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General and Comparative Endocrinology Sep 2018Environmental gestagens are an emerging class of contaminants that have been recently measured in surface water and can interfere with reproduction in aquatic...
Environmental gestagens are an emerging class of contaminants that have been recently measured in surface water and can interfere with reproduction in aquatic vertebrates. Gestagens include endogenous progestogens, such as progesterone (P4), which bind P4-receptors and have critically important roles in vertebrate physiology and reproduction. Gestagens also include synthetic progestins, which are components of human and veterinary drugs, such as melengestrol acetate (MGA). Endogenous progestogens are essential in the regulation of reproduction in mammalian species, but the role of P4 in amphibian larval development remains unclear. This project aims to understand the roles and the regulatory mechanisms of P4 in amphibians and to assess the consequences of exposures to environmental gestagens on the P4-receptor signaling pathways in frogs. Here, we established the developmental profiles of the P4 receptors: the intracellular progesterone receptor (ipgr), the membrane progesterone receptor β (mpgrβ), and the progesterone receptor membrane component 1 (pgrmc1) in Western clawed frog (Silurana tropicalis) embryos using real-time qPCR. P4-receptor mRNAs were detected throughout embryogenesis. Transcripts for ipgr and pgrmc1 were detected in embryos at Nieuwkoop and Faber (NF) stage 2 and 7, indicative of maternal transfer of mRNA. We also assessed the effects of P4 and MGA exposure in embryonic and early larval development. Endocrine responses were evaluated through transcript analysis of a suite of gene targets of interest, including: ipgr, mpgrβ, pgrmc1, androgen receptor (ar), estrogen receptor α (erα), follicle stimulating hormone β (fshβ), prolactin (prl), and the steroid 5-alpha reductase family (srd5α1, 2, and 3). Acute exposure (NF 12-46) to P4 caused a 2- to 5-fold change increase of ipgr, mpgrβ, pgrmc1, and ar mRNA levels at the environmentally relevant concentration of 195 ng/L P4. Acute exposure to MGA induced a 56% decrease of srd5α3 at 1140 ng/L MGA. We conclude that environmental exposure to P4 induced multiple endocrine-related transcript responses in amphibians; however, the differential responses of MGA suggest that the effects of MGA are not mediated through the classical P4 signaling pathway in S. tropicalis.
Topics: Animals; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Melengestrol Acetate; Progestins; RNA, Messenger; Receptors, Progesterone; Reproduction; Signal Transduction; Water; Xenopus
PubMed: 29778442
DOI: 10.1016/j.ygcen.2018.05.017 -
Journal of Animal Science Apr 2018Two experiments were conducted to evaluate the effects of a high concentrate, s.c. PGF2α compared with a conventionally concentrated, i.m. PGF2α in estrus...
Two experiments were conducted to evaluate the effects of a high concentrate, s.c. PGF2α compared with a conventionally concentrated, i.m. PGF2α in estrus synchronization protocols for heifers. In Exp. 1, 869 Angus-based beef heifers were enrolled at 8 locations. All heifers were exposed to the 7-d CO-Synch + controlled internal drug release (CIDR) estrus synchronization protocol. On day 7 of the protocol heifers received 100 µg of GnRH i.m., and a CIDR insert for 7 d. On day 0, at CIDR removal, estrous detection patches were applied to heifers and, within location, heifers randomly received 1 of 2 PGF2α treatments: 5 mL of Lutalyse i.m. (CONTROL; n = 434) or a 2 mL of Lutalyse HighCon s.c. (HiCON; n = 435). A second GnRH injection was administered at 54 ± 2 h and heifers were fixed-time AI (TAI). Heifers were evaluated for estrous activity at TAI by determining the activation of estrous detection patches. Pregnancy rates to AI (PR/AI) were diagnosed by transrectal ultrasonography between 35 and 55 d after TAI. The percentage of heifers exhibiting estrus between day 0 and TAI did not differ (P = 0.68) between CONTROL and HiCON treatments (47 vs. 46 ± 4%, respectively). Additionally, PR/AI were similar (P = 0.65) between CONTROL and HiCON treatments (46 vs. 45 ± 3%). In Exp. 2, 190 Angus-based beef heifers were enrolled at 2 locations. Heifers were exposed to the melengestrol acetate (MGA)-PGF2α protocol where they were offered 0.5 mg MGA per day from days 1 to 14. On day 33, heifers were randomly assigned to receive CONTROL (n = 95) or HiCON (n = 95) treatment, and estrous detection aids were applied. Heifers were exposed to AI 12 h after detection of estrus. Heifers not detected in estrus at location 1 received a second PGF2α injection 6 d after the initial PGF2α injection and were placed with fertile bulls. Heifers at location 2 that did not express estrus were administered 100 µg of GnRH i.m. and exposed to TAI 96 h after the initial PGF2α injection. Transrectal ultrasonography was used to diagnose PR/AI between 51 and 57 d after the initial PGF2α injection. The percentage of heifers exhibiting estrus during the estrus detection period was similar (P = 0.40) between CONTROL and HiCON treatments (82 vs. 87 ± 4%). Furthermore, PR/AI were similar (P = 0.62) between CONTROL and HiCON treatments (60 vs. 65 ± 5%). In summary, the 2 concentrations and corresponding routes of administration of PGF2α were similar in efficacy at synchronizing estrus in beef heifers.
Topics: Animals; Cattle; Delayed-Action Preparations; Dinoprost; Estrus; Estrus Detection; Estrus Synchronization; Female; Fertility; Gonadotropin-Releasing Hormone; Male; Melengestrol Acetate; Oxytocics; Pregnancy; Pregnancy Rate; Ultrasonography
PubMed: 29648600
DOI: 10.1093/jas/sky059 -
Journal of the American Veterinary... Apr 2018
Topics: Animals; Breeding; Calcinosis; Contraceptive Agents; Diagnosis, Differential; Drug Implants; Female; Melengestrol Acetate; Panthera; Ultrasonography; Uterine Diseases
PubMed: 29553900
DOI: 10.2460/javma.252.7.801 -
Water Research Apr 2018A broad number of natural and synthetic progestins are widely used in human and veterinary therapies. Although progestins exhibit adverse effects in aquatic organisms,...
A broad number of natural and synthetic progestins are widely used in human and veterinary therapies. Although progestins exhibit adverse effects in aquatic organisms, information about environmental occurrence and fate have been limited to several compounds, hampering the accuracy of risk assessments of the compounds. In this study, a selective and sensitive analytical method was established to simultaneously determine 19 natural and 42 synthetic progestins in environmental waters, and the synthetic progestins included 19-nortestosterone, 17α-hydroxyprogesterone and progesterone derivatives. All of the target compounds were effectively separated using an HSS T3 column, and the recoveries for effluent and river samples were 80-115% and 75-105%, respectively. The detection limits for the 61 analytes were in the range of 0.05-0.60 ng/L and 0.03-0.40 ng/L for the effluent and river samples, respectively. The developed method is applied to analyze the target progestogens in sewage effluent and river water samples from Beijing. The detected concentrations of natural progesterone metabolites (3α-hydroxy-5β-tetrahydroprogesterone) were up to 63 times higher than those of the parent compound. Of the three groups of synthetic progestins, the progesterone derivatives were detected for the first time and had the highest concentrations followed by the 19-nortestosterone and 17α-hydroxyprogesterone derivatives. In contrast to previous studies, the predominant derivative compounds of 19-nortestosterone were found to be 19-nortestosterone, gestodene and mifepristone, and those of 17α-hydroxyprogesterone were 6-epi-medroxy progesterone 17-acetate and melengestrol acetate. The toxicities and environmental risk of these emerging progestins deserves more attention in the future.
Topics: Beijing; Chromatography, High Pressure Liquid; Environmental Monitoring; Progestins; Rivers; Sewage; Tandem Mass Spectrometry; Water Pollutants, Chemical
PubMed: 29407696
DOI: 10.1016/j.watres.2018.01.030 -
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 -
Journal of Environmental Quality Sep 2016Hormone contamination of aquatic systems has been shown to have deleterious effects on aquatic biota. However, the assessment of hormone contamination of aquatic...
Hormone contamination of aquatic systems has been shown to have deleterious effects on aquatic biota. However, the assessment of hormone contamination of aquatic environments requires a quantitative evaluation of the potential effects of sample preservation on hormone concentrations. This study investigated the influence of acidification (pH 2) of surface water samples on the partitioning of hormones among filtrate, filter media, and filter-retained particulate matter. Hormones were spiked into unpreserved and sulfuric acid-preserved ultrapure water and surface water runoff samples. The samples were filtered, and hormones were extracted from the filter and filtrate and analyzed by high-performance liquid chromatography. Acidification did not influence the partitioning of hormones onto the filter media. For the majority of the hormones investigated in this study, the partitioning of hormones to the filter-retained particulate matter was not influenced by acidification. Acidification increased the partitioning of progesterone and melengestrol acetate onto the retained particulate matter (about 25% for both analytes). Incorporation of an isotopically labeled internal standard (ISTD) for progesterone accounted for the loss of progesterone to the filter-retained particulates and resulted in accurate concentrations of progesterone in the filtrate. The incorporation of an ISTD for melengestrol acetate, however, was unable to account for the loss of melengestrol acetate to the retained particulates and resulted in underestimations of melengestrol acetate in the filtrate. Our results indicate that the analysis of melengestrol acetate in acid preserved surface runoff samples should be conducted on the filter-retained particulates as well as the filtrate.
Topics: Filtration; Hormones; Particulate Matter; Water Movements; Water Pollutants, Chemical
PubMed: 27695756
DOI: 10.2134/jeq2016.01.0017 -
Journal of Separation Science Jul 2016A comprehensive strategy combining a quantitative method was developed for 30 banned drugs including β-agonists, hormones, glucocorticoid and psychiatric drugs in swine...
Targeted analysis and determination of β-agonists, hormones, glucocorticoid and psychiatric drugs in feed by liquid chromatography with electrospray ionization tandem mass spectrometry.
A comprehensive strategy combining a quantitative method was developed for 30 banned drugs including β-agonists, hormones, glucocorticoid and psychiatric drugs in swine and chicken feeds. This rapid, simple and effective extraction method was based on matrix solid-phase dispersion and electrospray ionization tandem mass spectrometry. The quantitative method was validated after previous statistical optimization of the main parameters of matrix solid-phase dispersion. The limit of quantification of dopamine hydrochloride, chlormadinone acetate, melengestrol acetate, testosterone propionate, nandrolone and midazolam was 2 μg/kg and that of the other 24 drugs was 1 μg/kg. The recoveries of β-agonists, hormones, glucocorticoid and psychiatric drugs spiked in swine and chicken feeds at a concentration range of 1-8 μg/kg were above 70.1% with inter-day relative standard deviations less than 15.8%. The analytical strategy was applied to 100 feed samples collected from a local market in Wuhan (China). Clenbuterol, ractopamine and melengestrol acetate were identified and quantified at the level 0.2∼3.5 μg/kg. The rapid and reliable method can be used to efficiently separate, characterize and quantify the residues of 30 banned drugs in swine and chicken feeds with advantages of simple pretreatment and environmental friendly nature.
Topics: Adrenergic beta-Agonists; Chromatography, High Pressure Liquid; Glucocorticoids; Hormones; Psychotropic Drugs; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry
PubMed: 27145483
DOI: 10.1002/jssc.201600011 -
Hormone Use in Food Animal Production: Assessing Potential Dietary Exposures and Breast Cancer Risk.Current Environmental Health Reports Mar 2015In recent years, increasing attention has been paid to the role of hormones in breast cancer etiology, following reports that heightened levels of endogenous hormones...
In recent years, increasing attention has been paid to the role of hormones in breast cancer etiology, following reports that heightened levels of endogenous hormones and exposure to exogenous hormones and other endocrine-disrupting chemicals through food and the environment are associated with increased breast cancer risk. Seven hormone drugs (testosterone propionate, trenbolone acetate, estradiol, zeranol, progesterone, melengestrol acetate, and bovine somatotropin) are approved by the U.S. Food and Drug Administration for use in food animals. There is concern that these drugs or their biologically active metabolites may accumulate in edible tissues, potentially increasing the risk of exposure for consumers. To date, the potential for human exposure to residues of these compounds in animal products, as well as the risks that may result from this exposure, is poorly understood. In this paper, we discuss the existing scientific evidence examining the toxicological significance of exposure to hormones used in food animal production in relation to breast cancer risk. Through a discussion of U.S. federal regulatory programs and the primary literature, we interpret the state of surveillance for residues of hormone drugs in animal products and discuss trends in meat consumption in relation to the potential for hormone exposure. Given the lack of chronic bioassays of oral toxicity of the seven hormone compounds in the public literature and the limitations of existing residue surveillance programs, it is not currently possible to provide a quantitative characterization of risks that result from the use of hormonal drugs in food animal production, complicating our understanding of the role of dietary hormone exposure in the population burden of breast cancer.
Topics: Animal Husbandry; Animals; Breast Neoplasms; Cattle; Diet; Drug Residues; Female; Hormones; Humans; Male; Meat; Mice; Milk; Rats; Risk Factors; United States
PubMed: 26231238
DOI: 10.1007/s40572-014-0042-8 -
Journal of Animal Science Jun 2015Two experiments were designed to evaluate the impact of puberty status and the administration of melengestrol acetate (MGA) before onset of the breeding period on... (Randomized Controlled Trial)
Randomized Controlled Trial
Two experiments were designed to evaluate the impact of puberty status and the administration of melengestrol acetate (MGA) before onset of the breeding period on ovulatory responses (Exp. 1) and conception rate after AI performed on estrus detection during 10 d and the pregnancy rate through 80 d of breeding period (Exp. 2) of pasture-grazed beef heifers. In Exp. 1, heifers (15 pubertal and 15 prepubertal) received 0.5 mg per heifer/d -1 of MGA over 14 d. No differences in the ovulatory responses were found 10 d after the MGA administration (pubertal = 46.7% vs. prepubertal P = 53.3%; P = 0.72). In Exp. 2, 368 heifers were randomly assigned to groups according to pubertal status and the MGA treatment. All heifers were inseminated on estrus detection for up 10 d after MGA administration and following exposure to bulls between 20 and 80 d. The MGA-treated heifers exhibited a greater AI service rate than control heifers (72.1 vs. 41.6%;P < 0.01); however, heifers receiving MGA had lower conception results following AI (51.6 vs. 71.4%; P = 0.01). In addition, MGA-treated heifers were more likely to have a corpus luteum in the middle of the breeding period (95.3 vs. 87.5%;P < 0.01), although the Cox proportional hazard of pregnancy rate was similar (P = 0.29) at the end of the breeding period. At onset of the breeding period, pubertal heifers presented a greater pregnancy rate following AI (pubertal P = 42.2% vs. prepubertal P = 24.9%; P = 0.01). Therefore, pubertal heifers seem to have greater overall reproductive efficiency than prepubertal heifers, particularly at the beginning of the breeding period. Interestingly, administration of MGA before the onset of the breeding period increased AI service rate but did not alter the rate of pregnancy throughout the breeding period of pasture-grazed beef heifers.
Topics: Animals; Breeding; Cattle; Dietary Supplements; Estrus Detection; Estrus Synchronization; Female; Fertilization; Insemination, Artificial; Male; Melengestrol Acetate; Ovulation; Pregnancy; Pregnancy Rate; Puberty; Reproduction
PubMed: 26115267
DOI: 10.2527/jas.2015-8799 -
Environmental Science & Technology Jul 2015Studies of steroid growth promoters from beef cattle feedyards have previously focused on effluent or surface runoff as the primary route of transport from animal...
Studies of steroid growth promoters from beef cattle feedyards have previously focused on effluent or surface runoff as the primary route of transport from animal feeding operations. There is potential for steroid transport via fugitive airborne particulate matter (PM) from cattle feedyards; therefore, the objective of this study was to characterize the occurrence and concentration of steroid growth promoters in PM from feedyards. Air sampling was conducted at commercial feedyards (n = 5) across the Southern Great Plains from 2010 to 2012. Total suspended particulates (TSP), PM10, and PM2.5 were collected for particle size analysis and steroid growth promoter analysis. Particle size distributions were generated from TSP samples only, while steroid analysis was conducted on extracts of PM samples using liquid chromatography mass spectrometry. Of seven targeted steroids, 17α-estradiol and estrone were the most commonly detected, identified in over 94% of samples at median concentrations of 20.6 and 10.8 ng/g, respectively. Melengestrol acetate and 17α-trenbolone were detected in 31% and 39% of all PM samples at median concentrations of 1.3 and 1.9 ng/g, respectively. Results demonstrate PM is a viable route of steroid transportation and may be a significant contributor to environmental steroid hormone loading from cattle feedyards.
Topics: Air Pollutants; Animal Feed; Animals; Cattle; Hormones; Particle Size; Particulate Matter; Red Meat; Steroids
PubMed: 26098147
DOI: 10.1021/acs.est.5b01881