Denatonium Benzoate-Induces Oxidative Stress in the Heart and Kidney of Chinese Fast Yellow Chickens by Regulating Apoptosis, Autophagy, Antioxidative Activities and Bitter Taste Receptor Gene Expressions

Abstract

Simple SummaryDenatonium benzoate is a strong bitter taste receptor agonist, extensively used for its activation of different cell pathways. Taste signals have been associated to food recognition and avoidance, and bitter taste provokes an aversive reaction and is assumed to protect chickens from consuming poisons and harmful toxic substances. The results of the study revealed that dietary supplementation with medium and high doses of denatonium benzoate damaged the epithelial cells of the heart and kidneys by inducing apoptosis and autophagy and reduced the growth of chickens, respectively. However, mRNA expressions of bitter taste receptors, downstream signaling effector genes, apoptosis-, autophagy- and antioxidant-related genes were higher on day 7, while these expressions were subsequently decreased on day-28 in the heart and kidney of Chinese Fast Yellow chickens in a dose-response manner.AbstractThe sense of taste which tells us which prospective foods are nutritious, poisonous and harmful is essential for the life of the organisms. Denatonium benzoate (DB) is a bitter taste agonist known for its activation of bitter taste receptors in different cells. The aim of the current study was to investigate the mRNA expressions of bitter taste, downstream signaling effectors, apoptosis-, autophagy- and antioxidant-related genes and effector signaling pathways in the heart/kidney of chickens after DB dietary exposure. We randomly assigned 240, 1-day-old Chinese Fast Yellow chicks into four groups with five replicates of 12 chicks and studied them for 28 consecutive days. The dietary treatments consisted of basal diet and feed containing DB (5, 20 and 100 mg/kg). The results revealed that dietary DB impaired (p < 0.05) the growth performance of the chickens. Haemotoxylin and eosin staining and TUNEL assays confirmed that medium and high doses of DB damaged the epithelial cells of heart/kidney and induced apoptosis and autophagy. Remarkably, the results of RT-PCR and qRT-PCR indicated that different doses of DB gradually increased (p < 0.05) mRNA expressions of bitter taste, signaling effectors, apoptosis-, autophagy- and antioxidant- related genes on day 7 in a dose-response manner, while, these expressions were decreased (p < 0.05) subsequently by day-28 but exceptional higher (P < 0.05) expressions were observed in the high-dose DB groups of chickens. In conclusion, DB exerts adverse effects on the heart/kidney of chickens in a dose-response manner via damaging the epithelium of the heart/kidney by inducing apoptosis, autophagy associated with bitter taste and effector gene expressions. Correlation analyses for apoptosis/autophagy showed agonistic relationships. Our data provide a novel perspective for understanding the interaction of bitter taste, apoptosis, autophagy and antioxidative genes with bitter taste strong activators in the heart/kidney of chicken. These insights might help the feed industries and pave the way toward innovative directions in chicken husbandry.

Denatonium Benzoate Exposure Promotes IgE-Mediated Mast Cell Degranulation and Allergy By Upregulating FcεRIα Expression

“…DB is a bitter substance and known agonist of bitter taste receptors (T2Rs) in different cells [20]. T2Rs are G protein-coupled receptors playing a primary role as central warning signals to induce aversion toward noxious or harmful substances.…”

Freeze-Dried Royal Jelly Proteins Enhanced the Testicular Development and Spermatogenesis in Pubescent Male Mice

“…The obtained tissue sections were collected on glass slides, deparaffinized and stained by hematoxylin and eosin stain for histopathological examination. Five sections of testis from each of three different doses were observed for the histological changes in the seminiferous tubules as the previous method reported [28,29,30,31]. (Total of 30 sections were observed from each mouse).…”

Cellular mechanisms and molecular pathways linking bitter taste receptor signalling to cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction in heart diseases

“…Therefore, research has revealed that denatonium benzoate, an agonist of TAS2R1, 2, 7, and α-gustducin, at low dose (5 mg/kg) and short period of treatment (i.e. 7 days) causes a decrease in the expression of apoptosis and autophagy-related genes—caspase (Casp) 2, Casp3, Casp7, Casp9, Bcl-2l1 (B cell lymphoma 2 like 1), Mcl (mantle cell lymphoma), Bid (BH3-interacting domain death agonist), and Noxa (NADPH oxidase activator), along with increased expression of antioxidant enzymes or mediators such as glutathione peroxidase 1 (Gpx1), catalase (CAT), superoxide dismutase 1 (SOD1) and calpain-1 in whole heart tissues of experimental animals (Hamdard et al 2019b ). However, at higher doses and chronic treatment with denatonium benzoate, Hamdard et al ( 2019a , b ) demonstrated increased expression of the apoptosis and autophagy-related genes, suggesting that TAS2R activation may be beneficial at low doses and acute treatment period (Hamdard et al 2019b ).…”

“…Flufenamic acid is a TAS2R14 agonist (Meyerhof et al 2010 ) and a member of the anthranilic acid derivative class of nonsteroidal anti-inflammatory drugs (Chi et al 2011 ). Though it is not exactly clear whether the anti-inflammatory effect of flufenamic acid is due to its stimulatory action on TAS2R, available data suggest that this TAS2R14 agonist can modulate the expression of COX-2 gene via interaction with the NF-κB pathway (vide infra) or NADH oxidase signalling (Hamdard et al 2019b ). Indeed, activation of TAS2R1, 8, 10, 13, 14, and 38 by the human gut microbiota-derived quorum-sensing signal molecule, 3-oxo-C12:2-HSL in LPS- and IFNγ-stimulated RAW264.7 macrophages reportedly resulted in decreased expression of the proinflammatory cytokines IL-1β and TNFα via modulation of the NF-κB, Janus kinases/Signal transducer and activator of transcription (JAK/STAT) and TNF signalling pathways (Coquant et al 2022 ).…”

“…TAS2Rs are expressed in blood monocytes or monocyte-derived macrophages (Grassin-Delyle et al 2019 ), neutrophils (Maurer et al 2015 ), keratinocytes (Wölfle et al 2015 ), thymus (Panneck et al 2014 ; Soultanova et al 2015 ), vascular smooth muscles (Lund et al 2013 ), pancreas (Gaida et al 2016 ), brain (Singh et al 2011 ), thyroid gland (Clark et al 2015 ), testis (Xu et al 2013 ), spermatozoa (Governini et al 2020 ), prostate (Dupre and Martin 2017 ; Martin et al 2019 ), vagina, cervix, endometrium, myometrium, placenta, ovary (Dupre and Martin 2017 ; Welcome 2020a ), urethra, ureter, bladder (Welcome 2020a ; Welcome et al 2021 ), and kidney (Liu et al 2015b ). Relatively more recently, independent groups of researchers have identified the expression of TAS2Rs in cells and tissues of the heart (Foster et al 2013 , 2014 ; Manson et al 2014 ), indicating that these receptors may be involved in mediating the inflammatory, oxidative stress responses, autophagy (Hamdard et al 2019b ), cardiac rhythm (Yuan et al 2020 ) and contractile activities (Manson et al 2014 ; Bloxham et al 2020 ; Yuan et al 2020 ) in this vital organ.…”