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PubMed1990

An animal model to study toxicity of central nervous system therapy for childhood acute lymphoblastic leukemia: effects on growth and craniofacial proportion.

Many long term survivors of childhood acute lymphoblastic leukemia have short stature, as well as craniofacial and dental abnormalities, as side effects of central nervous system prophylactic therapy. An animal model is presented to assess these adverse effects on growth. Cranial irradiation (1000 cGy) with and without prednisolone (18 mg/kg i.p.) and methotrexate (2 mg/kg i.p.) was administered to 17- and 18-day-old Sprague-Dawley male and female rats. Animals were weighed 3 times/week. Final body weight and body length were measured at 150 days of age. Femur length and craniofacial dimensions were measured directly from the bones, using calipers. For all exposed groups there was a permanent suppression of weight gain with no catch-up growth or normal adolescent growth spurt. Body length was reduced for all treated groups, as were the ratios of body weight to body length and cranial length to body length. Animals subjected to cranial irradiation exhibited microcephaly, whereas those who received a combination of radiation and chemotherapy demonstrated altered craniofacial proportions in addition to microcephaly. Changes in growth patterns and skeletal proportions exhibited sexually dimorphic characteristics. The results indicate that cranial irradiation is a major factor in the growth failure in exposed rats, but chemotherapeutic agents contribute significantly to the outcome of growth and craniofacial dimensions.

Animals↗
PubMed1982

Which mathematical model to study uremic toxicity? National Cooperative Dialysis Study.

Mathematical modelling advantages and limitations to study dialysis adequacy are evaluated, the use of the single pool urea model in the guidance of the National Cooperative Dialysis Study (NCDS) is described, and therapeutic control results from the Control phase of the NCDS are reported. The relevance of using urea as a target compound and the practicality of modelling its levels in clinical settings using a single pool model are discussed. The NCDS involves intensive participation of 8 geographically separate centers to control BUN at two weekly time averaged concentrations (50 +/- 5 and 100 +/- 5 mg/dl) using standard clinical dialyzers and two different lengths of dialysis (3 and 4.5 hr) in the presence of .8-1.4 g/kg/day protein intake. Control phase data on 195 patients indicates a remarkable level of clinical precision and method reproducibility as well as a high degree of patient compliance. Patient urea volumes averaged 39.8 +/- 8.9 liters, net rates of daily protein catabolism were 1.06 +/- .17 g/kg; daily weight gain: .96 +/0 .43 kg; and dialyzer clearances to maintain patients in the control phase for 3 to 6 months were 168 +/- 44 ml/min. Clearances required to randomize patients into four experimental groups ranged 40-250 ml/min. Less than 1/4 of dialyzers were larger than 1.8 m2 and were not specific to any experimental group.

Blood Urea Nitrogen↗
PubMed2000

Biologically based risk assessment models for developmental toxicity.

It is obvious that the task of incorporating mechanistic information into dose-response assessment for developmental toxicity is, by and large, still at its conceptual stage. Our immature understanding of embryogenesis and teratogenesis forces us to make simplifying biological assumptions that may turn out to be erroneous; therefore, these mechanistically based models should be constructed so as to be easily modified as new information becomes available. The data-intensive (and costly) nature of these modeling efforts may also limit their practice to extraordinary situations where, for instance, large segments of the human population are exposed to low levels of a compound and the determination of a safe level of exposure is of utmost importance, or where compounds are of such immense economic or therapeutic value that their use would warrant a concerted effort to minimize the uncertainties inherent in the current methods of extrapolation. Nevertheless, this chapter has presented several attempts to translate the concept of BBDR into practice. When these applications become successful, these models should provide risk assessors with more reliable response indicators at low doses (where human exposures are realistic) and more accurate cross-strain/cross-species comparisons as well as extrapolations across exposure conditions. Although the BBDR models do not necessarily redefine the current practice of risk assessment using either the NOAEL or the benchmark approach, information derived from these efforts should provide a credible scientific basis for the estimates of RfD.

Animals↗
PubMed2002

A QSAR model for predicting toxicity (LC50) to rainbow trout.

A fragment constant method for prediction of toxicity (LC50) to rainbow trout was developed based on the experimental LC50 values of 258 chemicals obtained from the literature. The dataset was randomly divided into a training set and a validation set for purposes of model development and validation. The final model was established using all of the experimental LC50 values by pooling the two sets together. The coefficient of the determination for the final model was 0.9495 with a mean residual of 0.42 log-units. The model's robustness was tested using jackknife tests.

Animals↗
PubMed2002

Huntington toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein Rnq1.

The cause of Huntington's disease is expansion of polyglutamine (polyQ) domain in huntingtin, which makes this protein both neurotoxic and aggregation prone. Here we developed the first yeast model, which establishes a direct link between aggregation of expanded polyQ domain and its cytotoxicity. Our data indicated that deficiencies in molecular chaperones Sis1 and Hsp104 inhibited seeding of polyQ aggregates, whereas ssa1, ssa2, and ydj1-151 mutations inhibited expansion of aggregates. The latter three mutants strongly suppressed the polyQ toxicity. Spontaneous mutants with suppressed aggregation appeared with high frequency, and in all of them the toxicity was relieved. Aggregation defects in these mutants and in sis1-85 were not complemented in the cross to the hsp104 mutant, demonstrating an unusual type of inheritance. Since Hsp104 is required for prion maintenance in yeast, this suggested a role for prions in polyQ aggregation and toxicity. We screened a set of deletions of nonessential genes coding for known prions and related proteins and found that deletion of the RNQ1 gene specifically suppressed aggregation and toxicity of polyQ. Curing of the prion form of Rnq1 from wild-type cells dramatically suppressed both aggregation and toxicity of polyQ. We concluded that aggregation of polyQ is critical for its toxicity and that Rnq1 in its prion conformation plays an essential role in polyQ aggregation leading to the toxicity.

Crosses, Genetic↗
PubMed1992

[Rainbow trout and zebrafish, two models for continuous toxicity tests: relative sensitivity, species and organ specificity in cytopathologic reaction of liver and intestines to atrazine].

In order to elucidate cytopathological alterations in hepatic and intestinal cells, immature rainbow trout (Oncorhynchus mykiss) were exposed for five weeks to 10, 20, 40, and 160 micrograms/l of the herbicide atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine; model 1). For comparison, ultrastructural changes in female zebra fish (Brachydanio rerio) liver were studied after exposure to 100, 1,000 and 10,000 micrograms/l atrazine for three months (exposure from egg stage to sexual maturation; model 2). Neither epithelial nor glandular cells in the gastrointestinal tract of rainbow trout reveal cytological modifications following exposure to atrazine. In contrast, hepatocytes of rainbow trout and zebra fish clearly display dose-dependent and species-specific cytopathological effects at 40 and 1000 micrograms/l, respectively. In rainbow trout (model 1), rough endoplasmic reticulum (RER) appears of particular diagnostic value for the effects of atrazine, since it already shows a full spectrum of cytological alterations after 40 micrograms/l, and since in cells without RER modifications no further cytopathological symptoms can be revealed. At 40 micrograms/l atrazine, further changes include disturbance of the intracellular compartmentation, increased heterogeneity of mitochondria (longitudinally arranged cristae, branching, size), formation of myelinated bodies as well as immigration of macrophages and granulocytes along the biliary system and the space of Disse. The separation of peripheral storage areas from the central organelle-containing cytoplasm is no longer evident at 80 micrograms/l, and the phagocytic activity of invading macrophages is drastically increased. Following exposure to 160 micrograms/l atrazine, additional pathological changes comprise clubshaped deformation of mitochondria, formation of myelinated bodies in the intermembranous space of mitochondria, increase of degranulated ER cisternae and lysosomes, as well as perisinusoidal accumulation of lipid droplets. Deformation of the nuclear envelope, elevated mitotic activity and an increased number of nuclei with two or more nucleoli indicate interactions between atrazine and the nucleus. In the liver of female zebra fish (model 2), atrazine-induced alterations are limited to increased parenchymal variability, disturbance of the intracellular compartmentation, partial RER fractionation and vesiculation, club-shaped deformation of mitochondria and an increase in the number of lysosomes, myelinated bodies and invading macrophages at 1000 micrograms/l atrazine. After three months at 10,000 micrograms/l, mortality of zebra fish is increased to 100%. According to cytopathological alterations of hepatocytes following long-term exposure, susceptibility of the test model rainbow trout to atrazine appears higher than that of the model zebra fish.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Isotype-restricted hyperimmunity in a murine model of the toxic oil syndrome.

The toxic oil syndrome is characterized by IgE elevation and eosinophilia, as well as scleroderma-like skin manifestations and other symptoms of autoimmune disease. Fatty acid anilides, found in large amounts in adulterated cooking oil, were suspected to be the etiologic agent in this disease. The capacity of oleic acid anilide to induce features of autoimmunity in vivo was investigated. B10.S mice were continuously treated i.p. with oleic acid anilide for 6 wk by using osmotic pumps. A significant increase in IgE and IgM serum levels was observed after 1 to 3 wk; subsequently five of six mice developed IgG1 levels 3.5- to 10-fold higher than the controls. Anilide-treated mice developed splenomegaly with a 2.1- and a 3.5-fold increase in IgM- and IgG-bearing splenocytes, respectively, and a 5.6- and 29-fold elevation in functional IgM- and IgG-secreting cells, respectively. Increased serum levels of predominantly IgM antibodies to histone, denatured DNA, and DNP as well as rheumatoid factor were detected. In vivo expression in the spleen of 10 cytokine genes was also examined, and mRNA encoding IL-1 beta and IL-6 were significantly elevated in splenocytes of anilide-treated mice. The enhanced Ig production suggests that anilide induced a cytokine-mediated polyclonal activation of B cells. Elicitation of IgM antibodies to denatured forms of autoantigens indicates that anilide treatment partially broke autoimmune tolerance in these mice. Anilide-treated mice may be a useful animal model for further exploring the mechanism and pathogenesis of systemic autoimmunity in the toxic oil syndrome.

Anilides↗
PubMed2006

Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy.

Myotonic dystrophy (DM1), the most common muscular dystrophy in adults, is caused by an expanded (CTG)n tract in the 3' UTR of the gene encoding myotonic dystrophy protein kinase (DMPK), which results in nuclear entrapment of the 'toxic' mutant RNA and interacting RNA-binding proteins (such as MBNL1) in ribonuclear inclusions. It is unclear if therapy aimed at eliminating the toxin would be beneficial. To address this, we generated transgenic mice expressing the DMPK 3' UTR as part of an inducible RNA transcript encoding green fluorescent protein (GFP). We were surprised to find that mice overexpressing a normal DMPK 3' UTR mRNA reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, histopathology and RNA splicing defects in the absence of detectable nuclear inclusions. However, we observed increased levels of CUG-binding protein (CUG-BP1) in skeletal muscle, as seen in individuals with DM1. Notably, these effects were reversible in both mature skeletal and cardiac muscles by silencing transgene expression. These results represent the first in vivo proof of principle for a therapeutic strategy for treatment of myotonic dystrophy by ablating or silencing expression of the toxic RNA molecules.

3' Untranslated Regions↗
PubMed1990

An animal model to study toxicity of central nervous system therapy for childhood acute lymphoblastic leukemia: effects on behavior.

Central nervous system prophylactic therapy used in the treatment of acute lymphoblastic leukemia can reduce intelligence quotient scores and impair memory and attention in children. Cranial irradiation, intrathecal methotrexate, and steroids are commonly utilized in acute lymphoblastic leukemia therapy. How they induce neurotoxicity is unknown. This study employs an animal model to explore the induction of neurotoxicity. Male and female Sprague-Dawley rats at 17 and 18 days of age were administered 18 mg/kg prednisolone, 2 mg/kg methotrexate, and 1000 cGy cranial irradiation. Another 18-day-old group was administered 1000 cGy cranial irradiation but no drugs. Matching controls received saline and/or a sham exposure to radiation. All animals at 6 weeks and 4 months of age were tested for alterations in spontaneous behavior. A computer pattern recognition system automatically recorded and classified individual behavioral acts displayed during exploration of a novel environment. Measures of behavioral initiations, total time, and time structure were used to compare treated and control animals. A permanent sex-specific change in the time structure of behavior was induced by the prednisolone, methotrexate, and radiation treatment but not by radiation alone. Unlike hyperactivity, the effect consisted of abnormal clustering and dispersion of acts in a pattern indicative of disrupted development of sexually dimorphic behavior. This study demonstrates the feasibility of an animal model delineating the agent/agents responsible for the neurotoxicity of central nervous system prophylactic therapy.

Animals↗
PubMed2002

Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease.

Recent epidemiological and clinical data suggest that persons with low folic acid levels and elevated homocysteine levels are at increased risk of Alzheimer's disease (AD), but the underlying mechanism is unknown. We tested the hypothesis that impaired one-carbon metabolism resulting from folic acid deficiency and high homocysteine levels promotes accumulation of DNA damage and sensitizes neurons to amyloid beta-peptide (Abeta) toxicity. Incubation of hippocampal cultures in folic acid-deficient medium or in the presence of methotrexate (an inhibitor of folic acid metabolism) or homocysteine induced cell death and rendered neurons vulnerable to death induced by Abeta. Methyl donor deficiency caused uracil misincorporation and DNA damage and greatly potentiated Abeta toxicity as the result of reduced repair of Abeta-induced oxidative modification of DNA bases. When maintained on a folic acid-deficient diet, amyloid precursor protein (APP) mutant transgenic mice, but not wild-type mice, exhibited increased cellular DNA damage and hippocampal neurodegeneration. Levels of Abeta were unchanged in the brains of folate-deficient APP mutant mice. Our data suggest that folic acid deficiency and homocysteine impair DNA repair in neurons, which sensitizes them to oxidative damage induced by Abeta.

Alzheimer Disease↗
PubMed2000

Maximum tolerated doses of methotrexate and 7-hydroxy-methotrexate in a model of acute toxicity in rats.

PURPOSE: After more than 50 years of methotrexate (MTX) treatment of acute lymphoblastic leukaemia (ALL), it is currently believed that as long as dose escalations are followed by adequate leucovorin rescue guided by monitoring MTX serum concentrations, hydration and urinary alkalinization, high-dose MTX (HD-MTX) can be tolerated without life-threatening toxicity. However, our recent experimental animal studies of the major metabolite of MTX, 7-OH-MTX, indicate that this concept may have some limitations. Animals with levels of 7-OH-MTX of 1 mM, which is below the levels routinely found in patients on HD-MTX, demonstrate intolerable toxicity and some animals die within 8 h. Electron microscopy indicates that endothelial cell and platelet functions are perturbed. Since animal data are lacking, and interspecies differences not known, we wanted to investigate the maximum tolerated doses of MTX and 7-OH-MTX in a rat model of short-term effects. The maximum tolerated dose was chosen instead of LD(50) for reasons of animal welfare. METHODS: We infused MTX and 7-OH-MTX into anaesthetized male Wistar rats and monitored the animals for 8 h. The drugs were given as a bolus plus continuous infusion. The dose-finding ranges were 1.8 11.3 g/kg MTX and 0.1-1.2 g/kg 7-OH-MTX. RESULTS: The maximum tolerated dose was between 3 and 5 g/kg for MTX and lower than 0.1 g/kg for 7-OH-MTX. The mean serum concentrations of MTX and 7-OH-MTX in animals that did not survive the 8-h period were 21.9 and 1.6 mM, respectively. The animals that received the highest MTX or 7-OH-MTX doses and concentrations died after sudden reductions in heart rate and blood pressure. CONCLUSIONS: We demonstrated a lower maximum tolerated dose of 7-OH-MTX than of MTX in rats after 8 h. The 7-OH-MTX concentrations were in the therapeutic range after HD-MTX. If the rat/human interspecies differences are not large, our data may indicate that HD-MTX regimens should not be further dose intensified, due not so much to the effects of MTX as to those of 7-OH-MTX.

Animals↗
PubMed1998

Strain-dependent cytokine profile and susceptibility to oleic acid anilide in a murine model of the toxic oil syndrome.

The toxic oil syndrome (TOS) was caused by the ingestion of an adulterated rapeseed oil containing oleic acid anilide (OAA). It was characterized by lethal symptoms in the acute phase and by symptoms of idiopathic autoimmune diseases in the chronic phase. The pathogenetic mechanisms remain unclear. In a murine model of TOS we demonstrate strain-dependent effects on the immune system after treatment with OAA intraperitoneally. While C57BL/6 (H-2b) mice develop a polyclonal B cell activation without disease symptoms, most A/J (H-2a) mice suffer an acute lethal wasting disease. These differences are reflected in the splenic cytokine gene expression and secretion and in the Ig production. Increased IgE serum levels and reduced TNF-beta mRNA suggest a Th2 cell response in C57BL/6 mice. In A/J mice, splenocytes express IL-1alpha, IL-10, and IFN-gamma mRNA in vivo and secrete high levels of TNF-alpha in vitro. These observations resemble the human condition in TOS with development of either an acute lethal disease or a chronic autoimmune-like disease. As in other chemical-induced reactions genetic susceptibility seems to be important.

Anilides↗
PubMed2005

Metabonomic modeling of drug toxicity.

Global metabolic profiling (metabonomics/metabolomics) has shown particular promise in the area of toxicology and drug development. In both preclinical screening and mechanistic exploration, metabolic profiling can offer rapid, noninvasive toxicological information that is robust and reproducible, with little or no added technical resources to existing studies in drug metabolism and toxicity. In this review, the study design and analytical technology required for metabonomics are discussed, along with key examples of how fundamental questions in drug development can be addressed. Strategies for metabonomic data analysis in toxicity assessment are detailed in both principle and practice, together with a description of toxicologically relevant metabolic biomarkers. Extended into the assessment of efficacy and toxicity in the clinic, metabonomics may prove crucial in making personalized therapy and pharmacogenomics a reality.

Animals↗
PubMed2006

Model of the toxic complex of anthrax: responsive conformational changes in both the lethal factor and the protective antigen heptamer.

The toxic complex of anthrax is formed when the monomeric protective antigen (PA) (83 kDa), while bound to its cell-surface receptor, is first converted to PA63 heptamers (PA63h) following N-terminal proteolytic cleavage, and then lethal (LF) (90 kDa) or edema factor (EF) binds to the heptamer. We report a "pseudoatomic" model for the complex of PA63h and full-length LF determined by applying the normal-mode flexible fitting procedure to a approximately 18 A cryo-electron microscopy (EM) density map of the complex. The model describes the interacting surface that buries a total area of approximately 10,140 A2 comprising approximately 40% charged, and approximately 30% each of polar and hydrophobic residues. For the heptamer, the buried surface, composed of approximately 110 residues, involves primarily three monomers and includes for two, similar stretches of the polypeptide chain from domain 1. For LF, the interface again involves approximately 110 residues, mostly from the N-terminal domain I (LF(N)), and the structurally homologous C-terminal domain IV. Most interestingly, bound LF displays a marked conformational change resulting from a "collapse" of domains I, III, and IV on domain II, with the largest movement of approximately 9 A noted for domain I. On the other hand, primarily, rigid-body movements, larger than approximately 10 A for three PA63 monomers, cause the hourglass-shaped heptamer lumen to enlarge by as much as approximately 50% near the middle of the molecule. Such concerted structural rearrangements in LF and the heptamer can facilitate ingress of the ligand into the heptamer lumen prior to unfolding and release through the PA63h channel formed in the acidic late endosomal membrane.

Antigens, Bacterial↗
PubMed1994

Hemodynamic effects of 3,4-diaminopyridine in a swine model of verapamil toxicity.

STUDY HYPOTHESIS: 3,4-Diaminopyridine (3,4-DAP) may reverse the hemodynamic effects of severe verapamil toxicity. DESIGN: A nonblinded acute animal preparation. INTERVENTIONS: Eighteen chloralose-anesthetized and instrumented swine were poisoned with verapamil at 10 mg/kg/hr for five minutes and then 5 mg/kg/hr until a systolic blood pressure of 55 mm Hg was achieved. Heart rate, lead II ECG, mean arterial pressure, left ventricular dP/dT max, and cardiac index were monitored. Nine control animals received 0.2 mL/kg/min infusion of normal saline, and nine treatment animals received similar volumes of 1 mg/kg/min 3,4-DAP until systolic blood pressure reached 100 mm Hg, an elapsed time of 30 minutes, or death. RESULTS: Verapamil toxicity was produced in all animals following an average dose of 1.38 +/- 0.44 mg/kg verapamil, and resulted in diminished mean arterial pressure, dP/dT max, cardiac index, and heart rate to average values of 47%, 32%, 46%, and 88% of baseline values, respectively. Transient atrioventricular dissociation was noted in only 22% of cases. 3,4-DAP treatment (with an average dose of 14 +/- 5.6 mg/kg) resulted in significant increases in mean arterial pressure, dP/dT max, cardiac index, and heart rate to 136%, 298%, 149%, and 158% of baseline values, respectively. Mortality was unchanged (22% in both groups). 3,4-DAP treatment was complicated by muscle twitching, tachycardia (rate of more than 180) and hypertension (diastolic blood pressure of more than 110 mm Hg) each in 44% of cases. CONCLUSION: Although 3,4-DAP reversed the hypotensive and negative inotropic effects of verapamil toxicity, it failed to improve survival and resulted in several complications including muscle twitching, tachycardia, and hypertension.

4-Aminopyridine↗
PubMed1993

Cell culture models for lead toxicity in neuronal and glial cells.

Two goals of lead (Pb) neurotoxicity research are to identify molecular and cellular alterations that underlie behavioral deficits and to define mechanisms of Pb uptake and tolerance in cells that accumulate Pb. Cell and tissue cultures are practical tools with which to pursue these goals, offering such advantages over in vivo methods as defined cell types, an extracellular environment that can be precisely manipulated, and direct observation. On the other hand, toxicity studies with cultured cells also present new challenges of design and interpretation. If a living vertebrate is like an orchestra playing a Beethoven symphony, then tissue culture is like two of the violinists playing their part alone. Historically, Pb toxicity studies with cell and tissue culture can be divided into an exploratory phase, an expansion phase, and a newly emerging intensification phase. In the exploratory phase, gross cytotoxic effects from massive Pb exposure (50-500 microM) were characterized. The collective data suggest differential sensitivity to Pb toxicity among various types of cultured neural cells, ranked as follows from most to least sensitive: myelinating cells, neurons, and astroglia. In addition, astroglia were shown to take up and store large amounts of Pb intracellularly, a phenomenon resembling the Pb-sequestering ability hypothesized for mature astroglia in vivo. The mechanisms of Pb entry may involve an anion exchanger, Ca2+ channels, or some other transport process. Three ingrained problems concerning the use of cell cultures began to emerge: appropriate dose regimens, biologically relevant forms of Pb (i.e. ionized or complexed with other molecules), and suitable measurements of Pb effects. These problems received scrutiny in the expansion phase, during which subcellular targets of Pb-induced damage were examined, specifically membranes, enzymes, and Ca-mediated cellular processes. Investigators attempted to define a biologically relevant dose regimen in vitro, as well as a threshold dose below which Pb had no biological effect. Effects of Pb at nanomolar concentrations in intact cells and tissue homogenates stimulated the metamorphosis of Pb toxicity studies in cell culture into a new phase, the intensification phase. Alterations in discrete molecular targets, particularly those effects in the cell that may be metabolically amplified, will be a major focus of this phase. Critical molecular targets for Pb-induced injury appear to be present during neuritogenesis and/or synaptogenesis. With the availability of cell culture models for neurite extension and synapse formation, this area may be another focus for innovative Pb neurotoxicity research.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Perilla ketone toxicity: a chemical model for the study of equine restrictive lung disease.

Perilla ketone was assessed for its usefulness as a model of equine restrictive pulmonary disease. Three ponies were given 18 mg/kg bodyweight synthetic perilla ketone in dimethyl-sulphoxide. Within 24 h of administration, respiratory rate, peak inspiratory and expiratory flow rates and minute volume were increased. By 48 h there was a significant decrease in tidal volume, and blood pH and base excess were also decreased but not outside normal limits. At necropsy there was congestion and oedema of the lungs. Histologically there was diffuse alveolar injury but no evidence of significant obstruction in bronchial or bronchiolar lumina. It is assumed that perilla ketone toxicity in ponies produces a restrictive disease without a significant obstructive component.

Animals↗