General Toxic Effects Research Articles

Study of combined multiple exposure and reproductive / developmental toxicity of 2-ethylhexanoic acid by screening method

Introduction. According to the normative and methodological documents of the Russian Federation, chemicals introduced into economic activities are subject to mandatory toxicological assessment and hygienic regulation. To substantiate the value of the hygienic standard of 2-ethylhexanoic acid, the production of which is planned in the country, additional test on its reproductive toxicity was required. The aim of the research was to determine the no-observed adverse effect levels of the 2-ethylhexanoic acid for maternal and reproductive toxicities in combined multiple exposure and the reproduction/developmental toxicity screening test (OECD 422). Materials and methods. The study was performed in accordance with the requirements of the OECD Test Guideline 422 «Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test». Results. During the experiment no animal deaths or clinical symptoms of the toxic effect of 2-ethylhexanoic acid were observed at all tested doses (250, 500 and 1000 mg/kg b.w.). The assessment of behavioural responses using the open field method showed no differences in animals from experimental and control group. Histological examination indicated the acid at doses of 500 and 1000 mg/kg b.w. to cause significant changes in bladder (increased sclerosis in the submucosa), lungs (increased proportion of emphysematous altered parenchyma), adrenal gland (increased cell alterations and lipomatous inclusions), thyroid gland (increased loci of interfollicular tissue) in males and females’ rats. The total weight of offspring in the experimental groups was found to be statistically dose-dependent reduced on days 4 and 13 after birth compared with the control. Limitations. The study had no limitations. Conclusion. 2-Ethylhexanoic acid has no effect on the reproductive function in experimental animals. Developmental toxicity, expressed in a decrease in the total weight of offspring, was observed at the level of general toxic effects and is not specific. NOAELs were established at the level of 250 mg/kg b.w. for general toxic effect, > 1000 mg/kg b.w. for reprotoxic effect.

Peat smoke exposure as a risk factor for deterioration of postnatal development

Introduction. In connection with the growing number and scale of wildfires, the problem of the toxic effect of biomass combustion products is relevant both in Russia and abroad. Data on the consequences of wildfire smoke exposure at various stages of ontogenesis are extremely scarce. The presence in smoke substances that, in addition to general toxic effects, have reprotoxic, gonadotoxic, and genotoxic effects, determines the need to study its effect on the reproductive potential and health of offspring. The purpose of the study was to assess the postnatal development of the offspring, the parent generation of which was exposed to peat smoke during puberty. Materials and methods. Exposure to peat smoke was carried out once for four hours on the 35th day of life for female and on the 45th day for male rats. The average concentrations of carbon monoxide in the exposure chambers were 29.3±11.1 mg/m3, and ultrafine PM2.5 particles – 0.39±0.61 mg/m3. At puberty, peat smoke exposed rats were mated with intact partners. In rat pups from the offspring there was studied the trend in body weight gain, physical development, and sensory-motor reflexes were assessed. Results. Acute exposure to peat smoke during puberty in white rats adversely affects the development of their offspring. A significant lag in the physical and sensory-motor development of rat pups from the offspring of animals exposed to smoke was revealed in comparison with rat pups from the control group. Limitations. The study was limited to the study of postnatal development of offspring obtained from rats exposed to peat smoke during puberty. Conclusion. Exposure to peat smoke during puberty leads to a delay in the physical and somatosensory development of the offspring during early postnatal ontogenesis.

Scientific substantiation of the maximum permissible concentration of the pharmaceutical substance osimertinib mesylate in the air of the working area

Introduction. Osimertinib, a 3rd generation epidermal growth factor receptor tyrosine kinase inhibitor, is currently the only drug registered for the treatment of metastatic non-small cell lung cancer in patients with a positive T790M mutation status. The production of osimertinib mesylate is planned on the territory of the Russian Federation, which necessitates research to substantiate the hygienic standard for the aerosol content of the substance in the air of the working area. Conducting research to substantiate the maximum permissible concentration of a substance requires significant material and time resources, while using the results of preclinical and clinical studies, mathematical modeling of processes, and risk assessment methodology allows for a comprehensive assessment of the substance, while significantly reducing the time and cost of work. The study aims to scientifically substantiate the maximum permissible concentration of the pharmaceutical substance osimertinib mesylate in the air of the working area using data from toxicological studies and mathematical modeling of the effects of the substance on humans in industrial conditions. Materials and methods. The materials used were domestic and international databases, reports, research protocols, scientific articles and monographs containing information on the physico-chemical and toxic properties, pharmacotherapeutic activity of osimertinib. Results. The specialists have conducted hygienic regulation of osimertinib, taking into account data on its toxicity, danger, pharmacotherapeutic activity, side effects, long-term consequences, pharmacokinetic studies and modeling. To substantiate the value of the maximum permissible concentration, the authors used the reference points: an inactive NOEL level of 1 mg/­kg/­day for general toxic effect, established in a 92-day experiment on rats with intragastric administration; the lowest observed level of adverse effects of LOAEL is 0.5 mg/kg/day for general toxic effect, established in a 180-day experiment on dogs with intragastric administration; the level that does not cause adverse effects of NOAEL is 10 mg/kg/day for general toxic effect, established in a 180-day experiment on mice with intragastric administration. Safe concentrations of osimertinib in the air of the work area were evaluated using reference points, including the pharmacological effect and the minimum daily therapeutic dose; toxicokinetic modeling of concentrations of a substance in the human body under production conditions and the level of minimal risk. Limitation. The study is limited to the review of open literature sources describing the toxicological/toxicokinetic characteristics of osimertinib mesylate. Conclusion. The most stringent indicators of safe exposure levels, established on the basis of pharmacological effect and toxicokinetic modeling in dogs, allowed us to recommend 0.005 mg/m3, aerosol, hazard class 1 as the maximum permissible concentration in the air of the working area for osimertinib mesylate. Ethics. This study did not require the conclusion of the Ethics Committee.

Assessment of health risks posed by heavy metal contamination of wild mushrooms and berries

BACKGROUND: One of the primary objectives in ensuring food security for the population is to reduce the mitigate the risk of chemical contamination in food. Wild mushrooms and berries have the potential to accumulate heavy metals from the environment, posing a threat to human health if consumed. AIM: To assess the risk of developing general toxic effects associated with the consumption of wild mushrooms and berries on health of the adults living in the Arkhangelsk region. MATERIAL AND METHODS: The amount and frequency of mushroom and berry consumption by the adult population of the Arkhangelsk region was assessed by a survey (n=445). Intake of heavy metals contaminating mushrooms and berries was calculated using four scenarios. Hazard Quotients (HQ) were used to characterize the risk of developing overall toxic effects due to exposure to mercury, arsenic, lead, and cadmium. Hazard Indexes (HI) for substances with unidirectional effects were employed to assess the risk of non-cancerous effects on critical organs and systems. Quantitative data were presented as medians (Me) with 95% confidence intervals (95% CI), and the 90th percentile (P90). RESULTS: In total, 82% and 70% of respondents were engaged in collection of mushrooms and wild berries, respectively. On average, they reported consuming 180 grams of fresh or frozen berries, 133 grams of berries with juice, and 50 grams of mushrooms in soup or boiled/fried form per week. The Hazard Quotients (HQ) for all heavy metals did not exceed 1.0. The Hazard Index (HI) calculated for the average consumption of mushrooms and berries, as well as the average heavy metal contamination of wild plants was below 1.0. However, at high levels of mushroom (P90 — 417 g/week) and berry (P90 — 900 g/week) consumption, along with high levels of heavy metal contamination, elevated risk of developing general toxic effects on the endocrine- (HI=2.27), cardiovascular- (HI=2.0), digestive- (HI=2.0), nervous- and immune systems (HI =1.81 for both) and kidneys (HI=1.25) were detected. Forest mushrooms and wild berries can be consumed without restriction at an average level of their contamination. However, in cases of heavy metal contamination of mushrooms and berries at the P90 level or above, it is not recommended to exceed daily consumption of 400 grams of forest mushrooms and 650 grams of wild berries. CONCLUSION: Consuming high amounts of wild mushrooms and berries at the upper limit of exposure to heavy metals, may lead to an elevated risk of developing toxic effects on endocrine, nervous, immune, cardiovascular, and digestive systems.

Качество атмосферного воздуха и риск развития болезней системы кровообращения у населения крупного города европейского севера

Cardiovascular diseases are the most frequent causes of premature mortality associated with ambient air quality. In the Arkhangelsk region, population mortality caused by diseases of the circulatory system is higher than the national average. The aim of this study was to assess ambient air quality in Arkhangelsk and associated health harm in adult population. The study relied on using data of ambient air monitoring in Arkhangelsk collected over 2011–2022. We analyzed average annual levels of 23 pollutants and primary incidence of diseases of the circulatory system (CVD) and calculated hazard quotients under chronic inhalation exposure (HQ), hazard index (HI) for the cardiovascular system, and the number of attributable deaths associated with exposure to PM10 and PM2.5. Over the analyzed period, the average long-term concentrations of most pollutants met hygienic standards. Average levels of formaldehyde, chromium, copper and benzene were found to exceed the MPL by 1.5–2.3 times. Hazard coefficients for formaldehyde (HQ = 2.3), copper (HQ = 1.8) and PM2.5 (HQ = 1.7) were established to be above their permissible value. The risk of developing general toxic effects is determined to be high (HI = 6.6) for the cardiovascular system. The main contribution to the risk level is made by copper and PM2.5. Attributable outcomes of primary cardiovascular incidence among the adult population of Arkhangelsk associated with exposure to PM10 and PM2.5 equaled 10.7 and 2.9 ‰ cases per year. The greatest harm under exposure to PM2.5 is due to the development of coronary artery disease and amounts to 1.9 ‰ cases per year.

Ambient air quality and risk of circulatory diseases for population of a large city in the European north of Russia

Cardiovascular diseases are the most frequent causes of premature mortality associated with ambient air quality. In the Arkhangelsk region, population mortality caused by diseases of the circulatory system is higher than the national average. The aim of this study was to assess ambient air quality in Arkhangelsk and associated health harm in adult population. The study relied on using data of ambient air monitoring in Arkhangelsk collected over 2011–2022. We analyzed average annual levels of 23 pollutants and primary incidence of diseases of the circulatory system (CVD) and calculated hazard quotients under chronic inhalation exposure (HQ), hazard index (HI) for the cardiovascular system, and the number of attributable deaths associated with exposure to PM10 and PM2.5. Over the analyzed period, the average long-term concentrations of most pollutants met hygienic standards. Average levels of formaldehyde, chromium, copper and benzene were found to exceed the MPL by 1.5–2.3 times. Hazard coefficients for formaldehyde (HQ = 2.3), copper (HQ = 1.8) and PM2.5 (HQ = 1.7) were established to be above their permissible value. The risk of developing general toxic effects is determined to be high (HI = 6.6) for the cardiovascular system. The main contribution to the risk level is made by copper and PM2.5. Attributable outcomes of primary cardiovascular incidence among the adult population of Arkhangelsk associated with exposure to PM10 and PM2.5 equaled 10.7 and 2.9 ‰ cases per year. The greatest harm under exposure to PM2.5 is due to the development of coronary artery disease and amounts to 1.9 ‰ cases per year.

Evaluation of XQ528 tartrate on embryo-fetus developmental toxicity in SD rats and genotoxicity

The effects of XQ528 tartrate on the embryonic and fetal development of fertile Sprague-Dawley (SD) rats, along with their embryos and littermates, were evaluated using an embryo-fetus developmental toxicity assay. fertile SD rats exhibited no significant general toxic effects when administered doses of 0.25, 1.25, and 5.0 mg/kg intranasally from days 6 to 15 of gestation. The genotoxicity of the compound was evaluated through an amalgam of tests that included the Ames test, the Chinese hamster ovary (CHO) cell chromosome aberration test, and the micronucleus test in ICR mice. The results from the Ames test indicated non-mutagenicity at concentrations of 5000, 500, 50.0, 5.0, and 0.5 μg/dish across strains TA97, TA98, TA100, TA102, and TA1535. Additionally, the chromosomal aberration rates in CHO cells were not significantly altered at concentrations of 50.5, 101.0, and 202.0 μg/mL. No micronuclei induction was observed in ICR mice at dosage levels of 11.25, 22.50, and 45.00 mg/kg post intranasal administration. In conclusion, the no observed adverse effect level (NOAEL) for developmental toxicity of XQ528 tartrate in fertile SD rats, embryos, and littermates under the test conditions in this study was established at 5.0 mg/kg/day. Under these test conditions, XQ528 tartrate did not exhibit any significant genotoxic or carcinogenic potential.

Improving approaches to hygienic rationing of antimicrobial drugs

Introduction. Currently, the production of medicines, including those with antimicrobial properties, is expanding at chemical and pharmaceutical enterprises. However, scientific approaches to hygienic regulation of the content of specific antimicrobials in the air of the work area are not yet available. The study aims to substantiate approaches to predicting approximate safe levels of exposure (ASLE) to substances with a specific antimicrobial effect. Materials and methods. The scientists have carried out the research in two stages. The first stage is an experimental study of the single inhalation effect of an antibiotic clarithromycin at concentrations of 54.2; 25.4; 15.3; 9.1; 2.8 and 0.9 mg/m3 on mongrel female rats weighing 230–250 g. The authors have evaluated the indicators of toxic (morphological and functional parameters of the nervous, cardiovascular and respiratory systems, biochemical parameters of the liver and kidneys, as well as the composition of peripheral blood) and specific effects (qualitative and quantitative composition of the microbiota of the large intestine of rats). The second stage was the analysis of the database on hygienic rationing of chemicals, which consisted in searching for hygienic standards (ASLE, MPC), threshold concentrations for the general toxic (Limint) and specific (Limbact) effects of antimicrobials. Results. During the experiment, experts have established the threshold of acute inhalation exposure (Limac int) of clarithromycin at a concentration of 25.4 mg/m3 according to the total toxic effects (peripheral blood counts, liver and kidney function). When exposed to an antibiotic at a concentration of 2.8 mg/m3, there was an imbalance of the intestinal microflora in the absence of a general toxic effect, which indicated a specific and selective antimicrobial effect of the drug. Based on the analysis of literature data, the parameters of toxicometry of 21 substances with antimicrobial effect were determined, their representative sample was justified and its regression analysis was carried out. Conclusion. Based on experimental and literary data, the authors established a significantly strong correlation (r=0.729) between the values of MPC (ASLE) and the threshold of antimicrobial action (Limbact). They also developed a mathematical equation to predict safe levels of antimicrobials based on their specific and selective activity.

Probabilistic Reference and 10% Effect Concentrations for Characterizing Inhalation Non-cancer and Developmental/Reproductive Effects for 2,160 Substances.

Chemicals assessment and management frameworks rely on regulatory toxicity values, which are based on points of departure (POD) identified following rigorous dose-response assessments. Yet, regulatory PODs and toxicity values for inhalation exposure (i.e., reference concentrations [RfCs]) are available for only ∼200 chemicals. To address this gap, we applied a workflow to determine surrogate inhalation route PODs and corresponding toxicity values, where regulatory assessments are lacking. We curated and selected inhalation in vivo data from the U.S. EPA's ToxValDB and adjusted reported effect values to chronic human equivalent benchmark concentrations (BMCh) following the WHO/IPCS framework. Using ToxValDB chemicals with existing PODs associated with regulatory toxicity values, we found that the 25th %-ile of a chemical's BMCh distribution () could serve as a suitable surrogate for regulatory PODs (Q2 ≥ 0.76, RSE ≤ 0.82 log10 units). We applied this approach to derive for 2,095 substances with general non-cancer toxicity effects and 638 substances with reproductive/developmental toxicity effects, yielding a total coverage of 2,160 substances. From these , we derived probabilistic RfCs and human population effect concentrations. With this work, we have expanded the number of chemicals with toxicity values available, thereby enabling a much broader coverage for inhalation risk and impact assessment.

A systematic toxicologic study of polycyclic aromatic hydrocarbons on aquatic organisms via food-web bioaccumulation

Pollution-induced declines in fishery resources restrict the sustainable development of fishery. As a kind of typical environmental pollutant, the mechanism of polycyclic aromatic hydrocarbons (PAHs) facilitating fishery resources declines needs to be fully illustrated. To determine how PAHs have led to declines in fishery resources, a systematic toxicologic analysis of the effects of PAHs on aquatic organisms via food-web bioaccumulation was performed in the Pearl River and its estuary. Overall, PAH bioaccumulation in aquatic organisms was correlated with the trophic levels along food-web, exhibiting as significant positive correlations were observed between PAHs concentration and the trophic levels of fishes in the Pearl River Estuary. Additionally, waterborne PAHs exerted significant direct effects on dietary organisms (P < 0.05), and diet-borne PAHs subsequently exhibited significant direct effects on fish (P < 0.05). However, an apparent block effect was found in dietary organisms (e.g., zooplankton) where 33.49 % of the total system throughput (TST) was retained at trophic level II, exhibiting as the highest PAHs concentration, bioaccumulation factor (BAF), and biomagnification factor (BMF) of ∑15PAHs in zooplankton were at least eight-fold greater than those in fishes in both the Pearl River and its estuary, thereby waterborne PAHs exerted either direct or indirect effects on fishes that ultimately led to food-web simplification. Regardless of the block effect of dietary organisms, a general toxic effect of PAHs on aquatic organisms was observed, e.g., Phe and BaP exerted lethal effects on phytoplankton Chlorella pyrenoidosa and zooplankton Daphnia magna, and decreased reproduction in fishes Danio rerio and Megalobrama hoffmanni via activating the NOD-like receptors (NLRs) signaling pathway. Consequently, an assembled aggregate exposure pathway for PAHs revealed that increases in waterborne PAHs led to bioaccumulation of PAHs in aquatic organisms along food-web, and this in turn decreased the reproductive ability of fishes, thus causing decline in fishery resources.

Development and validation of a method for the quantitative determination of metoprolol succinate in the air of the working area by high-performance liquid chromatography using mass spectra

Introduction. Metoprolol is a cardioselective blocker of β-adrenergic receptors. Drugs containing metoprolol have hypotensive, antianginal, antiarrhythmic effects. Moderately dangerous when taken orally, has a general toxic effect. Metoprolol is produced in two forms: in the form of salts of tartaric and succinic acids, the approximate safe level of exposure to which is 0.3 mg/m3. To ensure the safety of workers, it is necessary to carry out sanitary and hygienic air control. Methods for the quantitative analysis of metoprolol in the air of the working area, presented in the current scientific literature, allow monitoring only for metoprolol salts in the form of tartrate. &#x0D; The aim of the study is to develop and validate an analytical method for the quantitative determination &#x0D; of metoprolol succinate in the air of the working area by HPLC-MS. &#x0D; Materials and methods. For the analysis, standard samples of metoprolol succinate and air samples taken at all stages of the life cycle of the production of the drug metoproolol were used. Chromatographic separation and detection were performed on an Agilent 1260 Infinity G6125B high performance liquid chromatograph (Agilent Technologies, USA) equipped with a column and sample thermostat, a degasser, a pump, an autosampler, and a G6125B mass selective detector. A Waters Xbridge® C18 3.5 µm column was used; 2.1×30 mm (Waters, Ireland). Primary data were processed using Open Lab CDS ChemStation Edition (Rev. C.01.07 SR3) software (Agilent Technologies, USA).&#x0D; Results. A method for the quantitative determination of metoprolol succinate in air samples by HPLC-MS has been developed and validated. During the validation of the developed methodology, it was found that the validation characteristics (specificity, linearity, accuracy and precision, correctness, reproducibility) are within the acceptance criteria. The analytical range of the technique was 0.1–10.0 µg/ml and allows the developed technique to be used to control the average shift MPCs in the air of the working area.&#x0D; Limitations. The results of the study of the air in the working area are applicable only to the production of the drug metoprolol in the form of tablets; the study of air during the synthesis and packaging of the active pharmaceutical substance was not carried out. &#x0D; Conclusion. An analysis of air samples from the production of the drug metoprolol was carried out and the safety of working conditions was proved.

Public health risk associated with the quality of drinking water and food, and the incidence of colorectal cancer

Aim to assess the public health risk associated with the quality of drinking water and food in areas with different levels of incidence of colorectal cancer.&#x0D; Material and methods. An assessment was made of the carcinogenic risk and the risk of developing general toxic effects due to the intake of xenobiotics with food and drinking water in areas that differ in the incidence of colorectal cancer. To assess the risk, the results of laboratory studies performed as part of the social and hygienic monitoring for the period 2014-2021 were used.&#x0D; Results. Priority pollutants (plumbum, arsenic, cadmium, hexachloran, polychlorinated biphenyls) that make the greatest contribution to the carcinogenic risk have been identified. The range of total carcinogenic risk, depending on arsenic compounds, varies in the Arsky district from acceptable to high (from 4.98E-05 to 2.70E-03), in Drozhzhanovsky - from acceptable to alarming (from 6.81E-05 to 2.02E- 04); in Aznakaevsky - from alarming to high (from 1.99E-04 to 2.21E-03). In the Kamsko-Ustyinsky district, the risk is assessed as alarming (from 2.15E-04 to 4.13E-04), in Yutazinsky as high (from 2.91E-03 to 3.39E-03). The total hazard index caused by the intake of nitrates with food and drinking water varies from the minimum in the Arsky district (HI=0.31) to the alarming one in the Kamsko-Ustyinsky district (HI=3.13). A correlation was established between the content of nitrates in drinking water and the incidence of cancer of the rectum, rectosigmoid junction and anus (r=0.587; p=0.002133). The risk of developing non-carcinogenic effects on the part of the gastrointestinal tract, due to the natural characteristics of drinking water sources, is assessed as acceptable in all areas.&#x0D; Conclusion. In areas with an increased incidence of colorectal cancer, there are higher levels of carcinogenic health risk due to the intake of xenobiotics with food and drinking water (from alarming to high).

Justification of the maximum single maximum permissible concentration of dimethyl sulfoxide in the atmospheric air of urban and rural settlements

Introduction. Atmospheric air pollution by volatile sulfur compounds is one of the most urgent environmental and hygienic problems. However, the maximum single maximum permissible concentration (MPC) of dimethyl sulfoxide in the atmospheric air of urban and rural settlements has not yet been established.&#x0D; The study aims to substantiate the maximum single maximum permissible concentration оf dimethyl sulfoxide in the atmospheric air of urban and rural settlements.&#x0D; Materials and methods. White mongrel male rats weighing 180–240 gr., dimethyl sulfoxide (DMSO), CAS No. 67-68-5. The authors conducted the study in accordance with the current regulatory, methodological and instructional documents. Experts conducted surveys of experimental animals according to a generally accepted and unified methodology. Statistical processing of the research materials was carried out using standard Statistica 10.0 application programs.&#x0D; Results. During the study of dimethyl sulfoxide, researchers found that the threshold of acute inhalation general toxic effect (Limac) is a concentration of 2.4±0.09 mg/m3, the threshold of irritant effect (Limir) is 0.6±0.03 mg/m3, the odor threshold (Limolf) is 1.741 mg/m3. Unpleasant odors and general toxic effect of the substance are prevented by a concentration of 0.6 mg/m3, irritant effect — a concentration of 0.3 mg /m3.&#x0D; Conclusion. In accordance with the principle of the limiting index of harmfulness, a concentration of 0.3 mg/m3 is recommended as the concentration of dimethyl sulfoxide (DMSO) in the atmospheric air, which prevents odors, general toxic and irritating effects.&#x0D; Ethics. The material of the article was approved by the Ethics Committee at the Novosibirsk Research Institute of Hygiene of Rospotrebnadzor (No. 1 of January 21, 2022).

Safety of the Drug Prospekta: a Preclinical Study of Acute and Repeated Dose Toxicity.

General toxic effect of the drug Prospekta (modified affinity purified antibodies to the brain-specific S100 protein) was studied on mature male and female mice and rats: acute toxicity with double intragastric and intraperitoneal administration of the maximum permissible doses at a 2-h interval, repeated dose toxicity with intragastric administration of the maximum permissible and close to therapeutic doses for 6 months. No lethal and toxic effects on animals were observed, including no toxic effects on vital systems, i.e., CNS and cardiovascular system, as well systems with the functions that may be temporarily disrupted (excretory and digestive systems). All the differences between animals of the experimental and control groups varied within the physiological range. It can be concluded that the drug produces no general toxic effect on laboratory animals.

BMP2 gene transfer induces pericardial effusion and inflammatory response in the ischemic porcine myocardium.

Pro-angiogenic gene therapy is being developed to treat coronary artery disease (CAD). We recently showed that bone morphogenetic protein 2 (BMP2) and vascular endothelial growth factor-A synergistically regulate endothelial cell sprouting in vitro. BMP2 was also shown to induce endocardial angiogenesis in neonatal mice post-myocardial infarction. In this study, we investigated the potential of BMP2 gene transfer to improve cardiomyocyte function and neovessel formation in a pig chronic myocardial infarction model. Ischemia was induced in domestic pigs by placing a bottleneck stent in the proximal part of the left anterior descending artery 14 days before gene transfer. Intramyocardial gene transfers with adenovirus vectors (1 × 1012 viral particles/pig) containing either human BMP2 (AdBMP2) or beta-galactosidase (AdLacZ) control gene were performed using a needle injection catheter. BMP2 transgene expression in the myocardium was detected with immunofluorescence staining in the gene transfer area 6 days after AdBMP2 administration. BMP2 gene transfer did not induce angiogenesis or cardiomyocyte proliferation in the ischemic pig myocardium as determined by the quantitations of CD31 or Ki-67 stainings, respectively. Accordingly, no changes in heart contractility were detected in left ventricular ejection fraction and strain measurements. However, BMP2 gene transfer induced pericardial effusion (AdBMP2: 9.41 ± 3.17 mm; AdLacZ: 3.07 ± 1.33 mm) that was measured by echocardiography. Furthermore, an increase in the number of immune cells and CD3+ T cells was found in the BMP2 gene transfer area. No changes were detected in the clinical chemistry analysis of pig serum or histology of the major organs, implicating that the gene transfer did not induce general toxicity, myocardial injury, or off-target effects. Finally, the levels of fibrosis and cardiomyocyte apoptosis detected by Sirius red or caspase 3 stainings, respectively, remained unaltered between the groups. Our results demonstrate that BMP2 gene transfer causes inflammatory changes and pericardial effusion in the adult ischemic myocardium, which thus does not support its therapeutic use in chronic CAD.

Synthetic antioxidant TS-13 reduces doxorubicin cardiotoxicity

The antitumor antibiotic doxorubicin, a representative of a large group of anthriacyclines, is widely and quite effectively used to treat patients with malignant neoplasms. The aim of this study was to study the effect of TS-13, a synthetic phenolic antioxidant and an activator of the antioxidant-responsive element redox-sensitive signaling system Keap1/ Nrf2/ARE, on the functional parameters of an isolated rat heart after a course of doxorubicin administration. Material and methods. Male Wistar rats (n = 24) were divided into three groups: control (n = 10), doxorubicin group (n = 7) (3 weekly intraperitoneal injections of doxorubicin solution at a cumulative dose of 15 mg/kg) and doxorubicin + TS-13 (n = 7) (administration of doxorubicin according to a similar scheme, TS-13 solution with drinking water). On the 21st day after the start of the experiment, the cardioprotective effect of TS-13 was assessed on the ex vivo model of perfusion of the heart isolated according to Langendorff. Coronary flow, heart rate (HR), pressure in the left ventricle (myocardial contractility) were recorded as parameters of myocardial functional activity; the integral indicator of myocardial contractility (working capacity) was calculated as the product of HR and pressure in the left ventricle. Results and discussion. The general toxic effect of doxorubicin was manifested in a significant decrease in rat body weight (by 21 %), the administration of TS-13 reduced the cachectic effect of the cytostatic. Doxorubicin worsened heart work by all studied parameters (coronary flow, HR, myocardial contractility and integral index of contractility); the effect persisted throughout the entire perfusion period (40 min). Animals treated with intraperitoneal injections of doxorubicin and TS-13 per os lost weight to a lesser extent, the functional activity of isolated hearts improved significantly – coronary flow, pressure in the left ventricle, and working capacity increased. Conclusions. Since, as we have shown earlier, TS-13 administration not only does not cancel, but even potentiates the antitumor activity of doxorubicin, the results obtained indicate the promise of using TS-13 as an adjuvant therapy for malignant neoplasms, enhancing the antitumor effect of the cytostatic and leveling its side effects, including cardiotoxicity.

Combined reproductive and developmental toxicity study of pesticide abamectin on male and female Wistar Hannover rats

Abamectin is a widely used pesticide and anthelmintic for humans and animals. Previous toxicological studies showed evidence of adverse effects on reproduction, but the findings were inconclusive. Abamectin is known to exhibit teratogenic activity, causing different malformations during developmental stages in rats and rabbits. The present work aims at combining reproductive and developmental toxicological assessments in a single study to evaluate the impact of abamectin on reproductive, fertility, and developmental functions. Abamectin was administered orally to 20 male and 20 female rats at doses of 0, 0.1, 1.0, and 2.0 mg/kg body weight. Abamectin exposure was prolonged for 11 weeks for males and 10 weeks for females before mating. Females were also treated during mating and pregnancy. In this study, treated animals were mated with untreated intact animals to further assess the potential sex sensitivity effect. The results demonstrate that male rats were more susceptible to general toxic effects such as decreased body weight and showed a more toxic effect on reproductive function and fertility at doses of 1.0 and 2.0 mg/kg/day. Furthermore, stages of gametogenesis and early fetal development are the most vulnerable of the reproductive process to endocrine disruptors' action, leading to changes in the estrous cycle in females and sperm quality in males. Abamectin can produce developmental toxicity in rats at a dose of 2 mg/kg/day, which is not a maternally toxic dose. Accordingly, NOAEL for reproductive toxicity and developmental toxicity with fetotoxic effects were established at the dose level of 0.1 mg/kg/day and 1.0 mg/kg/day, respectively.

Характеристика модели асцитной карциномы Эрлиха и перспективы ее применения в экспериментальной фармакологии ветеринарных препаратов

The article provides an overview of the most significant works of domestic and foreign authors devoted to the Ehrlich ascites carcinoma biological model. The analysis of the available literary sources showed that despite the long history of the existence of this model and its application in biomedical research, it has not yet become widespread in veterinary medicine. It should be noted that the Ehrlich ascites carcinoma model has a number of peculiarities that allow it to be used for the needs of veterinary medicine, in particular, experimental pharmacology at the stage of drug design and its preclinical testing. The high resistance of malignant cells and tumor survival in experimental animals, as well as the ease of its cultivation and relatively rapid tumor growth, make this model a convenient biological object for research. The effect of tumor cells on the body of the animal with a tumor leads to a change in a number of biochemical indicators of various tissues and organs, and a general toxic effect. In this case, an imbalance of the free-radical and antioxidant systems is observed, the body is exposed to oxidative stress. The immune system under the effect of Ehrlich ascites carcinoma also undergoes a number of changes. Thus, in response to the development of tumor-induced pathological processes, recruitment of immunocompetent cells and an antitumor immune response are observed, which at the same time is suppressed as carcinoma cells grow under the action of immunosuppressive physiologically active compounds produced by the tumor, escape of tumor cells from immunological surveillance and remodelling of immune cells in the tumor microenvironment. These processes lead to suppression of the immune system and as a result to the death of animals. These peculiarities make it possible to use the Ehrlich transplantable ascites carcinoma model for testing new veterinary drugs with potential antiblastoma, immunomodulatory, antitoxic properties, as well as medicinal formulations for restoring biochemical indicators and redox homeostasis under conditions of tumor-induced immunosuppression and chronic inflammatory process, and also to study the mechanisms of cell adaptation, including the immune system, under the action of carcinogenesis factors.

Muc2-дефицитные мыши как модель хронического воспаления

The article provides an overview of the most significant works of domestic and foreign authors devoted to the Ehrlich ascites carcinoma biological model. The analysis of the available literary sources showed that despite the long history of the existence of this model and its application in biomedical research, it has not yet become widespread in veterinary medicine. It should be noted that the Ehrlich ascites carcinoma model has a number of peculiarities that allow it to be used for the needs of veterinary medicine, in particular, experimental pharmacology at the stage of drug design and its preclinical testing. The high resistance of malignant cells and tumor survival in experimental animals, as well as the ease of its cultivation and relatively rapid tumor growth, make this model a convenient biological object for research. The effect of tumor cells on the body of the animal with a tumor leads to a change in a number of biochemical indicators of various tissues and organs, and a general toxic effect. In this case, an imbalance of the free-radical and antioxidant systems is observed, the body is exposed to oxidative stress. The immune system under the effect of Ehrlich ascites carcinoma also undergoes a number of changes. Thus, in response to the development of tumor-induced pathological processes, recruitment of immunocompetent cells and an antitumor immune response are observed, which at the same time is suppressed as carcinoma cells grow under the action of immunosuppressive physiologically active compounds produced by the tumor, escape of tumor cells from immunological surveillance and remodelling of immune cells in the tumor microenvironment. These processes lead to suppression of the immune system and as a result to the death of animals. These peculiarities make it possible to use the Ehrlich transplantable ascites carcinoma model for testing new veterinary drugs with potential antiblastoma, immunomodulatory, antitoxic properties, as well as medicinal formulations for restoring biochemical indicators and redox homeostasis under conditions of tumor-induced immunosuppression and chronic inflammatory process, and also to study the mechanisms of cell adaptation, including the immune system, under the action of carcinogenesis factors.

Acute Toxicity Induced by Inhalation Exposure to Lead Oxide Nanoparticles in Rats

Introduction: Lead oxide nanoparticles are generated during high-temperature processes at metallurgical plants and emitted in the atmosphere, thus posing high risks of human inhalation exposures. Despite a well-known toxic effect of lead and its nano-sized compounds on the nervous, hematopoietic, urinary, and reproductive systems, data on specific features of an acute inhalation exposure to its nanoparticles are still scarce. Objective: To conduct an experimental study of acute toxicity induced by inhalation exposure to lead oxide nanoparticles in rats. Materials and methods: The experiment was carried out on outbred female rats with the body weight of 247.9 ± 10.5 g divided into two (exposure and control) groups of 10 animals each. A single inhalation exposure to lead oxide nanoparticles (PbO NPs) at the concentration of 0.215 mg/m3 lasted four hours. The nanoparticle shape was spherical with a mean diameter of 18.2 ± 4.2 nm. Blood was taken from the tail vein of the rats to assess its hematologic parameters while the bronchoalveolar lavage fluid (BALF) was obtained to establish its cytological and biochemical characteristics 24 hours after the exposure. Results: After the single inhalation exposure to PbO NPs, the results of the complete blood count showed an increased granulocyte count and a compensatory increase in erythropoiesis manifested by a significant growth of the reticulocyte percentage. The BALF analysis demonstrated that the exposure induced a pronounced cellular reaction in the lower airways accompanied by an increase in the neutrophil count and the neutrophil to alveolar macrophage ratio, which is an indicator of the cytotoxic effect of PbO NPs. Conclusion: Inhalation exposure to PbO NPs at the experimental dose causes both general toxic and cytotoxic effects. The foregoing justifies the necessity of further studies aimed at establishing a no-effect concentration for lead oxide nanoparticles.