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1.
Front Endocrinol (Lausanne) ; 12: 697505, 2021.
Article in English | MEDLINE | ID: mdl-34335472

ABSTRACT

Atrazine is one of the most commonly used pre-emergence and early post-emergence herbicides in the world. We have shown previously that atrazine does not directly stimulate the pituitary or adrenal to trigger hormone release but acts centrally to activate a stress-like activation of the hypothalamic-pituitary-adrenal axis. In doing so, atrazine treatment has been shown to cause adrenal morphology changes characteristic of repeated stress. In this study, adrenals from atrazine treated and stressed animals were directly compared after 4 days of atrazine treatment or restraint stress. Both atrazine and stressed animals displayed reduced adrenocortical zona glomerulosa thickness and aldosterone synthase (CYP11B2) expression, indicative of repeated adrenal stimulation by adrenocorticotropic hormone. To determine if reduced CYP11B2 expression resulted in attenuated aldosterone synthesis, stressed and atrazine treated animals were challenged with angiotensin II (Ang II). As predicted, stressed animals produced less aldosterone compared to control animals when stimulated. However, atrazine treated animals had higher circulating aldosterone concentrations compared to both stressed and control groups. Ang II-induced aldosterone release was also potentiated in atrazine pretreated human adrenocortical carcinoma cells (H295R). Atrazine pretreated did not alter the expression of the rate limiting steroidogenic StAR protein or angiotensin II receptor 1. Atrazine treated animals also presented with higher basal blood pressure than vehicle treated control animals suggesting sustained elevations in circulating aldosterone levels. Our results demonstrate that treatment with the widely used herbicide, atrazine, directly increases stimulated production of aldosterone in adrenocortical cells independent of expression changes to rate limiting steroidogenic enzymes.


Subject(s)
Adrenal Glands/drug effects , Aldosterone/metabolism , Angiotensin II/pharmacology , Atrazine/pharmacology , Adrenal Glands/metabolism , Adrenal Glands/pathology , Aldosterone/biosynthesis , Animals , Cells, Cultured , Drug Synergism , Female , Herbicides/pharmacology , Rats , Rats, Sprague-Dawley , Restraint, Physical/psychology , Stress, Psychological/metabolism , Stress, Psychological/pathology
2.
Genesis ; 59(7-8): e23438, 2021 08.
Article in English | MEDLINE | ID: mdl-34124835

ABSTRACT

Cilia on neurons play critical roles in both the development and function of the central nervous system (CNS). While it remains challenging to elucidate the precise roles for neuronal cilia, it is clear that a subset of G-protein-coupled receptors (GPCRs) preferentially localize to the cilia membrane. Further, ciliary GPCR signaling has been implicated in regulating a variety of behaviors. Melanin concentrating hormone receptor 1 (MCHR1), is a GPCR expressed centrally in rodents known to be enriched in cilia. Here we have used MCHR1 as a model ciliary GPCR to develop a strategy to fluorescently tag receptors expressed from the endogenous locus in vivo. Using CRISPR/Cas9, we inserted the coding sequence of the fluorescent protein mCherry into the N-terminus of Mchr1. Analysis of the fusion protein (mCherry MCHR1) revealed its localization to neuronal cilia in the CNS, across multiple developmental time points and in various regions of the adult brain. Our approach simultaneously produced fortuitous in/dels altering the Mchr1 start codon resulting in a new MCHR1 knockout line. Functional studies using electrophysiology show a significant alteration of synaptic strength in MCHR1 knockout mice. A reduction in strength is also detected in mice homozygous for the mCherry insertion, suggesting that while the strategy is useful for monitoring the receptor, activity could be altered. However, both lines should aid in studies of MCHR1 function and contribute to our understanding of MCHR1 signaling in the brain. Additionally, this approach could be expanded to aid in the study of other ciliary GPCRs.


Subject(s)
Melanins/metabolism , Neurons/metabolism , Receptors, Somatostatin/metabolism , Alleles , Animals , Cilia/metabolism , Homozygote , Mice , Mice, Inbred C57BL , Neurons/physiology , Receptors, Somatostatin/genetics , Synapses/metabolism , Synapses/physiology , Synaptic Potentials
3.
Cell Tissue Res ; 383(1): 549-557, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33404845

ABSTRACT

The necklace glomeruli are a loosely defined group of glomeruli encircling the caudal main olfactory bulb in rodents. Initially defined by the expression of various immunohistochemical markers, they are now better understood in the context of the specialized chemosensory neurons of the main olfactory epithelium and Grueneberg ganglion that innervate them. It has become clear that the necklace region of the rodent main olfactory bulb is composed of multiple distinct groups of glomeruli, defined at least in part by their afferent inputs. In this review, we will explore the necklace glomeruli and the chemosensory neurons that innervate them.


Subject(s)
Olfactory Bulb/physiology , Olfactory Pathways/physiology , Animals , Rodentia
4.
Physiol Behav ; 227: 113150, 2020 12 01.
Article in English | MEDLINE | ID: mdl-32841674

ABSTRACT

Animals use social communication to learn important information from conspecifics that can guide appropriate behavioral choices. For example, during the social transmission of food preference (STFP), conspecific semiochemicals detected by mouse olfactory sensory neurons (OSNs) expressing the atypical olfactory receptor guanylyl cyclase D (GC-D+ OSNs) promote the acquisition of food preferences in the recipient animal, mitigating the risk of ingesting food contaminated with toxins or pathogens. However, it is unclear if GC-D+ OSNs mediate preference learning outside this specific context. Here, we report that GC-D+ OSNs are required for the acquisition of odor preferences by both adult and juvenile mice, and that GC-DD-dependent preference could be formed for conditionally aversive odors. We used a two-choice olfactory behavioral test to assess odor preferences in adult Gucy2d +/+, +/- and -/- mice that encountered novel odors together with GC-D+ OSN stimuli (guanylin family peptides), during social investigation of a live conspecific, or during suckling as pups. Gucy2d +/+ and +/- mice (which express functional GC-D), but not Gucy2d -/- littermates, successfully acquire a preference for the demonstrated odor in any of these behavioral paradigms. Mice could even acquire a GC-D-dependent preference for odors to which they had recently formed a conditioned aversion. Together, these results demonstrate that GC-D+ OSNs mediate the acquisition of socially-transmitted odor preferences in different social and experiential contexts and at different life stages.


Subject(s)
Olfactory Receptor Neurons , Receptors, Odorant , Animals , Guanylate Cyclase , Mice , Odorants , Receptors, Cell Surface , Smell , Social Environment
5.
Mol Pharmacol ; 98(4): 292-302, 2020 10.
Article in English | MEDLINE | ID: mdl-32690627

ABSTRACT

Many synthetic compounds to which we attribute specific activities are produced as racemic mixtures of stereoisomers, and it may be that all the desired activity comes from a single enantiomer. We have previously shown this to be the case with the α7 nicotinic acetylcholine receptor positive allosteric modulator (PAM) 3a,4,5,9b-Tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS) and the α7 ago-PAM 4BP-TQS. Cis-trans-4-(2,3,5,6-tetramethylphenyl)-3a,4,5,9b-te-trahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (2,3,5,6TMP-TQS), previously published as a "silent allosteric modulator" and an antagonist of α7 allosteric activation, shares the same scaffold with three chiral centers as the aforementioned compounds. We isolated the enantiomers of 2,3,5,6TMP-TQS and determined that the (-) isomer was a significantly better antagonist than the (+) isomer of the allosteric activation of both wild-type α7 and the nonorthosterically activatible C190A α7 mutant by the ago-PAM GAT107 (the active isomer of 4BP-TQS). In contrast, (+)2,3,5,6TMP-TQS proved to be an α7 PAM. (-)2,3,5,6TMP-TQS was shown to antagonize the allosteric activation of α7 by the structurally unrelated ago-PAM B-973B as well as the allosteric activation of the TQS-sensitive α4ß2L15'M mutant. In silico docking of 2,3,5,6TMP-TQS in the putative allosteric activation binding site suggested a specific interaction of the (-) enantiomer with α7T106, and allosteric activation of α7T106 mutants was not inhibited by (-)2,3,5,6TMP-TQS, confirming the importance of this interaction and supporting the model of the allosteric binding site. Comparisons and contrasts between 2,3,5,6TMP-TQS isomers and active and inactive enantiomers of other TQS-related compounds identify the orientation of the cyclopentenyl ring to the plane of the core quinoline to be a crucial determinate of PAM activity. SIGNIFICANCE STATEMENT: Many synthetic ligands are in use as racemic preparations. We show that one enantiomer of the TQS analog Cis-trans-4-(2,3,5,6-tetramethylphenyl)-3a,4,5,9b-te-trahydro-3H-cyclopenta[c]quinoline-8-sulfonamide, originally reported to lack activity when used as a racemic preparation, is an α7 nicotinic acetylcholine receptor positive allosteric modulator (PAM). The other enantiomer is not a PAM, but it is an effective allosteric antagonist. In silico studies and structural comparisons identify essential elements of both the allosteric ligands and receptor binding sites important for these allosteric activities.


Subject(s)
Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Xenopus laevis/genetics , alpha7 Nicotinic Acetylcholine Receptor/chemistry , alpha7 Nicotinic Acetylcholine Receptor/metabolism , Allosteric Regulation/drug effects , Animals , Animals, Genetically Modified , Binding Sites , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Mutation , Stereoisomerism , Sulfonamides/chemistry , Xenopus laevis/metabolism , alpha7 Nicotinic Acetylcholine Receptor/genetics
6.
Endocrinology ; 159(9): 3378-3388, 2018 09 01.
Article in English | MEDLINE | ID: mdl-30060079

ABSTRACT

Atrazine (ATR) is a commonly used pre-emergence and early postemergence herbicide. Rats gavaged with ATR and its chlorometabolites desethylatrazine (DEA) and deisopropylatrazine (DIA) respond with a rapid and dose-dependent rise in plasma corticosterone, whereas the major chlorometabolite, diaminochlorotriazine (DACT), has little or no effect on corticosterone levels. In this study, we investigated the possible sites of ATR activation of the hypothalamic-pituitary-adrenal (HPA) axis. ATR treatment had no effect on adrenal weights but altered adrenal morphology. Hypophysectomized rats or rats under dexamethasone suppression did not respond to ATR treatment, suggesting that ATR does not directly stimulate the adrenal gland to induce corticosterone synthesis. Immortalized mouse corticotrophs (AtT-20) and primary rat pituitary cultures were treated with ATR, DEA, DIA, or DACT. None of the compounds induced an increase in ACTH secretion or potentiated ACTH release in conjunction with CRH on ACTH release. In female rats gavaged with ATR, pretreatment with the CRH receptor antagonist astressin completely blocked the ATR-induced rise in corticosterone concentrations, implicating CRH release in ATR-induced HPA activation. Intracerebroventricular infusion of ATR, DEA, and DIA but not DACT at concentrations equivalent to peak plasma concentrations after gavage dosing resulted in an elevation of plasma corticosterone concentrations. However, ATR did not induce c-Fos immunoreactivity in the paraventricular nucleus of the hypothalamus. These results indicate that ATR activates the HPA axis centrally and requires CRH receptor activation, but it does not stimulate cellular pathways associated with CRH neuronal excitation.


Subject(s)
Atrazine/pharmacology , Corticotrophs/drug effects , Herbicides/pharmacology , Hypothalamo-Hypophyseal System/drug effects , Pituitary Gland/drug effects , Pituitary-Adrenal System/drug effects , Adrenal Glands/drug effects , Adrenal Glands/pathology , Adrenocorticotropic Hormone/drug effects , Adrenocorticotropic Hormone/metabolism , Animals , Atrazine/analogs & derivatives , Cell Line , Corticosterone/metabolism , Corticotrophs/metabolism , Dexamethasone/pharmacology , Female , Glucocorticoids/pharmacology , Hypothalamo-Hypophyseal System/metabolism , Mice , Organ Culture Techniques , Organ Size , Pituitary Gland/metabolism , Pituitary Gland/surgery , Pituitary-Adrenal System/metabolism , Rats , Triazines/pharmacology
7.
Xenobiotica ; 48(9): 867-881, 2018 Sep.
Article in English | MEDLINE | ID: mdl-28882082

ABSTRACT

1. To determine the effects of repeated atrazine (ATR) treatment on hepatic phase I and II enzymes, adult female rats were treated with vehicle or 100 mg/kg of ATR for 1, 2, 3 or 4 days. Glutathione-s-transferases (GST) mRNA expression, protein levels (mu, pi, alpha, omega), and activity (cytosolic and microsomal), along with bioavailable glutathione (GSH) were assayed. 2. GST expression, concentrations and activity were increased, along with GSH levels, in animals treated with ATR for 3 and 4 days. 3. A subsequent study was performed with animals treated with vehicle, 6.5, 50 or 100 mg/kg/day for 4, 8 or 14 days. Expression of hepatic phase I CYP 450 enzymes was evaluated in conjugation with GST expression, protein and activity. Nineteen of the 45 CYP enzymes assayed displayed increased mRNA levels after eight days of treatment in animals treated with 50 or 100 mg/kg/day. After 14 days of treatment, all CYP expression levels returned to control levels except for CYP2B2, CYP2B3, CYP2C7, CYP2C23, CYP2E1, CYP3A9, CYP4A3 and CYP27A1, which remained elevated. 4. Results indicate that there may be a habituation or adaptation of liver phase I and phase II expression following repeated ATR treatment.


Subject(s)
Atrazine/toxicity , Enzymes/metabolism , Inactivation, Metabolic/drug effects , Inactivation, Metabolic/physiology , Liver/drug effects , Animals , Atrazine/administration & dosage , Cytochrome P-450 CYP2J2 , Cytochrome P-450 Enzyme System/genetics , Cytochrome P-450 Enzyme System/metabolism , Enzymes/genetics , Female , Gene Expression Regulation, Enzymologic , Glutathione/metabolism , Glutathione Transferase/genetics , Glutathione Transferase/metabolism , Liver/metabolism , Rats, Sprague-Dawley
8.
Endocrinology ; 158(10): 3526-3539, 2017 10 01.
Article in English | MEDLINE | ID: mdl-28977590

ABSTRACT

Although kisspeptin is the primary stimulator of gonadotropin-releasing hormone secretion and therefore the hypothalamic-pituitary-gonadal axis, recent findings suggest kisspeptin can also regulate additional neuroendocrine processes including release of growth hormone (GH). Here we show that central delivery of kisspeptin causes a robust rise in plasma GH in fasted but not fed sheep. Kisspeptin-induced GH secretion was similar in animals fasted for 24 hours and those fasted for 72 hours, suggesting that the factors involved in kisspeptin-induced GH secretion are responsive to loss of food availability and not the result of severe negative energy balance. Pretreatment with the neuropeptide Y (NPY) Y1 receptor antagonist, BIBO 3304, blocked the effects of kisspeptin-induced GH release, implicating NPY as an intermediary. Kisspeptin treatment induced c-Fos in NPY and GH-releasing hormone (GHRH) cells of the arcuate nucleus. The same kisspeptin treatment resulted in a reduction in c-Fos in somatostatin (SS) cells in the periventricular nucleus. Finally, blockade of systemic ghrelin release or antagonism of the ghrelin receptor eliminated or reduced the ability of kisspeptin to induce GH release, suggesting the presence of ghrelin is required for kisspeptin-induced GH release in fasted animals. Our findings support the hypothesis that during short-term fasting, systemic ghrelin concentrations and NPY expression in the arcuate nucleus rise. This permits kisspeptin activation of NPY cells. In turn, NPY stimulates GHRH cells and inhibits SS cells, resulting in GH release. We propose a mechanism by which kisspeptin conveys reproductive and hormone status onto the somatotropic axis, resulting in alterations in GH release.


Subject(s)
Ghrelin/metabolism , Growth Hormone/drug effects , Kisspeptins/pharmacology , Neuropeptide Y/metabolism , Somatostatin-Secreting Cells/drug effects , Animals , Arcuate Nucleus of Hypothalamus/drug effects , Arcuate Nucleus of Hypothalamus/metabolism , Arginine/analogs & derivatives , Arginine/pharmacology , Atropine/pharmacology , Fasting/metabolism , Female , Fluorescent Antibody Technique , Growth Hormone/metabolism , Growth Hormone-Releasing Hormone , Muscarinic Antagonists/pharmacology , Oligopeptides/pharmacology , Proto-Oncogene Proteins c-fos/drug effects , Proto-Oncogene Proteins c-fos/metabolism , Receptors, Ghrelin/antagonists & inhibitors , Receptors, Neuropeptide Y/antagonists & inhibitors , Sheep , Sheep, Domestic , Somatostatin-Secreting Cells/metabolism
9.
Regul Toxicol Pharmacol ; 89: 200-214, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28736286

ABSTRACT

T cell-dependent IgM antibody production and natural killer cell (NKC) activity were assessed in SD rats orally administered atrazine for 28 days to males (0, 6.5, 25, or 100 mg/kg/day) or females (0, 3, 6, or 50 mg/kg/day), or 30 or 500 ppm in diet (3 or 51 mg/kg/day). Anti-asialo GM1 antibodies (NKC) and cyclophosphamide (antibody-forming cell assay [AFC]) served as positive controls. Pituitary (ACTH, prolactin), adrenal (corticosterone, progesterone, aldosterone), and gonadal (androgens, estrogens) hormones were assessed after 1, 7, and/or 28 days of treatment. Food intake and body weights were significantly reduced in the highest dosed males, and transiently affected in females. Urinary corticosterone levels were not increased in atrazine-treated groups in either sex at any time point measured (10, 22, or 24 days). Corticosterone and progesterone were elevated in males after a single atrazine dose ≥6.5 mg/kg/day, but not after 7, 14, or 28 doses. There were no effects on adrenal, pituitary, or gonadal hormones in females. Atrazine did not suppress the AFC response or decrease NKC function after 28 days in males or females. Atrazine had no effect on spleen weights or spleen cell numbers in males or females, although thymus weights were elevated in males receiving the highest dose. The lack of immunotoxic effect of atrazine was associated with diminished adrenal activation over time in males, and no effects on adrenal hormones in females.


Subject(s)
Adrenal Glands/drug effects , Atrazine/toxicity , Herbicides/toxicity , Immunoglobulin M/metabolism , Killer Cells, Natural/drug effects , T-Lymphocytes/drug effects , Adrenal Glands/immunology , Adrenal Glands/metabolism , Animals , Atrazine/administration & dosage , Atrazine/immunology , Female , Herbicides/administration & dosage , Herbicides/immunology , Killer Cells, Natural/immunology , Male , Pituitary Gland/drug effects , Pituitary Gland/immunology , Pituitary Gland/metabolism , Rats , Rats, Sprague-Dawley , Sex Factors , T-Lymphocytes/immunology
10.
Mol Ther ; 25(4): 904-916, 2017 04 05.
Article in English | MEDLINE | ID: mdl-28237838

ABSTRACT

Olfactory dysfunction is a pervasive but underappreciated health concern that affects personal safety and quality of life. Patients with olfactory dysfunctions have limited therapeutic options, particularly those involving congenital diseases. Bardet-Biedl syndrome (BBS) is one such disorder, where olfactory loss and other symptoms manifest from defective cilium morphology and/or function in various cell types/tissues. Olfactory sensory neurons (OSNs) of BBS mutant mice lack the capacity to build/maintain cilia, rendering the cells incapable of odor detection. Here we examined OSN cilium defects in Bbs1 mutant mice and assessed the utility of gene therapy to restore ciliation and function in young and adult mice. Bbs1 mutant mice possessed short residual OSN cilia in which BBSome protein trafficking and odorant detection were defective. Gene therapy with an adenovirus-delivered wild-type Bbs1 gene restored OSN ciliation, corrected BBSome cilium trafficking defects, and returned acute odor responses. Finally, using clinically approved AAV serotypes, we demonstrate, for the first time, the capacity of AAVs to restore ciliation and odor detection in OSNs of Bbs1 mutants. Together, our data demonstrate that OSN ciliogenesis can be promoted in differentiated cells of young and adult Bbs1 mutants and highlight the potential of gene therapy as a viable restorative treatment for congenital olfactory disorders.


Subject(s)
Bardet-Biedl Syndrome/genetics , Bardet-Biedl Syndrome/physiopathology , Genetic Therapy , Olfactory Receptor Neurons/metabolism , Alleles , Animals , Bardet-Biedl Syndrome/therapy , Cilia/metabolism , Cilia/pathology , Dependovirus/genetics , Disease Models, Animal , Ectopic Gene Expression , Gene Expression , Gene Transfer Techniques , Genetic Vectors/administration & dosage , Genetic Vectors/genetics , Humans , Mice , Mice, Knockout , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Mutation , Olfactory Perception/genetics , Phenotype , Protein Transport , Transduction, Genetic
11.
Am J Physiol Regul Integr Comp Physiol ; 308(6): R543-55, 2015 Mar 15.
Article in English | MEDLINE | ID: mdl-25568075

ABSTRACT

We previously reported that a 2-day peripheral infusion of glucosamine caused leptin resistance in rats, suggesting a role for the hexosamine biosynthetic pathway (HBP) in the development of leptin resistance. Here we tested leptin responsiveness in mice in which HBP activity was stimulated by offering 30% sucrose solution in addition to chow and water or by infusing glucosamine. Mice were leptin resistant after 33 days of access to sucrose. Resistance was associated with increased activity of the HBP and with phosphorylation of transcription factor signal transducer and activator of transcription-3 Tyr705 [pSTAT3(Y705)] but inhibition of suppressor of cytokine signaling 3 in the liver and hypothalamus. Intravenous infusion of glucosamine for 3 h stimulated pSTAT3(Y705) but prevented leptin-induced phosphorylation of STAT3(S727). In an in vitro system, glucose, glucosamine, and leptin each dose dependently increased O-linked ß-N-acetylglucosamine (O-GlcNAc) protein and pSTAT3(Y705) in HepG2 cells. To test the effect of glucose on leptin responsiveness cells were incubated in 5.5 mM (LG) or 20 mM (HG) glucose for 18 h and were treated with 0 or 50 ng/ml leptin for 15 min. HG alone and LG + leptin produced similar increases in O-GlcNAc protein, glutamine fructose-6-phosphate amidotransferase (GFAT), and pSTAT3(Y705) compared with LG media. Leptin did not stimulate these proteins in HG cells, suggesting leptin resistance. Leptin-induced pSTAT3(S727) was prevented by HG media. Inhibition of GFAT with azaserine prevented LG + leptin and HG stimulation of pSTAT3. These data demonstrate development of leptin resistance in sucrose-drinking mice and provide new evidence of leptin-induced stimulation of the HBP.


Subject(s)
Brain Stem/metabolism , Dietary Sucrose/metabolism , Hexosamines/biosynthesis , Leptin/metabolism , Liver/metabolism , STAT3 Transcription Factor/metabolism , Acetylglucosamine/metabolism , Animals , Blood Glucose/metabolism , Dietary Sucrose/administration & dosage , Glucosamine/administration & dosage , Glucosamine/metabolism , Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)/metabolism , Hep G2 Cells , Humans , Infusions, Intravenous , Insulin/blood , Leptin/blood , Male , Mice, Inbred C57BL , Phosphorylation , STAT3 Transcription Factor/blood , Signal Transduction , Time Factors
12.
Biol Reprod ; 88(1): 9, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23197165

ABSTRACT

Atrazine (ATR) is a commonly used pre-emergence/early postemergence herbicide. Previous work has shown that exposure to high doses of ATR in rats results in blunting of the hormone-induced luteinizing hormone (LH) surge and inhibition of pulsatile LH release without significantly reducing pituitary sensitivity to a gonadotropin-releasing hormone (GnRH) agonist. Accompanying the reduction in the LH surge was an attenuation of GnRH neuronal activation. These findings suggest that ATR exposure may be acting to inhibit GnRH release. In this study, we examined GnRH directly to determine the effect of high doses of ATR on GnRH pulsatile release, gene expression, and peptide levels in the female rat. Ovariectomized adult female Wistar rats were treated with ATR (200 mg/kg) or vehicle for 4 days via gavage. Following the final treatment, GnRH release was measured from ex vivo hypothalamic explants for 3 h. In another experiment, animals were administered either vehicle or ATR (50, 100, or 200 mg/kg) daily for 4 days. Following treatment, in situ hybridization was performed to examine total GnRH mRNA and the primary GnRH heterogeneous nuclear RNA transcript. Finally, GnRH immunoreactivity and total peptide levels were measured in hypothalamic tissue of treated animals. ATR treatment resulted in no changes to GnRH gene expression, peptide levels, or immunoreactivity but a reduction in GnRH pulse frequency and an increased pulse amplitude. These findings suggest that ATR acts to inhibit the secretory dynamics of GnRH pulses without interfering with GnRH mRNA and protein synthesis.


Subject(s)
Atrazine/pharmacology , Gonadotropin-Releasing Hormone/antagonists & inhibitors , Gonadotropin-Releasing Hormone/metabolism , Herbicides/pharmacology , Animals , Atrazine/administration & dosage , Dose-Response Relationship, Drug , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Gonadotropin-Releasing Hormone/genetics , Herbicides/administration & dosage , Hypothalamus/drug effects , Hypothalamus/physiology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats
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