administered at 200 and 400 mg/kg body weight twice daily for 21 days, in addition to metformin (MET: 500 mg/kg body weight) control. Molecular docking analysis was performed to determine the binding affinity of H. crinita extracts to the DNA binding domains of peroxisome proliferator-activated receptor (Ppar) and retinoid x receptor (Rxr) protein crystal structures, showing different binding affinities for putative active compounds from the plant. Fasting blood glucose (FBG), body and organ weight changes were determined showing that H. crinita extract induced an anti-hyperglycemic effect in the treated animals, with changes (either decrease or increase) in liver and kidney weights. A decrease in mRNA expression of peroxisome proliferator-activated receptors (ppar), sterol regulatory element-binding protein 1 (srebp-1c), liver x-receptor (lxr), retinoid x receptors (rxr), cytochrome p45041 (cyp4a1) and acyl-CoA oxidase (acox1) in diabetic animals were observed, compared to the control. A dose-specific decrease or increase in antioxidant enzymes (superoxide dismutase: SOD, catalase: CAT, reduced glutathione: GSH, glutathione peroxidase: GPx) transcripts and activity levels were also observed. We also observed exposure-specific decrease or increase of malondialdehyde (MDA) levels. Our data suggested that H. crinita extract possesses protective effects against diabetes-induced oxidative stress. These effects might be attributed to their binding and activation of nuclear receptors, indicating their cellular mode of action that is comparable to MET.

The effect of Abrus cantoniensis Hance on liver damage in mice

The liver is a well-known organ contributing to digestion, hemostasis and detoxification, while liver injury is a world-widely distributed health problem with limited treatment choices. We detected the protective effect of Abrus cantoniensis Hance (ACH) on Carbon tetrachloride-induced (CCl4) liver injury in mice. Fifty ICR (Institute of Cancer Research) animals were grouped into five groups of control (a), CCl4 (d), ACH (25 mg/kg) treated group (c), ACH (50 mg/kg) treated group (b), and ACH (100 mg/kg) treated group (e). Mice in groups d, c, b, and e were given CCl4 every four days, and treated animals received daily ACH supplementation. The results showed that the daily body weights in CCl4-induced animals were slightly lower; however, the weight of ACH-treated mice increased, particularly in the higher dose group. Treatment with CCl4 led to increased liver weight and liver indices in mice, whereas supplementation with ACH reduced both liver weights and liver indices in animals. Histo-pathological analysis indicated that CCl4 led to inflammatory cell infiltration and hepatocellular degeneration, with collagenous fibers proliferation in ICR animals. In contrast, supplementation with ACH prominently decreased inflammatory cells and degeneration of hepatocytes and inhibited collagen fiber hyperplasia. Furthermore, the levels or concentrations of AST (p < 0.0001), ALT (p < 0.0001), MDA (p < 0.0001), IL-1β (p < 0.01), TNF-α (p < 0.01) and IL-6 (p < 0.01) were significantly higher in CCl4 induced ICR animals in group d. However, mice treated with ACH showed lower levels or concentrations of those indices in dose dependent manner. The levels of GSH-px (p < 0.0001), CAT (p < 0.0001) and SOD (p < 0.0001) were significantly reduced in CCl4 group; however, all these three enzymes exhibited significant (p < 0.05) increase in animals supplemented with ACH in dose dependent manner. The microbiome sequencing generated 1,168,327 filtered reads in the mice samples. A notable difference was observed in the composition of 6 phyla and 37 genera among the five ICR animal groups. Supplementation with ACH increased the abundance of beneficial genera of Coprococcus, Blautia and Clostridium, while concurrently decreased the presence of pathogenic genera of Mycoplasma and Helicobacter. In conclusion, we revealed that Abrus cantoniensis Hance has the potential to relieve liver damage induced by CCl4, through the reduction of inflammation, enhancement of antioxidant capacity, and regulation of intestinal microbiota.

Maternal low-protein diet alters hepatic lipid accumulation and gene expression related to glucose metabolism in young adult mouse offspring fed a postweaning high-fat diet

Maternal consumption of low-protein (LP) diet during pregnancy has been demonstrated to increase the chances of adult offspring developing metabolic syndrome, and this risk can be exacerbated when the postnatal diets do not align with the prenatal conditions. However, in our previous study, focusing on serum parameters and gene expression patterns within adipose tissue, we discovered the presence of “healthy obesity” in young adult offspring from dams that were fed an LP, as a response to a postweaning high-fat (HF) diet. Here, we subsequently investigated the role played by the liver and skeletal muscle in alleviation of insulin resistance in male offspring that were fed either control (C/C group) or HF diet (C/HF and LP/HF groups) for 22 weeks. While a postweaning HF diet increased liver weight and hepatic triglyceride (TG) and cholesterol levels in offspring of control dams, these levels were lower in the LP/HF group compared to the C/HF group. Analysis of the liver transcriptome identified 430 differentially expressed genes (DEGs) in the LP/HF and C/HF comparison. Especially, downregulated DEGs were enriched in carbohydrate metabolism and the levels of DEGs were significantly correlated with the levels of markers for serum glucose homeostasis and hepatic lipid accumulation. In the LP/HF group compared to the C/HF group, there was a decrease in the gastrocnemius muscle weight, while no differences were observed in gene expression levels associated with muscle fiber phenotype, mitochondrial function, and inflammation. In conclusion, maternal LP diet induced changes in lipid and glucose metabolism within the liver, similar to what was observed in adipose tissue, while there were no alterations in metabolic functions in the skeletal muscle in young offspring mice fed an HF diet. Further research that investigating the enduring impact of nutritional transition on offspring is essential to gain a comprehensive grasp of developmental programming throughout their entire lifespan.

Comparison of female rat reproductive effects of pubertal versus adult exposure to known endocrine disruptors.

A prevailing challenge when testing chemicals for their potential to cause female reproductive toxicity is the lack of appropriate toxicological test methods. We hypothesized that starting a 28-day in vivo toxicity study already at weaning, instead of in adulthood, would increase the sensitivity to detect endocrine disruptors due to the possibility of including assessment of pubertal onset. We compared the sensitivity of two rat studies using pubertal or adult exposure. We exposed the rats to two well-known human endocrine disruptors, the estrogen diethylstilbestrol (DES; 0.003, 0.012, 0.048 mg/kg bw/day) and the steroid synthesis inhibitor ketoconazole (KTZ; 3, 12, 48 mg/kg bw/day). Specifically, we addressed the impact on established endocrine-sensitive endpoints including day of vaginal opening (VO), estrous cyclicity, weights of reproductive organs and ovarian histology. After 28 days of exposure, starting either at weaning or at 9 weeks of age, DES exposure altered estrous cyclicity, reduced ovary weight as well as number of antral follicles and corpora lutea. By starting exposure at weaning, we could detect advanced day of VO in DES-exposed animals despite a lower body weight. Some endpoints were affected mainly with adult exposure, as DES increased liver weights in adulthood only. For KTZ, no effects were seen on time of VO, but adrenal and liver weights were increased in both exposure scenarios, and adult KTZ exposure also stimulated ovarian follicle growth. At first glance, this would indicate that a pubertal exposure scenario would be preferrable as timing of VO may serve as sensitive indicator of endocrine disruption by estrogenic mode of action. However, a higher sensitivity for other endocrine targets may be seen starting exposure in adulthood. Overall, starting a 28-day study at weaning with inclusion of VO assessment would mainly be recommended for substances showing estrogenic potential e.g., in vitro, whereas for other substances an adult exposure scenario may be recommended.

Brown adipocyte mineralocorticoid receptor deficiency impairs metabolic regulation in diet-induced obese mice

Activation of brown adipose tissue (BAT) contributes to energy dissipation and metabolic health. Although mineralocorticoid receptor (MR) antagonists have been demonstrated to improve metabolism under obesity, the underlying mechanisms remain incompletely understood. We aimed to evaluate the role of BAT MR in metabolic regulation. After 8 weeks of high-fat diet (HFD) feeding, BAT MR KO (BMRKO) mice manifested significantly increased bodyweight, fat mass, serum fasting glucose, and impaired glucose homeostasis compared with littermate control (LC) mice, although insulin resistance and fasting serum insulin were not significantly changed. Metabolic cage experiments showed no change in O2 consumption, CO2 production, or energy expenditure in obese BMRKO mice. RNA sequencing analysis revealed downregulation of genes related to fatty acid metabolism in BAT of BMRKO-HFD mice compared with LC-HFD mice. Moreover, H&E and immunohistochemical staining demonstrated that BMRKO exacerbated HFD-induced macrophage infiltration and proinflammatory genes in epididymal white adipose tissue (eWAT). BMRKO-HFD mice also manifested significantly increased liver weights and hepatic lipid accumulation, an increasing trend of genes related to lipogenesis and lipid uptake, and significantly decreased genes related to lipolytic and fatty acid oxidation in the liver. Finally, the level of insulin-induced AKT phosphorylation was substantially blunted in eWAT but not liver or skeletal muscle of BMRKO-HFD mice compared with LC-HFD mice. These data suggest that BAT MR is required to maintain metabolic homeostasis, likely through its regulation of fatty acid metabolism in BAT and impacts on eWAT and liver.

A ketogenic diet pattern during lactation increases visceral fat, glucose, and cholesterol levels and reduces beneficial fecal bacteria in dams and offspring

A ketogenic diet (KD) is a dietary pattern characterized by high fat, moderate protein, and low carbohydrates. The present study evaluated the effects of a KD with saturated fat content during lactation on biochemical outcomes and selected fecal bacterial groups in dams and offspring. Wistar rat dams were assigned to the experimental groups (control or ketogenic), and pups from both dams received a standard chow diet from weaning until 60 days of age. KD consumption during lactation increased liver weight in dams, glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol in pups and visceral and retroperitoneal fat in both dams and pups. Furthermore, KD increased Enterobacteriaceae and Bacteroides spp. While decreased Lactobacillus spp. and Bifidobacterium spp. counts in the feces of dams and pups. Results show that KD consumption during lactation increased fat deposition, impaired fecal microbial counts in dams, and induced short- and long-term adverse effects on lipid profile and fecal microbial counts in offspring. Findings indicate that consuming a KD with a high saturated fat content during lactation affects biochemical parameters and influences fecal bacteria associated with health in dams and pups.

Refined mackerel oil increases hepatic lipid accumulation and reduces choline and choline-containing metabolites in the liver tissue in mice fed a Western diet

In this study, we aimed to evaluate the impact of consuming refined mackerel oil (MO) from rest raw material on hepatic fat accumulation, glucose tolerance, and metabolomic changes in the liver from male C57BL/6N mice. The mice were fed either a Western diet (WD) or a chow diet, with 30 g or 60 g MO per kg of diet (3% or 6%) for 13 weeks. Body weight, energy intake, and feed efficiency were monitored throughout the experiment. A glucose tolerance test was conducted after 11 weeks, and metabolomic analyses of the liver were performed at termination.Inclusion of MO in the WD, but not in the chow diet, led to increased liver weight, hepatic lipid accumulation, elevated fasting blood glucose, reduced glucose tolerance, and insulin sensitivity. Hepatic levels of eicosapentaenoic and docosahexaenoic acid increased, but no changes in levels of saturated and monounsaturated fatty acids were observed. The liver metabolomic profile was different between mice fed a WD with or without MO, with a reduction in choline ether lipids, phosphatidylcholines, and sphingomyelins in mice fed MO.This study demonstrates that supplementing the WD, but not the chow diet, with refined MO accelerates accumulation of hepatic fat droplets and negatively affects blood glucose regulation. The detrimental effects of supplementing a WD with MO were accompanied by increased fat digestibility and overall energy intake, and lower levels of choline and choline-containing metabolites in liver tissue.

CAR requires Gadd45β to promote phenobarbital-induced mouse liver tumors in early stage.

Phenobarbital (PB) is an archetypal substance used as a mouse hepatocellular carcinoma (HCC) promotor in established experimental protocols. Our previous results showed CAR is the essential factor for PB induced HCC promotion. Subsequent studies suggested Gadd45β, which is induced by PB through CAR activation, is collaborating with CAR to repress TNF-α induced cell death. Here, we used Gadd45β null mice (Gadd45β KO) treated with N-diethylnitrosamine (DEN) at 5 weeks of age and kept the mice with PB supplemented drinking water from 7 to 57 weeks old. Compared with wild type mice, Gadd45β KO mice developed no HCC in the PB treated group. Increases in liver weight were more prominent in wild type mice than KO mice. Microarray analysis of mRNA derived from mouse livers found multiple genes specifically up or down regulated in wild type mice but not null mice in DEN + PB groups. Further qPCR analysis confirmed two genes, Tgfbr2 and irisin/Fndc5, were up-regulated in PB treated wild type mice but no significant increase was observed in Gadd45β KO mice. We focused on these two genes because previous reports showed that hepatic Irisin/Fndc5 expression was significantly higher in HCC patients and that irisin binds to TGF-β receptor complex that includes TGFBR2 subunit. Our results revealed irisin peptide in cell culture media increased the growth rate of mouse hepatocyte-derived AML12 cells. Microarray analysis revealed that irisin-regulated genes in AML12 cells showed a significant association with the genes in the TGF-β pathway. Expression of irisin/Fndc5 and Tgfbr2 induced growth of human HCC cell line HepG2. Thus, Gadd45β plays an indispensable role in mouse HCC development regulating the irisin/Fndc5 and Tgfbr2 genes.

Responses of broiler chickens to incremental levels of water deprivation: Growth performance, carcass characteristics, and relative organ weights

Abstract The objective of the study was to assess the effect of varying levels of water deprivation on growth performance, carcass characteristics, and internal organ weight of broiler chickens. Ninety unsexed Ross 308 chicks 2 weeks old were randomly assigned to five water deprivation periods of 0, 6, 12, 18, and 24 h. Each treatment was replicated three times with six birds per replicate. Broiler chickens were given water ad libitum (0 h) or for 30 min at 6-, 12-, 18-, and 24-h intervals. Average daily feed intake (ADFI), average daily gain (ADG), and feed conversion ratio (FCR) were determined on a weekly basis. A negative linear relationship (P &lt; 0.05) existed between water deprivation and ADFI. The increase in water deprivation level resulted in ADFI decreasing at an increasing rate. The R 2 value was 0.94. There was no relationship between water deprivation on ADG and FCR (P &gt; 0.05). There was a quadratic relationship between water deprivation and cold dress mass (CDM) and warm dress mass. As the level of water deprivation increased, there were linear increases in relative weight of gizzard, spleen, heart, lungs, liver, and gastrointestinal tract (P &lt; 0.001). The organ weights of the broiler chickens revealed the ability of birds to withstand of up to 24 h. Using differential of quadratic equations, the maximum time of water deprivation that did not negatively affect CDM was estimated to be 4 h.

Validating Rat Model of Polycystic Ovary Syndrome Induced Non-Alcoholic Fatty Liver Disease: Role of Hyperandrogenism and Insulin Resistance

Background Polycystic ovary syndrome (PCOS) is a highly prevalent endocrinemetabolic disorder. PCOS is frequently associated with abdominal adiposity, insulin resistance, and cardiovascular risk factors. Increased prevalence of NAFLD has been reported in patients with PCOS. Aim to validate a model of PCO induced NAFLD and determine the role of androgen and insulin resistance in the model pathogenesis. Material and Method Testosterone Enanthate (TE) was used to induce PCOS in female wistar rats by receiving TE subcutaneously at a dose of 7.5 mg dissolved in sesame oil by S.C. injection daily from embryonic day 16 (E16) to E19, female offsprings are divided into; control group, model group. Results PCO produced significant increase in body weight, liver weight, ALT/AST ratio, testosterone (T), Luteinizing hormone (LH), fasting glucose, serum insulin, HOMA-IR and serum c-peptide with dyslipidemia and decrease in serum estradiol (E2) level. The picture of PCOS and NAFLD was clearly seen biochemically and histologically. Conclusion our study validated the model of PCO induced NAFLD as manifested by the biochemical and histological analysis. .

Comparative Toxicity of Seven Aqueous Film-Forming Foam to In Vitro Systems and Mus.

The comparative toxicity of six per- and polyfluoroalkyl substance (PFAS)-free and one PFAS-containing aqueous film-forming foam (AFFF) was evaluated in an outbred mouse species as well as several in vitro assays. The in vivo toxicological profile of PFAS-free AFFFs in short-term, high-concentration exposures is different than that of a PFAS-containing AFFF. The PFAS-containing reference product induced increased liver weights, while the PFAS-free AFFFs were linked to either decreased or unaffected relative liver weights. The in vitro toxicological profile across PFAS-free AFFFs was uniform except in the Microtox® assay, where thresholds were variable and spanned several orders of magnitude. This direct comparison of products through short-term toxicity tests and in vitro screenings represents early data to support evaluation of potential regrettable substitutions when selecting alternative PFAS-free AFFFs. Further work in diverse taxa (e.g., aquatic organisms, terrestrial invertebrates, birds) and mammalian studies capturing sensitive life stages will refine and expand this data set across a range of risk-relevant toxicological endpoints. Environ Toxicol Chem 2023;42:2364-2374. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.

An evaluation of the genotoxicity and 90-day repeated-dose toxicity of a CBD-rich hemp oil.

Currently, there is much interest in the sales and study of consumable Cannabis sativa L. products that contain relatively high levels of cannabidiol (CBD) and low levels of Δ-9-tetrahydrocannabinol. While there are published safety evaluations for extracts containing low concentrations of CBD, toxicological assessments for those with higher concentrations are still scant in the public domain. In this paper, genotoxicity tests and a 90-day repeated-dose toxicity study of an ethanolic extract of C. sativa containing ~85% CBD were performed following relevant OECD guidelines. No increased gene mutations were observed in a bacterial reverse mutation assay compared to controls up to the maximum recommended concentration of the guideline. An in vitro chromosomal aberration assay showed no positive findings in the short-term (3 h) treatment assays. Long-term treatment (20 h) showed an increased number of cells containing aberrations at the highest dose of 2 μg/mL, which was outside of historical control levels, but not statistically significantly different from the controls. An in vivo micronucleus study showed no genotoxic potential of the test item in mice. A 90-day repeated-dose gavage study using 0, 75, 125, and 175 mg/kg bw/day showed several slight findings that were considered likely to be related to an adaptive response to consumption of the extract by the animals but were not considered toxicologically relevant. These included increases in liver and adrenal weights compared to controls. The NOAEL was determined as 175 mg/kg bw/day, the highest dose tested (equivalent to approximately 150 mg/kg bw/day of CBD).

Productive Performance, Physiological Variables, and Carcass Quality of Finishing Pigs Supplemented with Ferulic Acid and Grape Pomace under Heat Stress Conditions.

The effect of individual and combined supplementation of FA and GPM on physiological variables, productive performance, and carcass characteristics of finishing pigs under heat stress conditions were investigated. Forty Yorkshire × Duroc pigs (80.23 kg) were individually housed and randomly distributed into 4 groups under a 2 × 2 factorial arrangement (n = 10): Control (basal diet, BD); FA, BD + 25 mg FA; GPM, BD with 2.5% GPM; and MIX, BD with 25 mg FA and 2.5% GPM. Additives were supplemented for 31 days. The inclusion of FA or GPM did not modify rectal temperature and respiratory rate. There was an effect of the interaction on FI, which increased when only GPM was supplemented, with respect to Control and MIX (p < 0.05). Average daily gain (ADG) and feed conversion (FC) were not affected by treatments (p > 0.05). The inclusion of FA improved hot and cold carcass weight, while the addition of GPM decreased the marbling (p < 0.05) and tended to increase loin area (p < 0.10). GPM increased liver weight (p < 0.05). The addition of GPM and FA can improve some carcass characteristics under heat stress conditions. It is necessary to continue investigating different levels of inclusion of GPM and FA in finishing pigs' diets.

Hepatic and ovarian effects of perfluorooctanoic acid exposure differ in lean and obese adult female mice

Obesity and overweight cause poor oocyte quality, miscarriage, infertility, polycystic ovarian syndrome, and offspring birth defects and affects 40% and 20% of US women and girls, respectively. Perfluorooctanoic acid (PFOA), a per- and poly-fluoroalkyl substance (PFAS), is environmentally persistent and has negative female reproductive effects including endocrine disruption, oxidative stress, altered menstrual cyclicity, and decreased fertility in humans and animal models. PFAS exposure is associated with non-alcoholic fatty liver disease which affects ∼24–26% of the US population. This study investigated the hypothesis that PFOA exposure impacts hepatic and ovarian chemical biotransformation and alters the serum metabolome. At 7 weeks of age, female lean, wild type (KK.Cg-a/a) or obese (KK.Cg-Ay/J) mice received saline (C) or PFOA (2.5 mg/Kg) per os for 15 d. Hepatic weight was increased by PFOA exposure in both lean and obese mice (P < 0.05) and obesity also increased liver weight (P < 0.05) compared to lean mice. The serum metabolome was also altered (P < 0.05) by PFOA exposure and differed between lean and obese mice. Exposure to PFOA altered (P < 0.05) the abundance of ovarian proteins with roles in xenobiotic biotransformation (lean - 6; obese - 17), metabolism of fatty acids (lean – 3; obese - 9), cholesterol (lean – 8; obese – 11), amino acids (lean – 18; obese – 19), glucose (lean – 7; obese – 10), apoptosis (lean – 18; obese – 13), and oxidative stress (lean – 3; obese – 2). Use of qRT-PCR determined that exposure to PFOA increased (P < 0.05) hepatic Ces1 and Chst1 in lean but Ephx1 and Gstm3 in obese mice. Also, obesity basally increased (P < 0.05) Nat2, Gpi and Hsd17b2 mRNA levels. These data identify molecular changes resultant from PFOA exposure that may cause liver injury and ovotoxicity in females. In addition, differences in toxicity induced by PFOA exposure occurs in lean and obese mice.

1688-P: Glucokinase Activator Triggers PERK-UPR Pathway in Diet-Induced Obese Mice via Inducing Hepatic Lipid Accumulation

Background: To investigate the effect of glucokinase activation on glucose and lipid metabolism in diet-induced obese mice. Methods: Mice fed with High-fat-diet (HFD) or control diet for 16 weeks were subjected to glucokinase activator (GKA) or vehicle treatment by gavage for 4 weeks. Glucose tolerance tests were performed to evaluate the glucose-lowering effect of GKA. Hepatic lipid accumulation was assessed by H&amp;E, Oil-red’O staining, and transmission electronic microscopy. The underlying mechanism and subsequent effects of glucokinase activation-induced lipid accumulation was analyzed in liver. Protein levels of related genes were analyzed in mouse livers or AML12 cells. Results: Glucokinase activation improved glucose tolerance and insulin sensitivity in obese mice. Moreover, increased liver weight and TG Content were found in GKA-treated obese mice. Significant hepatic lipid accumulation was observed by multiple assays. RNA sequencing analysis indicated the increased expression of lipogenesis genes and activated PERK-UPR pathway in the liver. Inhibition of the lipogenesis-related gene Acc reduced the lipid levels caused by GKA treatment and alleviated PERK-UPR pathway in AML12 cell line. Conclusions: Glucokinase activation improved glucose tolerance while induced hepatic lipid accumulation through increased lipogenesis, which subsequently triggered PERK-UPR signaling pathway. Disclosure N.Cai: None. L.Zeng: None. X.Chen: None. J.Liu: None. Z.Wen: None. S.Wen: None. W.Zeng: None. S.Lin: None. Y.Chen: None. G.Shi: None. Funding National Natural Science Foundation of China (81770826, 82070811); National Key R&amp;D Program of China (2017YFA0105803); Key Area R&amp;D Program of Guangdong Province (2019B020227003); Sci-Tech Research Development Program of Guangzhou City (202201020497); Natural Science Foundation of Guangdong Province (2018B030311012)