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Environmental Science and Pollution... Nov 2020The toxicity of endocrinologically active pharmaceuticals finasteride (FIN) and melengestrol acetate (MGA) was assessed in freshwater mussels, including acute (48 h)...
The toxicity of endocrinologically active pharmaceuticals finasteride (FIN) and melengestrol acetate (MGA) was assessed in freshwater mussels, including acute (48 h) aqueous tests with glochidia from Lampsilis siliquoidea, sub-chronic (14 days) sediment tests with gravid female Lampsilis fasciola, and chronic (28 days) sediment tests with juvenile L. siliquoidea, and in chronic (42 days) sediment tests with the amphipod Hyalella azteca and the mayfly Hexagenia spp. Finasteride was not toxic in acute aqueous tests with L. siliquoidea glochidia (up to 23 mg/L), whereas significant toxicity to survival and burial ability was detected in chronic sediment tests with juvenile L. siliquoidea (chronic value (ChV, the geometric mean of LOEC and NOEC) = 58 mg/kg (1 mg/L)). Amphipods (survival, growth, reproduction, and sex ratio) and mayflies (growth) were similarly sensitive (ChV = 58 mg/kg (1 mg/L)). Melengestrol acetate was acutely toxic to L. siliquoidea glochidia at 4 mg/L in aqueous tests; in sediment tests, mayflies were the most sensitive species, with significant growth effects observed at 37 mg/kg (0.25 mg/L) (ChV = 21 mg/kg (0.1 mg/L)). Exposure to sublethal concentrations of FIN and MGA had no effect on the (luring and filtering) behaviour of gravid L. fasciola, or the viability of their brooding glochidia. Based on the limited number of measured environmental concentrations of both chemicals, and their projected concentrations, no direct effects are expected by these compounds individually on the invertebrates tested. However, organisms are exposed to contaminant mixtures in the aquatic environment, and thus, the effects of FIN and MGA as components of these mixtures require further investigation.
Topics: Animals; Bivalvia; Ephemeroptera; Female; Finasteride; Invertebrates; Melengestrol Acetate; Pharmaceutical Preparations; Water Pollutants, Chemical
PubMed: 32696412
DOI: 10.1007/s11356-020-10121-7 -
Environmental Science and Pollution... Jan 2021
PubMed: 33216304
DOI: 10.1007/s11356-020-11617-y -
Food Safety (Tokyo, Japan) Dec 2017Food Safety Commission of Japan (FSCJ) conducted a risk assessment of melengestrol acetate (MGA, CAS No. 2919-66-6), a synthetic hormone, based on results from various...
Food Safety Commission of Japan (FSCJ) conducted a risk assessment of melengestrol acetate (MGA, CAS No. 2919-66-6), a synthetic hormone, based on results from various studies. MGA was recognized to have no genotoxicity relevant to human health, and it enabled FSCJ to specify an acceptable daily intake (ADI) in the assessment. studies using various human hormone-receptors showed that MGA exerts biological action primarily as progestogens and secondarily as glucocorticoids. Major adverse effects of MGA observed were mammary gland hyperplasia, endometrial hyperplasia, and a lack of corpora lutea, accompanying the elevated level of serum prolactin. Increased incidence of mammary gland tumor was observed in C3Han/f mice at the dose of 1.5 mg/kg bw/day in a carcinogenicity study. The increase was presumably due to MGA-induced hyperprolactinemia, but not a direct effect of MGA from the experiment, using a prolactin inhibitor. Inhibitions of estrus and ovulation, in addition to dystocia, were observed in female animals in the reproductive and developmental toxicity studies. Malformations such as cleft palate, clubfoot, umbilical hernia, and defective skeletal ossification were observed in rabbits at doses of 0.8 and 1.6 mg/kg bw/day in a developmental toxicity study. However, these were likely due to the corticosteroidal (glucocorticoid) action of MGA. The no-observed-adverse-effect level (NOAEL) was obtained from a rhesus monkey study given orally 1.5 µg/kg bw/day of MGA over the one menstrual-cycle. The value was, however, the result of the study using the large common ratio of 10. In another study, the lowest-observed-adverse-effect level (LOAEL) of 5 µg/kg bw/day, obtained from a cynomolgus monkey given MGA over the three menstrual-cycles. The LOAEL value was estimated close to the biological threshold, because of no obvious hormonal disorders despite of minimal change of menstrual cycle. Therefore, FSCJ considered it appropriate to specify an ADI on the basis of the LOAEL obtained from a cynomolgus monkey study over the three menstrual-cycles, and to add an additional safety factor of 2. Consequently, FSCJ specified the ADI of 0.025 µg/kg bw/day by applying a safety factor of 200 to the LOAEL of 5 µg/kg bw/day in a cynomolgus monkey study over the three menstrual-cycles.
PubMed: 32231940
DOI: 10.14252/foodsafetyfscj.2017009s -
Environmental Health Perspectives Nov 2001The steroids trenbolone acetate (TbA) and melengestrol acetate (MGA) are licensed as growth promoters for farm animals in several meat-exporting countries. Although many...
The steroids trenbolone acetate (TbA) and melengestrol acetate (MGA) are licensed as growth promoters for farm animals in several meat-exporting countries. Although many studies have explored their safety for both animals and consumers, little is known about their fate after excretion by the animal. Our study aimed to determine the residues and degradation of trenbolone and MGA in solid dung, liquid manure, and soil. In animal experiments lasting 8 weeks, cattle were treated with TbA and MGA. Solid dung and, in case of trenbolone, liquid manure were collected and spread on maize fields after 4.5 and 5.5 months of storage, respectively. Determination of the hormone residues in all samples included extraction, clean-up (solid-phase extraction), separation of metabolites and interfering substances by HPLC (RP-18), and quantification by sensitive enzyme immunoassay. Procedures were validated by mass spectrometry (MS) methods. During storage of liquid manure the level of trenbolone decreased from 1,700 to 1,100 pg/g (17alpha-isomer), corresponding to a half-life of 267 days. Before storage, the concentrations in the dung hill ranged from 5 to 75 ng/g TbOH and from 0.3 to 8 ng/g MGA. After storage, levels up to 10 ng/g trenbolone, and 6 ng/g MGA were detected. In the soil samples trenbolone was traceable up to 8 weeks after fertilization, and MGA was detected even until the end of the cultivation period. The results show that these substances should be investigated further concerning their potential endocrine-disrupting activity in agricultural ecosystems.
Topics: Agriculture; Anabolic Agents; Animal Husbandry; Animals; Cattle; Chromatography, High Pressure Liquid; Ecosystem; Environmental Exposure; Female; Glucocorticoids; Manure; Mass Spectrometry; Melengestrol Acetate; Soil Pollutants; Trenbolone Acetate
PubMed: 11713000
DOI: 10.1289/ehp.011091145 -
Poultry Science Nov 2005Induced molting increases egg quality and egg production and extends the productive life of hens. Molting is accomplished by feed withdrawal, which has been criticized... (Randomized Controlled Trial)
Randomized Controlled Trial
Melengestrol acetate in experimental diets as an effective alternative to induce a decline in egg production and reversible regression of the reproductive tract in laying hens. I. Determining an effective concentration of melengestrol acetate.
Induced molting increases egg quality and egg production and extends the productive life of hens. Molting is accomplished by feed withdrawal, which has been criticized for not addressing hen well-being, and current alternatives have resulted in poor postmolt performance and inadequate well-being. Molting leads to regression of follicles on the ovary and causes loss of steroidogenic support for the oviduct, leading to cessation of lay. Melengestrol acetate (MGA), an orally active progestin, may decrease support for the ovary, resulting in loss of support for the oviduct, while hens are fed a balanced diet. In this experiment, a dose response study, Hy-Line W-36 hens were fed 0, 0.1, 1, 4, or 8 mg of MGA per hen/d in a balanced diet for 28 d and then returned to a normal diet. Four birds on d 0 and 4 birds per treatment on d 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44 were euthanized. The weight of the ovary with follicles, magnum, shell gland, and oviduct were determined. A decrease in egg production was observed in those groups receiving 4 and 8 mg of MGA, until removal of MGA from the diet. After d 28, egg production increased to the production level of hens fed 0, 0.1, or 1 mg of MGA. The weight of the ovary with follicles, oviduct, magnum, and shell gland were unchanged throughout in groups fed 0, 0.1, or 1 mg of MGA. However, groups fed 4 or 8 mg of MGA exhibited a decrease (P < 0.05) in the weight of the ovary with follicles, oviduct, magnum, and shell gland until d 28. Recrudescence of the large yellow follicles as well as rejuvenation of the oviduct and its components, the magnum and shell gland, in the 4 and 8 mg MGA groups occurred by d 44. Melengestrol acetate, fed to hens on a balanced layer diet, caused reversible regression of follicles and, therefore, removal and return of support for the oviduct.
Topics: Aging; Animal Feed; Animals; Body Weight; Chickens; Diet; Dose-Response Relationship, Drug; Female; Genitalia, Female; Glucocorticoids; Melengestrol Acetate; Oviposition; Time Factors
PubMed: 16463972
DOI: 10.1093/ps/84.11.1750 -
Poultry Science Nov 2005Induced molting increases egg quality and egg production and extends the productive life of hens. Molting is accomplished by feed withdrawal, which has received... (Randomized Controlled Trial)
Randomized Controlled Trial
Melengestrol acetate as an effective alternative to induce a decline in egg production and reversible regression of the reproductive tract in laying hens. II. Effects on postmolt egg quality.
Induced molting increases egg quality and egg production and extends the productive life of hens. Molting is accomplished by feed withdrawal, which has received criticism, and alternatives described thus far result in poor postmolt performance. Melengestrol acetate at a dosage of 4 or 8 mg/d, in a balanced diet, leads to reversible regression of the reproductive tract. However, this alternative must also increase egg quality after rest to be considered an adequate method by the industry. Hy-Line W-36 (n = 497) laying hens were assigned randomly to a diet containing 0 mg of melengestrol acetate (MGA; control) throughout the experiment or 4 or 8 mg of MGA/d for 2, 4, or 6 wk. Upon reaching 50 and 70% lay, after MGA removal, eggs were collected for measurements of egg quality, including Haugh units (i.e., internal egg quality), shell thickness, and breaking strength (i.e., external egg quality). Haugh units were greater (P < 0.05) for eggs laid by hens molted with a diet containing 8 mg of MGA for all durations compared with controls. Shell thickness was greater (P < 0.05) when hens were treated with 4 mg of MGA for 6 wk and 8 mg of MGA for 4 and 6 wk compared with control. Egg breaking strength was greater (P < 0.05) than controls for all hens fed MGA, regardless of dosage or duration of feeding. A subset of hens was fed 8 mg of MGA per hen/d for 2 wk, and eggs were collected for 3 wk. Seven days after MGA was removed from the diet, the amount of MGA in the yolk was below the level of detection of the assay, and the concentration found in the eggs at all time points was 3 orders of magnitude below the Food and Drug Administration's tolerance for MGA in edible tissue. When used as an alterative method to induce a rest, MGA leads to an increase in the internal and external egg quality of hens compared with nonmolted hens.
Topics: Aging; Animal Feed; Animals; Chickens; Dose-Response Relationship, Drug; Drug Administration Schedule; Egg Shell; Female; Genitalia, Female; Glucocorticoids; Melengestrol Acetate; Oviposition; Ovum
PubMed: 16463973
DOI: 10.1093/ps/84.11.1757 -
Journal of Dairy Science Dec 1978Effects of melengestrol acetate on reproductive performance of 48 female rats and 20 of their female progeny were evaluated in two experiments. Treatments of 0, .01, and...
Effects of melengestrol acetate on reproductive performance of 48 female rats and 20 of their female progeny were evaluated in two experiments. Treatments of 0, .01, and .1 mg in .1 ml of propylene glycol were given three groups of 16 rats for 7 days. From day 7 following sperm detection (10-day breeding period), half from each group received .1 mg per day for 14 days. Experiment 2 tested performance of 10 progeny exposed or unexposed to in utero treatment. Cyclic changes in Experiment 1 were inhibited only in animals receiving daily initial treatment of .1 mg. Estrus was detected in 61.5% of animals within 48 h of treatment withdrawal. Synchronization caused no significant changes in conception rates or postbreeding results of treatment. Treatment during gestation lowered weight gain for dams, increased gestation length, and decreased number of pups per litter. Treatment lowered mean weight per litter and weight per pup. It also caused high mortality among pups. In Experiment 2, there were no differences between progeny groups in gestation length, litter size, weight per litter, weight per pup, or mortality rate.
Topics: Animals; Body Weight; Estrus Synchronization; Female; Gestational Age; Maternal-Fetal Exchange; Melengestrol Acetate; Pregnadienes; Pregnancy; Rats; Reproduction; Vagina
PubMed: 570575
DOI: 10.3168/jds.S0022-0302(78)83802-8 -
Antimicrobial Agents and Chemotherapy 2014Candida species are the cause of 60% of all mycoses in immunosuppressed individuals, leading to ∼150,000 deaths annually due to systemic infections, whereas the...
Candida species are the cause of 60% of all mycoses in immunosuppressed individuals, leading to ∼150,000 deaths annually due to systemic infections, whereas the current antifungal therapies either have toxic side effects or are insufficiently efficient. We performed a screening of two compound libraries, the Enzo and the Institute for Molecular Medicine Finland (FIMM) oncology collection library, for anti-Candida activity based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. From a total of 844 drugs, 26 agents showed activity against Candida albicans. Of those, 12 were standard antifungal drugs (SADs) and 7 were off-target drugs previously reported to be active against Candida spp. The remaining 7 off-target drugs, amonafide, tosedostat, megestrol acetate, melengestrol acetate, stanozolol, trifluperidol, and haloperidol, were identified with this screen. The anti-Candida activities of the new agents were investigated by three individual assays using optical density, ATP levels, and microscopy. The antifungal activities of these drugs were comparable to those of the SADs found in the screen. The aminopeptidase inhibitor tosedostat, which is currently in a clinical trial phase for anticancer therapy, displayed a broad antifungal activity against different Candida spp., including Candida glabrata. Thus, this screen reveals agents that were previously unknown to be anti-Candida agents, which allows for the design of novel therapies against invasive candidiasis.
Topics: Antifungal Agents; Antineoplastic Agents; Candida; Clinical Trials as Topic; Drug Discovery; Drug Repositioning; Drug Resistance, Fungal; Glycine; High-Throughput Screening Assays; Humans; Hydroxamic Acids; Microbial Sensitivity Tests; Small Molecule Libraries
PubMed: 24277040
DOI: 10.1128/AAC.01087-13 -
Shokuhin Eiseigaku Zasshi. Journal of... 2024The present study verified that it is possible to analyze melengesterol acetate using the existing multi-residue method. Melengestrol acetate was extracted from...
The present study verified that it is possible to analyze melengesterol acetate using the existing multi-residue method. Melengestrol acetate was extracted from livestock products using acidic acetonitrile acidified with acetic acid in the presence of n-hexane and anhydrous sodium sulfate. The crude extracts were cleaned up using an octadecylsilanized silica gel cartridge column. Separation by HPLC was performed using an octadecylsilanized silica gel column with linear gradient elution of 0.1 vol% formic acid and acetonitrile containing 0.1 vol% formic acid. For the determination of the analyte, tandem mass spectrometry with positive ion electrospray ionization was used. In recovery tests using four livestock products fortified with maximum residue limits levels of melengestrol acetate (0.001-0.02 mg/kg), the truenesses ranged from 82% to 100%, and the repeatabilities for the entire procedure ranged from 0.5 RSD% to 5.6 RSD%. In recovery tests using 11 livestock products fortified with 0.0005 mg/kg of melengestrol acetate, the truenesses ranged from 88% to 99%, and the repeatabilities ranged from 1.3 RSD% to 5.4 RSD%. The limit of quantification for melengestrol acetate in livestock products was 0.0005 mg/kg.
Topics: Animals; Liquid Chromatography-Mass Spectrometry; Melengestrol Acetate; Chromatography, Liquid; Livestock; Silica Gel; Tandem Mass Spectrometry; Acetonitriles; Formates
PubMed: 38432897
DOI: 10.3358/shokueishi.65.15 -
Journal of Agricultural and Food... Jun 2023Gestagens, a class of veterinary drugs also called progestogens, are synthetic hormones used to increase feed efficiency and rate of gain in heifers. The Canadian Food...
Gestagens, a class of veterinary drugs also called progestogens, are synthetic hormones used to increase feed efficiency and rate of gain in heifers. The Canadian Food Inspection Agency analyzes progestogens melengestrol acetate (MGA), megestrol acetate, and chlormadinone acetate using liquid chromatography-mass spectrometry (LC-MS). Our conventional gestagen method for kidney fat has many time-consuming steps, including solid-phase extraction. A sample preparation procedure having fewer clean-up steps was developed for routine diagnostic analysis of kidney fat and provided similar results faster, and at lower cost. A confirmatory liver method for gestagens, developed using salt-assisted extraction, employed minimal clean-up steps that resulted in high chemical background at the desired lower limit of quantification (LLOQ). Differential ion mobility spectrometry, specifically high-field asymmetric waveform ion mobility spectrometry (FAIMS), was used to filter chemical background in the gas phase. The effect of the ionization probe position on FAIMS parameters, including sensitivity, is described. With LC-FAIMS-MS, chemical background for each gestagen was virtually eliminated, resulting in a quantitative liver method having the desired 0.6 ng/g LLOQ and estimated limits of detection (LODs) up to 140 times lower than LC-MS. Incurred MGA samples, analyzed using kidney fat and liver methods from the same animal, show levels within the quantitative ranges of both methods.
Topics: Animals; Cattle; Female; Progestins; Canada; Chromatography, Liquid; Mass Spectrometry; Melengestrol Acetate; Liver
PubMed: 37319426
DOI: 10.1021/acs.jafc.3c01200