Effects of α-olefin sulfonate (AOS) on Tubifex tubifex: toxicodynamic-toxicokinetic inferences from the general unified threshold (GUTS) model, biomarker responses and molecular docking predictions.

We investigated the potential ecological risks and harm to aquatic organisms posed by anionic surfactants such as α-olefin sulfonate (AOS), which are commonly found in industrial and consumer products, including detergents. This study assessed acute (96-h) and subchronic (14-day) responses using antioxidant activity, protein levels, and histopathological changes in Tubifex tubifex exposed to different AOS concentrations (10% of the LC50, 20% of the LC50, and a control). Molecular docking was used to investigate the potential interactions between the key stress biomarker enzymes (superoxide dismutase, catalase, and cytochrome c oxidase) of Tubifex tubifex. Acute AOS exposure showed a concentration-dependent decrease in survival, and the general unified threshold (GUTS) model revealed that survivorship is linked to individual response patterns rather than random (stochastic) fluctuations. The GUTS model also revealed dose-dependent toxicity patterns in Tubifex tubifex exposed to α-olefin sulfonate (AOS), with adaptive mechanisms at lower concentrations but significant increases in mortality beyond a certain threshold, emphasizing the role of the AOS concentration in shaping its toxicological impact. Exposure to AOS disrupted antioxidant activity, inducing oxidative stress, with GST and GPx showing positive associations with surfactant concentration and increased lipid peroxidation (elevated MDA levels); moreover, AOS exposure decreased protein concentration, signifying disturbances in vital cellular processes. Histopathological examinations revealed various tissue-level alterations, including cellular vacuolation, cytoplasmic swelling, inflammation, necrosis, and apoptosis. Molecular docking analysis demonstrated interactions between AOS and enzymes (-catalase, superoxide dismutase, and cytochrome c oxidase) in Tubifex tubifex, including hydrophobic and hydrogen bond interactions, with the potential to disrupt enzyme structures and activities, leading to cellular process disruptions, oxidative stress, and tissue damage. According to the species sensitivity distribution (SSD), the difference in toxicity between Tilapia melanopleura (higher sensitivity) and Daphnia magna (low sensitivity) to AOS suggests distinct toxicokinetic and toxicodynamic mechanisms attributable to more complex physiology in Tilapia and efficient detoxification in Daphnia due to its smaller size.

Oxidative DNA damage and multi-organ pathologies in male mice subchronically treated with aflatoxin B1.

Although the acute and/or chronic exposure to AFB1 has been widely investigated, the study on the toxic effects resulted from the subchronic exposure of AFB1 which is more close to the real scenario in view of the regional and seasonal characters of aflatoxin-producing strains is still limited. To understand the subchronically toxic effects of AFB1, we studied the AFB1-induced oxidative damage, reproductive impairment as well as their potential correlations and mechanisms at the molecular level. Generally, our results showed that subchronic exposure of AFB1 gave rise to pathological and oxidative damages in mice, disrupted oxidation-reduction homeostasis, activated mitochondrial apoptotic and p53-regulated signaling pathways, induced DNA and chromosomal damages and increased the rate of sperm malformation. Importantly, reproductive toxic effects were detected in AFB1-treated mice under a subchronic exposure, which was evidenced by the ascended sperm malformation. Based on our pilot study, it's speculated that the partial mechanism of reproductive toxicity may be the oxidative damages, especially DNA damages directly induced by AFB1. In short, our study demonstrated that severe damages can be caused even by a subchronic exposure as well as hinted that reproductive toxicity also should be taken into consideration when conducting risk assessments of the subchronic exposure of AFB1.

Efficacy assessment of co-treated alpha-ketoglutarate and N-acetyl cysteine against the subchronic toxicity of cyanide in rats.

Cyanide is an important industrial pollutant, major occupational hazard, and a potential chemical warfare agent. Its intentional or accidental exposure to humans is a big clinical problem because of its rapid mode of action. Certain plant origin foods also contain substantial amount of cyanide and cause chronic toxicity. This study explores the protective efficacy of co-treatment of alpha-ketoglutarate (AKG) and an antioxidant N-acetyl cysteine (NAC) against toxicity of subchronically exposed cyanide in rats. We explore the effect of AKG + NAC co-treatment on oxidative stress, inflammation, and histological changes induced due to long-term sublethal cyanide exposure. Cyanide induces oxidative stress by inhibiting metalloenzymes (catalase and superoxide dismutase) causing increase in lipid peroxidation (malondialdehyde) and decrease in reduced glutathione (GSH). It also increases the activity of cyclo-oxygenase enzymes causing oxidative stress-mediated inflammation in the brain. Cyanide exposure also causes degenerative changes in the brain as shown in histology. It also causes pathology in liver and kidney. AKG is known to form cyanohydrins with cyanide reducing the free cyanide levels, and its combination with NAC showed overall improvement in by reducing the oxidative stress and subsequent neuroinflammation. Their combination was also found to improve the histological outcome of vital tissues. AKG, an over-the-counter sport medicine, and the antioxidant NAC per se did not show any detrimental effects in any tested parameter. Hence, oral treatment with AKG and NAC can be beneficial for the treatment of chronic cyanide poisoning.

Respiratory Health and Lung Function in Children Exposed to the World Trade Center Disaster.

OBJECTIVES: To compare lung function in a representative sample of World Trade Center (WTC)-exposed children with matched comparisons, and examine relationships with reported exposures. STUDY DESIGN: Study population consisted of 402 participants. Oscillometry, spirometry, and plethysmography were performed on WTC Health Registry (WTCHR) respondents who were ≤8 years of age on September 11, 2001 (n = 180) and a sociodemographically matched group of New York City residents (n = 222). We compared lung function by study arm (WTCHR and comparison group) as well as dust cloud (acute); home dust (subchronic); and other traumatic, nondust exposures. RESULTS: In multivariable models, post-9/11 risk of incident asthma was higher in the WTCHR participants than in the comparison group (OR 1.109, 95% CI 1.021, 1.206; P = .015). Comparing by exposure rather than by group, dust cloud (OR 1.223, 95% CI 1.095, 1.365; P < .001) and home dust (OR 1.123, 95% CI 1.029, 1.226; P = .009) exposures were also associated with a greater risk of incidence of post-9/11 asthma. No differences were identified for lung function measures. CONCLUSIONS: Although we cannot exclude an alternative explanation to the null findings, these results may provide some measure of reassurance to exposed children and their families regarding long-term consequences. Further study with bronchodilation and/or methacholine challenge may be needed to identify and further evaluate effects of WTC exposure. Biomarker studies may also be more informative in delineating exposure-outcome relationships. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02068183.

Subchronic bisphenol S exposure affects liver function in mice involving oxidative damage.

Bisphenol S (BPS) has been widely used in the manufacturing industry as a substitute for bisphenol A (BPA). Emerging evidences, mostly from in vitro studies, suggest that BPS may exert a variety of toxicological effects and have the potential to induce oxidative stress. Nevertheless, few data are available for the in vivo effects of BPS on liver, an important target of drug toxicity. For the first time, our study systematically investigated the effects of BPS at a wide range of doses on liver function in mice upon oral administration. We found that treatment with 5000 µg/kg BPS for 8 weeks resulted in liver injury with increased plasma levels of alanine aminotransferase, aspartate aminotransferase and total bilirubin, as well as defects in hepatic morphology. Moreover, such exposure to BPS induced oxidative stress in the liver of mice by decreasing activities of antioxidant enzymes, and increasing lipid peroxidation level and expression of two biomarker genes, HO-1 and GADD45B. No significant changes were observed for treatment with lower doses (5-500 µg/kg) or shorter duration (4 weeks). In conclusion, subchronic BPS exposure could affect liver function in mice by inducing oxidative damage, indicating that BPS may be not an absolutely safe alternative to BPA.

Association between subchronic and chronic lead exposure and levels of antioxidants and chemokines.

PURPOSE: This study aimed to compare the influence of lead on the non-enzymatic antioxidant defenses and the levels of chemokines in workers subchronically and chronically exposed to lead. METHODS: The study population was divided into three groups. The first group consisted of male workers subchronically exposed to lead for 40 ± 3.2 days, while the second group included male workers chronically exposed to lead. The third group was a control group. RESULTS: The levels of uric acid and bilirubin were significantly higher after a subchronic exposure to lead compared to the baseline by 22 and 35 %, respectively. Similarly, the values of total antioxidant capacity (TAC), total oxidant status (TOS), and oxidative stress index (OSI) increased by 15, 50, and 33 %, respectively. At the same time, the levels of thiol groups and albumin decreased by 5 and 8 %, respectively. Additionally, the levels of interleukin-8 (IL-8) and macrophage inflammatory protein-1ß (MIP-1ß) were significantly higher after a subchronic exposure to lead compared to the baseline by 34 and 20 %, respectively. Moreover, IL-8 level was significantly higher by 40 % in the group of workers chronically exposed to lead than in the control group, while the level of interferon gamma-induced protein-10 (IP-10) was significantly lower by 28 %. CONCLUSIONS: Similar to chronic lead exposure, subchronic exposure to lead is associated with elevated blood levels of uric acid and bilirubin in humans. This probably results in increased TAC value despite thiol depletion. However, the compensatory activation of non-enzymatic antioxidant defenses seems to be insufficient to protect against lead-induced oxidative stress, which may be additively enhanced by the pro-inflammatory action of chemokines, especially IL-8.

Cyanobacterium producing cylindrospermopsin cause histopathological changes at environmentally relevant concentrations in subchronically exposed tilapia (Oreochromis niloticus).

The acute toxicity of cylindrospermopsin (CYN) has been established in rodents, based on diverse intraperitoneal an oral exposure studies and more recently in fish. But no data have been reported in fish after subchronic exposure to cyanobacterial cells containing this cyanotoxin, so far. In this work, tilapia (Oreochromis niloticus) were exposed by immersion to lyophilized Aphanizomenon ovalisporum cells added to the aquaria using two concentration levels of CYN (10 or 100 µg CYN L(-1)) and deoxy-cylindrospermopsin (deoxy-CYN) (0.46 or 4.6 µg deoxy-CYN L(-1)), during two different exposure times: 7 or 14 d. This is the first study showing damage in the liver, kidney, hearth, intestines, and gills of tilapia after subchronic exposure to cyanobacterial cells at environmental relevant concentrations. The major histological changes observed were degenerative processes and steatosis in the liver, membranous glomerulopathy in the kidney, myofibrolysis and edema in the heart, necrotic enteritis in the gastrointestinal tract, and hyperemic processes in gill lamellae and microhemorrhages. Moreover, these histopathological findings confirm that the extent of damage is related to the CYN concentration and length of exposure. Results from the morphometric study indicated that the average of nuclear diameter of hepatocytes and cross-sections of proximal and distal convoluted tubules are useful to evaluate the damage induced by CYN in the main targets of toxicity.

Behavioural and Electrophysiological Evidence of Impaired Learning and Memory in Male Sprague Dawley Rats following Subchronic Exposure to Standardised Methanolic Extract of Mitragyna speciosa Korth.

BACKGROUND: Mitragyna speciosa (MS) or ketum is primarily found in Southeast Asia, particularly in northern Malaysia and Thailand. The medicinal value of this plant has attracted significant attention from both herbal medicine practitioners and scientists worldwide. Despite having illegal consumption status, the plant merits study. We conducted a series of experiments to test our hypothesis that ketum impairs both learning and memory in rats. METHODS: Ketum leaves were extracted using methanol and standardised for the amount of its pure compound, mitragynine. Rats were divided into groups for a passive avoidance task and long-term potentiation (LTP) extracellular recording. In the extracellular recording condition, rats were grouped into control, MS100 (100 mg/kg of ketum extract), MS200 (200 mg/kg of ketum extract), and MS500 (500 mg/kg of ketum extract) groups. An additional group that received morphine was included in the passive avoidance task (10 mg/kg), and there were six animals per group. Rats received daily treatments orally for 28 days for both experiments. RESULT: Using a passive avoidance task, our data revealed that the rats' memory significantly increased with increasing doses of MS compared to the morphine-treated group. Our findings from LTP recordings showed that LTP was fully blocked by the higher doses of MS. CONCLUSION: We speculate on the possibility that additional factors were involved in the passive avoidance task because it was an in vivo animal study, while the LTP experiment solely involved brain slices.

Subchronic neurotoxicity of chlorpyrifos, carbaryl, and their combination in rats.

Anticholinesterase pesticides have been widely used in agricultural and domestic settings and can be detected in the environment after long-term use. Although the acute toxic effects of chlorpyrifos and carbaryl have been well described, little is known about the chronic toxicity of the pesticides mixture. To investigate their chronic neurotoxicity, Wistar rats were exposed to chlorpyrifos, carbaryl, and their mixture (MIX) for 90 consecutive days. The activities of serum cholinesterase (ChE) as well as acetylcholinesterase (AChE) and neuropathy target esterase (NTE) in nerve tissues were determined. Furthermore, the histopathological examination was carried out. The results showed that ChE activity significantly decreased in all treated rats except the rats treated with low dose carbaryl. Treatment with middle- and high-dose chlorpyrifos and MIX in rats significantly inhibited AChE activity in the central nervous tissues, whereas treatment with carbaryl alone did not. In sciatic nerve, AChE activity was significantly inhibited by high-dose carbaryl and MIX, but not by chlorpyrifos alone. No significant NTE inhibition was observed in all treatment groups. Histopathological examination revealed that both chlorpyrifos and MIX treatment induced hippocampal damage. However, no obvious hippocampal damage was found in carbaryl-treated rats. Carbaryl and MIX, but not chlorpyrifos alone, induced pathological damage of sciatic nerve. Taken together, all of the results indicated that chlorpyrifos and carbaryl have different toxicological target tissues in nervous system and showed corresponding effects in the nervous tissues, which may reflect the different sensitivity of central and peripheral nervous tissues to different pesticides individually and in combination.

Genotoxicity of Formaldehyde: Effect of Whole-Body Exposure on Polychromatic Erythrocyte/Normochromatic Erythrocyte Ratio in Male and Female Rats.

Every day, millions of individuals are exposed to formaldehyde (FA) due to its extensive presence and versatile use. Many in vivoand in vitroexperiments revealed that the mechanism of genotoxicity induced by FA exposure is complex yet toxicity upon whole-body exposure (WBE) to FA is less. As teachers, students, and skilled assistants in the health care sectors are also extensively exposed to FA vapors, it might result in genotoxicity. However, the effects of subchronic exposure to FA at low concentrations are not clear. Hence, analysis of the micronucleus (MN) was necessary to study the genetic toxicity triggered by FA in the bone marrow of male and female experimental rats. The present study is a gender- and duration of exposure-based assessment of the geno- and cytotoxicity in bone marrow cells of Wistar rats to study the effect of WBE to 10% FA on polychromatic erythrocytes/normochromatic erythrocytes (PCE/NCE) ratio and micronucleated polychromatic erythrocytes (MnPCE) in experimental rats. The obtained result clearly showed that WBE to FA for 60 days at concentrations between 1 and 1.1 ppm (0, 1, and 1.5 h) induced genotoxic effects in both male and female rats by altering the MnPCE% and significantly increasing the ratio of PCE/NCE (1.07 ± 0.23, 1.20 ± 0.20, 1.22 ± 0.14). The PCE/NCE ratio in male rats was lesser (0.98, 1.12, and 1.18) when compared with female rats (1.17, 1.29, and 1.26) with 0, 1, and 1.5 h exposure, respectively. Thus, the genetic/cellular sensitivity to FA differs among the sexes and also depends on the exposure duration.

Size-dependent toxicological effects of polystyrene microplastics in the shrimp Litopenaeus vannamei using a histomorphology, microbiome, and metabolic approach.

Due to the wide application of plastic products in human life, microplastic pollution in water has recently attracted more attention. Many studies have revealed the size-dependent toxicity of microplastics. Here, we investigated the toxicological effects of polystyrene microplastics (PS-MPs) on the white leg shrimp, Litopenaeus vannamei, a profitable aquaculture species, using a comprehensive histomorphological, microbiome, and metabolomic approach to verify whether smaller particles are more toxic than larger particles. L. vannamei were experimentally exposed to water containing PS-MPs of four sizes (0.1, 1.0, 5.0, and 20.0 µm) for 24 h at 10 mg/L (acute experiment) and 12 d at 1 mg/L (subchronic experiment). After 24 h of acute exposure, PS-MP accumulation in shrimp indicated that the ingestion and egestion of PS-MPs had a size-dependent effect, and smaller particles were more bioavailable. The tissue morphological results of subchronic experiments showed that, for the guts and gills, the smaller sizes of the PS-MPs exhibited greater damage. In addition, 16 S rRNA gene amplicon sequencing showed that the alpha diversity was higher under larger PS-MP exposure. Correlated with changes in intestinal bacteria, we found a greater enrichment of metabolic pathways in hemolymph proteins and metabolites in larger PS-MP groups, such as "arginine and proline metabolism", "protein digestion and absorption", "lysine degradation". Interestingly, the activity or content of biomarkers of oxidative stress showed a peak at 1 µm and 5 µm. Under specific sizes of PS-MPs, the abundance of the pathogen Vibrio and probiotic bacteria Rhodobacter (5-µm) and Bacillus and Halomonas (1-µm) were simultaneously enriched. Our results indicated that PS-MP exposure can cause size-dependent damage to shrimp, yet specific particle size can be influential differently in regard to some research indicators. Therefore, it can enhance our comprehensive understanding of the impacts of microplastics on shrimp health and suggests that specific particle size should be considered when assessing the size-dependent toxicity of microplastics.

Subchronic Exposure to Polystyrene Microplastic Differently Affects Redox Balance in the Anterior and Posterior Intestine of Sparus aurata.

Microplastics (MPs) are pollutants widely distributed in aquatic ecosystems. MPs are introduced mainly by ingestion acting locally or in organs far from the gastroenteric tract. MPs-induced health consequences for fish species still need to be fully understood. We aimed to investigate the effects of the subchronic oral exposure to polystyrene microplastics (PS-MPs) (1-20 µm) in the gilthead seabreams (Sparus aurata) used as the experimental model. We studied the detrimental impact of PS-MPs (25 and 250 mg/kg b.w./day) on the redox balance and antioxidant status in the intestine using histological analysis and molecular techniques. The research goal was to examine the anterior (AI) and posterior intestine (PI) tracts, characterized by morphological and functional differences. PS-MPs caused an increase of reactive oxygen species and nitrosylated proteins in both tracts, as well as augmented malondialdehyde production in the PI. PS-MPs also differently affected gene expression of antioxidant enzymes (i.e., superoxide dismutase, catalase, glutathione reductase). Moreover, an increased up-regulation of protective heat shock proteins (HSPs) (i.e., hsp70 and hsp90) was observed in PI. Our findings demonstrate that PS-MPs are responsible for oxidative/nitrosative stress and alterations of detoxifying defense system responses with differences in AI and PI of gilthead seabreams.

Rat tight junction proteins are disrupted after subchronic exposure to okadaic acid.

Okadaic acid (OA), a lipophilic phycotoxin distributed worldwide, causes diarrheic shellfish poisoning and even leads to tumor formation. Currently, the consumption of contaminated seafood is the most likely cause of chronic OA exposure, but there is a serious lack of relevant data. Here, the Sprague-Dawley rats were exposure to OA by oral administration at 100 µg/kg body weight, and the tissues were collected and analyzed to assess the effect of subchronic OA exposure. The results showed that subchronic OA administration disturbed colonic mucosal integrity and induced colitis. The colonic tight junction proteins were disrupted and the cell cycle of colonic epithelial cells was accelerated. It is inferred that disruption of the colonic tight junction proteins might be related to the development of chronic diarrhea by affecting water and ion transport. Moreover, the accelerated proliferation of colonic epithelial cells indicated that subchronic OA exposure might promote the restitution process of gut barrier or induce tumor promoter activity in rat colon.

Perfluorooctanoic acid-induced liver injury is potentially associated with gut microbiota dysbiosis.

Perfluorooctanoic acid (PFOA), an environmental pollutant, is widely engaged in industrial products and tends to accumulate in the liver. Emerging evidence has suggested that the gut microbiome is a pivotal player in maintaining animal health and can potentially altered by xenobiotic. However, few studies explored whether PFOA-induced liver injury is associated with gut microbiota dysbiosis. In the present study, the effects of subacute and subchronic PFOA exposure on liver and gut microbiota in C57BL/6J mice were investigated. Our findings showed that both subacute and subchronic exposure to PFOA induced the liver inflammation, disrupted antioxidative homeostasis and caused liver histological abnormalities with detectable hepatomegaly, ultimately triggering liver injury. Besides, 16S rRNA sequencing analysis revealed that subacute PFOA exposure caused significant changes in the abundances of intestinal flora known to contribute to liver inflammation and oxidative stress, such as the Dehalobacterium and Bacteroides genera. Exposure to subchronic toxicity mainly induced the decrease in commensal probiotics including Lactobacillus and Bifidobacterium genera, which are potentially beneficial to liver damage, compared with that in the untreated group. They also resulted in disturbed functional capabilities of the microbial communities by a Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis. Additionally, the levels of short-chain fatty acids (SCFAs), especially butyric acid, were significantly reduced by PFOA administration. Collectively, our observations suggested that liver damage induced by both subacute and subchronic PFOA exposures probably partly related to the gut microbiota dysbiosis and provided a new insight into the role of PFOA in liver injury.

Strategies for cadmium detoxification in the white shrimp Palaemon argentinus from clean and polluted field locations.

In this study, we investigated the metal handling capacity of non-tolerant and tolerant populations of Palaemon argentinus to cadmium (Cd), through evaluating of the main mechanisms of metal detoxification, metallothioneins (MT) and metal-rich granules (MRG), to probe that the presence of MRG in the second population is responsible of that condition. The tolerant population were exposed to 3.06 and 12.26 µg Cd·L-1, while the non-tolerant shrimp were exposed to 3.06 µg Cd·L-1. Each experiment involved the exposure during 3, 7, 10 and 15 days and, the depuration during 7, 14, 21 and 28 days, for which shrimp were transferred to clean water. The range values of MT concentrations for non-tolerant shrimp were: 12.24-23.91 µg g (w.w), while for tolerant shrimp were: 8.75-16.85 µg g (w.w); MRG levels were: 0.12-0.57 µg g (w.w) and 0.3-2.1 µg g (w.w), respectively. The results showed different strategies for Cd detoxification: the induction of MT was the main pathway in the non-tolerant population, while the formation of Cd-MRG was the main mechanism for tolerant shrimp. These differences could be related to the environmental history and the health status of each populations.

Safety assessment of the pharmacological excipient, diethylene glycol monoethyl ether (DEGEE), using in vitro and in vivo systems.

BACKGROUND: Diethylene glycol monoethyl ether (DEGEE) is widely used as a solubilizer in cosmetics as well as in oral, topical, transdermal and injectable pharmaceutical formulations. Due to the unavailability of detailed toxicological studies on DEGEE, the Scientific Committee on Consumer Products (SCCP) found its toxicological reports to be unsatisfactory, comprising only summaries. Also, a few reports have raised concern on the use of DEGEE as it might cause damage to the kidneys. OBJECTIVE: Safety assessment of DEGEE using in vitro and in vivo models. METHODS: In vitro effects of DEGEE (0.5-25 mg/ml) were assessed in the HEK293 human embryonic kidney cells. In vivo effects were evaluated after single acute exposure of DEGEE via intraperitoneal route in Swiss albino mice and further, a 28 days subchronic exposure study was conducted where DEGEE was administered orally, once daily. RESULTS: DEGEE was cytotoxic to HEK293 cells, and an IC50 of 15 mg/ml was established. An increase in the intracellular levels of ROS and alteration in the mitochondrial membrane potential led to nuclear fragmentation and induction of apoptosis in these cells. Survival rate of animals administered intraperitoneally with a single acute dose of 1000 mg/kg DEGEE was 100% with no significant changes in the behavioural and histological parameters. However, the dose of 3000 mg/kg and above led to total mortality within 14 days of acute exposure. Subchronic oral exposure of 500-2000 mg/kg DEGEE showed no significant changes in the hematological, biochemical and histopathological parameters. CONCLUSIONS: The in vitro findings indicate that the nephrotoxic potential of DEGEE cannot be ruled out. The results of the in vivo studies reveal that the degree of toxic effects shown by DEGEE varies, depending on the dose, duration of exposure and routes of administration. Therefore, the present findings are of relevance and thorough studies should be conducted before using this substance in clinical formulations. Graphical abstract Evaluation of the toxic potential of Diethylene glycol monoethyl ether.

Subchronic exposure to palladium nanoparticles affects serum levels of cytokines in female Wistar rats.

Recently, palladium nanoparticles (PdNPs) have been increasingly used in many industrial sectors, and this has led to a significant release of nano-sized palladium particles into the environment. However, despite the increase in occupational and general population exposure, information on the potential adverse effects of these PdNPs is still limited and their impact on the immune system constitutes a major health concern. Therefore, the aim of this study was to investigate the potential adverse effects induced by subchronic intravenous administration of PdNPs on the immune system of female Wistar rats by evaluating alterations in Interleukin (IL)-1α, IL-2, IL-4, IL-6, IL-10, IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), Interferon (INF)-γ, and Tumor Necrosis Factor (TNF)-α serum levels. Exposed and control animals were randomly divided into five groups (0, 0.012, 0.12, 1.2, and 12 µg PdNPs per kg body weight) which were treated with repeated intravenous injections of vehicle or PdNPs (on day 1, 30, and 60). Subchronic exposure to PdNPs induced a decreasing trend in serum levels in most of the cytokines investigated, with the highest concentration (12 µg/kg) determining significant inhibitory effects. Overall, these results showed that PdNPs are able to alter cytokine serum levels in subchronically treated Wistar rats, suggesting a possible impact of these xenobiotics on the immune system after long-term exposures.

Reproductive and developmental F1 toxicity following exposure of pubescent F0 male mice to bisphenol A alone and in a combination with X-rays irradiation.

Exposure to environmental toxicants may affect reproduction and development of subsequent generations. This study was aimed at determining the male-mediated F1 effects induced following 8-weeks of subchronic exposure of F0 male mice to bisphenol A (BPA) alone and in a combination with X-rays irradiation (IR) started during their puberty. 4.5 weeks old F0 male mice were exposed to BPA dissolved in ethyl alcohol and diluted in drinking water at the following doses: 5 mg/kg bw, 10 mg/kg bw, 20 mg/kg bw or irradiated with X-rays (0.05 Gy) or exposed to a combination of low doses of both agents (0.05 Gy + 5 mg/kg bw BPA). Immediately after the end of the 8 weeks exposure F0 males were caged with two unexposed females each. Three quarters of the mated females from each group were sacrificed 1 day before expected parturition for examination of prenatal development of the offspring. The remainder of the females from each group were allowed to deliver and rear litters. Pups of exposed males were monitored for postnatal development for 8 weeks. At 8-9 weeks of age 6-8 males from each group of F1 generation were sacrificed to determine sperm count and quality. The current results, compared to the earlier results, showed that exposure of pubescent males to BPA alone or in combination with irradiation may be more damaging to their offspring than the exposure of adult males. The exposure of pubescent males to BPA alone and in combination with irradiation significantly increased the frequency of abnormal skeletons of surviving fetuses, increased the percent of mortality of pups in the F1 generation, reduced the sperm motility of F1 males and may induce obesity. Additionally, the combined BPA and irradiation exposure reduced the number of total and live implantations, whereas the exposure to BPA alone disturbed the male:female sex ratio. The above results may be caused by genetic or by epigenetic mechanisms. Limitation of use of products including BPA, especially by children and teenagers, is strongly recommended.

Lung and liver responses to 1- and 7-day treatments with LASSBio-596 in mice subchronically intoxicated by microcystin-LR.

Microcystin-LR (MC-LR) can cause serious injuries upon short- and long-term exposures that can be prevented by LASSBio-596 (LB-596), an anti-inflammatory compound. We aimed to test LB-596 following subchronic exposure to MC-LR. Swiss mice received 10 intraperitoneal injections of distilled water (DW) or MC-LR (20 µg/kg bw) every 2 days. On the 10th injection animals receiving DW were gavaged with DW or 50 mg/kg bw of LB-596 for 1 or 7 days (C1D, C7D, CL1D and CL7D groups), whereas those exposed to MC-LR received either DW or 50 mg/kg of LB-596 for 1 or 7 days (T1D, T7D, TL1D and TL7D groups). Twelve hours after the last gavage we assessed respiratory mechanics, and extracted lung and liver for histology, apoptosis, inflammatory biomarkers and MC-LR content. C1D, C7D, CL1D and CL7D were all similar. Mechanical parameters were significantly higher in T1D and T7D compared to the other groups. LB-596 reversed these changes on day 1 of administration. LB-596 reduced inflammatory mediators in lung and liver on day 1 of treatment. On day 7 apoptosis in liver and lung fell even more. Briefly, 7-day administration completely reversed lung and liver changes.

Effect of subchronic exposure to inorganic arsenic on the structure and function of the intestinal epithelium.

Inorganic arsenic (As), the most toxic form of As found in water and food, is considered a human carcinogen. Numerous studies show its systemic toxicity, describing pathologies associated with chronic exposure. The main pathway of exposure to inorganic As is oral, but many of the events that occur during its passage through the gastrointestinal tract are unknown. This study evaluates the effect of subchronic exposure to inorganic As [As(III): 0.025-0.1 mg/L; As(V): 0.25-1 mg/L, up to 21 days] on the intestinal epithelium, using Caco-2 cells as in vitro model. Inorganic As produces a pro-inflammatory response throughout the exposure time, with an increase in IL-8 release (up to 488%). It also causes changes in the program of cell proliferation and differentiation, which leads to impairment of the cell repair process. In addition, subchronic exposure affects the epithelial structure, causing loss of microvilli, fundamental structures in the processes of intestinal absorption and digestion. Moreover, the exposure affects the epithelial barrier function, evidenced by an increase of Lucifer Yellow transport (103-199%). Therefore, it can be concluded that subchronic exposure to inorganic As can alter intestinal homeostasis, affecting the mucosal layer, which performs the most important functions of the intestinal wall.