Effect of Thyromimetic GC-1 Selective Signaling on Reproductive and Lactational Performance in the Hypothyroid Rat.
Ontology highlight
ABSTRACT: Introduction
The potential of the thyroid hormone receptor β (TRβ1) selective analog GC-1 has been widely proven in animal models and humans. However, its effect on the reproductive stage of the female rat has not been evaluated.Methods
The effect of the administration of GC-1 or equimolar doses of triiodothyronine (T3) was evaluated on the reproductive performance of the hypothyroid female rat and the indirect effect on pup thyroid status, weight, and survival.Results
Hypothyroidism reduced the number of embryos implanted in the uterus, whereas T3 and GC-1 treatment in hypothyroid females reestablished the number of implanted embryos to normal. Initiation of labor was delayed by hypothyroidism, and T3 replacement treatment reinstated the normal timing of parturition. The administration of GC-1 alone to the lactating mother did not affect pup survival, weight, or thyroidal status.Conclusions
Our findings show the differential effect of thyroid hormone selective signaling during gestation and the indirect exposure of the pups; we also emphasize the plausible use of GC-1 for treatment of hypothyroid mothers during the lactation period.
SUBMITTER: Rinaldini E
PROVIDER: S-EPMC8406258 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Amphipathic carboxylates, of varying hydrophobic backbones, which act as peroxisomal proliferators (aryloxyalkanoic acids, methyl-substituted dicarboxylic acid) induce in euthyroid or thyroidectomized rats, as well as in rat hepatocytes cultured in 3,5,3'-tri-iodo-L-thyronine (T3)-free media, liver enzyme activities that are classically considered to be thyroid-hormone-dependent (malic enzyme, mitochondrial alpha-glycerophosphate dehydrogenase, glucose-6-phosphate dehydrogenase and S14). The dose required in vivo for the thyromimetic effect of peroxisomal proliferators was 10(3)-fold higher than the dose of T3 required. Similarly, peroxisomal proliferators were active in culture in the range 1-100 microM compared with 1 nM for T3. Their maximal inductive capacities were, however, similar to or greater than that of T3. The thyromimetic effect of peroxisomal proliferators was only partially correlated with their capacities as inducers of liver peroxisomal enzymes. The thyromimetic effect with respect to liver malate dehydrogenase and S14 resulted from an increase in their mRNA contents. The increase in liver S14 mRNA was accounted for by transcriptional activation of the S14 gene. T3 binding to isolated liver nuclei or nuclear extract was competitively displaced by some but not all of the non-thyroidal inducers of the above liver activities. In contrast with the thyromimetic effect induced in liver cells, no increase in growth hormone mRNA was observed in cultured GH1 pituitary cells incubated in the presence of non-thyroidal amphipathic carboxylates. The characteristics of the thyromimetic effect of amphipathic carboxylic peroxisomal proliferators indicate that these agents may act as transcriptional activators of thyroid-hormone-dependent genes in the rat liver.
| S-EPMC1149974 | biostudies-other
Project description:Sows suffering excess weight loss during lactation may delay weaning to estrus interval (WEI) and have a detrimental effect on subsequent reproductive performance, however, the underlying mechanism is not completely clear. Therefore, the goal of this study was to investigate physiological profiles manifested in plasma originating from high (HWL) and low lactational weight loss (LWL) sows. The plasma biochemical parameters, hormones, antioxidant parameters, and milk compositions were assessed. Furthermore, plasma metabolites were analyzed using ultrahigh-performance liquid chromatography/time-of-flight mass spectrometry in positive and negative ion modes. Results showed that HWL sows had a lower feed intake and higher lactational weight loss and prolonged WEI, but had similar litter performance and milk composition compared to LWL sows. These changes were associated with lower plasma insulin-like growth factor 1 and higher fibroblast growth factor 21 levels in the HWL sows. Moreover, HWL led to a severe oxidative stress and metabolic damage, as accompanied by excessive protein breakdown and lipids mobilization at weaning. Metabolomic analysis revealed differences in 46 compounds between HWL and LWL sows, and the identified compounds were enriched in metabolic pathways related to amino acids metabolism, fatty acids oxidation metabolism, bile acids biosynthesis, and nucleoside metabolism. These results provide the evidence for physiological mechanism in sows with excessive lactational weight loss that delayed the WEI. Metabolomic data provides essential information and gives rise to potential targets for the development of nutritional intervention strategies.
| S-EPMC6950487 | biostudies-literature
Project description:Thyroid hormones (THs), namely, 3,5,3'-triiodo-l-thyronine (T3) and 3,5,3',5'-tetraiodo-l-thyronine (thyroxine or T4), influence a variety of physiological processes that have important implications in fetal development, metabolism, cell growth, and proliferation. While THs elicit several beneficial effects on lipid metabolism and improve myocardial contractility, these therapeutically desirable effects are associated to a thyrotoxic state that severely limits the possible use of THs as therapeutic agents. Therefore, several efforts have been made to develop T3 analogs that could retain the beneficial actions (triglyceride, cholesterol, obesity, and body mass lowering) without the adverse TH-dependent side effects. This goal was achieved by the synthesis of TR?-selective agonists. In this review, we summarize the current knowledge on the effects of one of the best characterized TH analogs, the TR?1-selective thyromimetic, GC-1. In particular, we review some of the effects of GC-1 on different liver disorders, with reference to its possible clinical application. A brief comment on the possible therapeutic use of GC-1 in extrahepatic disorders is also included.
| S-EPMC5885148 | biostudies-other
Project description:BACKGROUND:2-Hydroxy-4-methoxybenzophenone (HMB) is an ultraviolet (UV) absorbing compound used in many cosmetic products as a UV-protecting agent and in plastics for preventing UV-induced photodecomposition. HMB has been detected in over 95% of randomly collected human urine samples from adults and from premature infants, and it may have estrogenic potential. METHODS:To determine the effects of maternal and lactational exposure to HMB on development and reproductive organs of offspring, time-mated female Harlan Sprague-Dawley rats were dosed with 0, 1000, 3000, 10,000, 25,000, or 50,000 ppm HMB (seven to eight per group) added to chow from gestation day 6 until weaning on postnatal day (PND) 23. RESULTS AND CONCLUSION:Exposure to HMB was associated with reduced body and organ weights in female and male offspring. No significant differences were observed in the number of implantation sites/litter, mean resorptions/litter, % litters with resorptions, number and weights of live fetuses, or sex ratios between the control and HMB dose groups. Normalized anogenital distance in male pups at PND 23 was decreased in the highest dose group. Spermatocyte development was impaired in testes of male offspring in the highest dose group. In females, follicular development was delayed in the highest dose group. However, by evaluating levels of the compound in rat serum, the doses at which adverse events occurred are much higher than usual human exposure levels. Thus, exposure to less than 10,000 ppm HMB does not appear to be associated with adverse effects on the reproductive system in rats.
| S-EPMC4353586 | biostudies-literature
Project description:The reproductive system is extremely susceptible to environmental insults, for example exogenous steroids during gestational development and differentiation. Experimental induction of androgen excess during prenatal life in female animal models reprograms their reproductive physiology, however the fetal programming of the male reproductive system by androgen excess has not been well studied. We aimed to determine the effect of prenatal exposure of two different doses of testosterone on different gestational days, on the male reproductive system using a rat model. Sixteen pregnant rats were randomly divided into two experimental groups and two control groups. Experimental group І were subcutaneously injected with 3 mg free testosterone on gestational days 16-19 and its controls received solvent for that time; experimental group П were subcutaneously injected with 20 mg free testosterone on day 20 of gestational period and its controls received solvent at the same time. The reproductive system morphology and function of 32 male offspring of these study groups were compared at days 6-30-60 of age and after puberty. The anogenital distance of the male offspring of both experimental groups had no significant differences on the different days of measurement, compared with controls. In the offspring of experimental group І, the testes weight, number of Sertoli, Spermatocyte and Spermatid cells, sperm count and motility and the serum concentration of testosterone after puberty were significantly decreased; except for reduction of sperm motility (p< 0.01), the other effects were not observed in the offspring of experimental group ІІ. In summary, our data show that prenatal exposure of male rat fetuses to excess testosterone disrupted reproductive function, an effect highly dependent on the time, duration and level of exposure. It seems that the reproductive system in individuals exposed to high levels of androgens during fetal life should be evaluated at puberty and likely to be treated.
| S-EPMC3744450 | biostudies-literature
Project description:Changes in thyroid status are associated with profound alterations in biochemical and physiological functioning of cardiac muscle, although its impact on cardiac energy metabolism is still debated. Similarities between the changes in cardiac gene expression in pathological hypertrophy leading to heart failure and hypothyroidism prompted scientists to suggest a role for thyroid hormone status in the development of metabolic and functional alterations in this disease. We thus investigated the effects of hypothyroidism on cardiac energy metabolism. Hypothyroid state (HYPO) was induced by thyroidectomy and propyl-thio-uracyl in male rats for 3 weeks. We examined the effects of hypothyroid state on oxidative capacity and mitochondrial substrate utilization by measuring oxygen consumption of saponin permeabilized cardiac fibers, mitochondrial biogenesis by reverse transcription polymerase chain reaction and energy metabolism, and energy transfer enzymes by spectrophotometry. The results show that maximal oxidative capacity of the myocardium was decreased from 24.9 +/- 0.9 in control (CT) to 19.3 +/- 0.7 micromol O(2) min(-1) g dry weight(-1) in HYPO. However, protein content and messenger RNA (mRNA) of PGC-1alpha and mRNA of its transcription cascade that is thought to control mitochondrial content in normal myocardium and heart failure, were unchanged in HYPO. Mitochondrial utilization of glycerol-3P (-70%), malate (-45%), and octanoate (-24%) but not pyruvate was decreased in HYPO. Moreover, the creatine kinase system and energy transfer were hardly affected in HYPO. Besides, hypothyroidism decreased the activation of other signaling pathways like p38 mitogen-activated protein kinases, AMP-activated protein kinase, and calcineurin. These results show that cellular hypothyroidism can hardly account for the specific energetic alterations of heart failure.
| S-EPMC4710782 | biostudies-literature
Project description:Background: Monocarboxylate transporter 8 (MCT8) deficiency is a rare X-linked disease where patients exhibit peripheral hyperthyroidism and cerebral hypothyroidism, which results in severe neurological impairments. These brain defects arise from a lack of thyroid hormones (TH) during critical stages of human brain development. Treatment options for MCT8-deficient patients are limited and none have been able to prevent or ameliorate effectively the neurological impairments. This study explored the effects of the TH agonist sobetirome and its CNS-selective amide prodrug, Sob-AM2, in the treatment of pregnant dams carrying fetuses lacking Mct8 and deiodinase type 2 (Mct8/Dio2 KO), as a murine model for MCT8 deficiency. Methods: Pregnant dams carrying Mct8/Dio2 KO fetuses were treated with 1 mg of sobetirome/kg body weight/day, or 0.3 mg of Sob-AM2/kg body weight/day for 7 days, starting at embryonic day 12.5 (E12.5). As controls, pregnant dams carrying wild-type and pregnant dams carrying Mct8/Dio2 KO fetuses were treated with daily subcutaneous injections of vehicle. Dams TH levels were measured by enzyme-linked immunosorbent assay (ELISA). Samples were extracted at E18.5 and the effect of treatments on the expression of triiodothyronine (T3)-dependent genes was measured in the placenta, fetal liver, and fetal cerebral cortex by real-time polymerase chain reaction. Results: Maternal sobetirome treatment led to spontaneous abortions. Sob-AM2 treatment, however, was able to cross the placental as well as the brain barriers and exert thyromimetic effects in Mct8/Dio2 KO fetal tissues. Sob-AM2 treatment did not affect the expression of the T3-target genes analyzed in the placenta, but it mediated thyromimetic effects in the fetal liver by increasing the expression of Dio1 and Dio3 genes. Interestingly, Sob-AM2 treatment increased the expression of several T3-dependent genes in the brain such as Hr, Shh, Dio3, Kcnj10, Klf9, and Faah in Mct8/Dio2 KO fetuses. Conclusions: Maternal administration of Sob-AM2 can cross the placental barrier and access the fetal tissues, including the brain, in the absence of MCT8, to exert thyromimetic actions by modulating the expression of T3-dependent genes. Therefore, Sob-AM2 has the potential to address the cerebral hypothyroidism characteristic of MCT8 deficiency from fetal stages and to prevent neurodevelopmental alterations in the MCT8-deficient fetal brain.
| S-EPMC10171952 | biostudies-literature
Project description:The reproductive performance of a sheep flock is dependent on a multitude of complex interacting factors. Achieving optimal flock performance requires knowledge of the reproductive steps and how these are linked and related to available measurements of the state and performance of the flock. The goal was to use previously collected data from a research flock that had undergone selection for fecundity (11,369 lambing records), to model the key reproductive steps affecting flock reproductive performance. The model was used to investigate how changes in liveweight, age, ovulation rate, number of fetuses at midpregnancy, number of lambs born, and birthweight affect the number of lambs weaned and the weaning weight of each lamb in this flock. The data available from the research flock were used to parameterize models of each reproductive step and assess the role of ewe age and premating liveweight on each reproductive step. These models were then linked together as a simulation tool to assess the role of different parameters on flock reproductive performance, which was defined as the total weight of lambs weaned per ewe exposed to the ram. Flock elasticities were calculated that characterize the relative importance of the effect of average premating ewe liveweight (0.81), average ovulation rate (0.33), variance in ovulation rate (-0.095), embryo survival (0.72), lamb survival (1.03), conception failure (0.35), and average ewe age (0.056) on the total kilograms of lamb liveweight at weaning per ewe exposed to the ram. The largest elasticity for lamb survival indicated that a 1% increase in lamb survival is expected to have a 1.03% increase in the total kilograms of lamb liveweight at weaning per ewe exposed to the ram in this flock. Assuming similar costs, interventions to increase lamb survival for this flock will provide the largest increase in the total kilograms of lamb liveweight at weaning per ewe exposed to the ram, which is a key metric of flock performance.
| S-EPMC7076130 | biostudies-literature
Project description:Thousands of organohalogen compounds, including hazardous chemicals such as polychlorinated biphenyls (PCBs) and other persistent organic pollutants (POPs), were selectively and simultaneously detected and identified with simple, or no, purification from environmental sample extracts by using several advanced methods. The methods used were software extraction from two-dimensional gas chromatography-high-resolution time-of-flight mass spectrometry (GC × GC-HRTofMS) data, measurement by negative chemical ionization with HRTofMS, and neutral loss scanning (NLS) with GC × GC-MS/MS. Global and selective detection of organochlorines and bromines in environmental samples such as sediments and fly ash was achieved by NLS using GC × GC-MS/MS (QQQ), with the expected losses of 35Cl and 79Br. We confirmed that negative chemical ionization was effective for sensitive and selective ionization of organohalogens, even using GC × GC-HRTofMS. The 2D total ion chromatograms obtained by using negative chemical ionization and selective extraction of organohalogens using original software from data measured by electron impact ionization were very similar; the software thus functioned well to extract organohalogens. Combining measurements made by using these different methods will help to detect organohalogens selectively and globally. However, to compare the data obtained by individual measurements, the retention times of the peaks on the 2D chromatograms need to match.
| S-EPMC5847631 | biostudies-literature
Project description:Despite the growing popularity of the zebrafish model system, the optimal husbandry conditions for this animal are not well defined. The aim of this study was to examine the effect of stocking density on reproductive performance in zebrafish. In this study, undertaken by eight different zebrafish facilities, clutches of at least 200 wild-type zebrafish embryos from a single pairwise mating were produced at each participating institution and subsequently reared according to "in-house protocols" until they were 14 weeks old. Fish were then randomly assigned into treatment groups with balanced sex ratios and densities of 3, 6, or 12 fish/L. After a 1-month acclimation period, fish were spawned in pair crosses every 2 weeks for 3 months, for a total of six spawning dates. The number of viable and nonviable embryos produced in each clutch were counted at 1 day postfertilization. Although there was a great deal of variability in clutch size and percent spawning success among laboratories, there were no significant differences in average clutch size, spawning success, or percent viable among the treatment densities. These data suggest that using stocking densities as high as 12 fish/L does not have a negative impact on performance, when measured by reproductive performance.
| S-EPMC3180766 | biostudies-literature