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Protein kinase C inhibition induced steroid hormonal perturbation in rat in vivo
S172
Abstracts / Toxicology Letters 221S (2013) S59–S256
P13-19 Polyphenolic compounds from Aronia melanocarpa berries protect from hydrogen peroxide accumulation in the bone tissue of cadmium-exposed rats Alicja Roszczenko ∗ , Malgorzata M. Brzóska, Joanna Rogalska
P13-21 Protein kinase C inhibition induced steroid hormonal perturbation in rat in vivo Schadt Heiko, Dincer Zuhal, Schwald Marianne, Dietz Audrey, Ledieu David, Cordier Andre, Papoutsi Maria, Junker Walker Ursula, Spence Fiona, Chibout Salah-Dine, Wolf Armin, Pognan Francois
Department of Toxicology, Medical University of Bialystok, Poland Oxidative/antioxidative status of the bone tissue plays a crucial role in its physiology and pathology. During bone resorption reactive oxygen species (ROS), including particularly hydrogen peroxide and superoxide anion, are generated. ROS inhibit osteoblasts differentiation and mediate osteoclasts formation stimulating further processes of bone resorption. Recent data indicate that oxidative stress is involved in the mechanisms of damaging cadmium action in the bone tissue. The aim of the present study was to investigate whether enhanced consumption of polyphenolic compounds, characterized by antioxidative properties, may protect from cadmium-induced ROS production and accumulation in the bone tissue. The concentration of hydrogen peroxide and the activities of antioxidative enzymes involved in its detoxification (catalase and glutathione peroxidase) as well as total antioxidative status and total oxidative status were determined in the bone tissue at the femoral distal end (trabecular bone region) of the female Wistar rats administered 0.1% water extract of polyphenols from the berries of Aronia melanocarpa or/and cadmium in diet (1 and 5 mg/kg) for 24 months. The administration of polyphenolic compounds under the exposure to cadmium improved the bone antioxidative capacity and importantly protected from this heavy metal-induced hydrogen peroxide accumulation and development of oxidative stress. The results show that polyphenolic compounds may prevent from cadmium-induced hydrogen peroxide accumulation and development of oxidative stress in the bone tissue, and in this way protect from skeleton damage under exposure to this heavy metal. http://dx.doi.org/10.1016/j.toxlet.2013.05.376
P13-20 Protective efficacy of selenite against lead-induced neurotoxicity in Caenorhabditis elegans Vivian Hsiu-Chuan Liao ∗ , Wen-Hsuan Li, Yeu-Ching Shi, I.-Ling Tseng Department of Bioenvironmental Systems Engineering, National Taiwan University, No. 1 Roosevelt Road, Sec. 4, Taipei 106, Taiwan Background: Selenium is an essential micronutrient that has a narrow exposure window between its beneficial and toxic effects. This study investigated the protective potential of selenite (IV) against lead (Pb(II))-induced neurotoxicity in Caenorhabditis elegans. Principal findings: The results showed that Se(IV) (0.01 M) pretreatment ameliorated the decline of locomotion behaviors (frequencies of body bends, head thrashes, and reversal) of C. elegans that are damaged by Pb(II) (100 M) exposure. The intracellular ROS level of C. elegans induced by Pb(II) exposure was significantly lowered by Se(IV) supplementation prior to Pb exposure. Finally, Se(IV) protects AFD sensory neurons from Pb(II)induced toxicity. Conclusions: Our study suggests that Se(IV) has protective activities against Pb(II)-induced neurotoxicity through its antioxidant property. http://dx.doi.org/10.1016/j.toxlet.2013.05.377
Preclinical Safety, Novartis Institutes for Biomedical Research, Basel, Switzerland Steroid hormones are critical endogenous mediators synthesized and secreted into the bloodstream by endocrine glands, such as the adrenal cortex or gonads. They mediate a wide variety of physiological functions. Since protein kinase C (PKC) is involved in the regulation and signal transduction of various hormones, its inhibition could potentially affect steroid hormone regulation. To investigate this hypothesis, a 2-week oral mechanistic study was conducted in rats with special focus on histopathology, genomic investigations and hormone measurements. After treatment with 100 mg/kg/day or 200 mg/kg/day of a protein kinase C inhibitor for 2 weeks, androstenedione and testosterone were both decreased in plasma, adrenals and testes of male animals. In female rats, a reduction of estrogens and its precursor androstenedione was observed in ovaries, whereas progesterone was increased in ovaries and adrenals, yet decreased in plasma. Luteinizing Hormone, which is released by the anterior pituitary and regulates sex hormones, was decreased in blood and could consequently have triggered the reduction of androgens, estrogens and plasma progesterone. However, as progesterone levels were elevated in ovaries, the PKC inhibitor might have an additional direct effect in the corpora lutea independently of the LH reduction which could have led to the observed disturbances in estrous cycle. In both gender, aldosterone was elevated in plasma and adrenals which was associated with adrenal gland cortical vacuolation. In summary, these data support possible PKCi induced hormonal imbalances in the rat, likely due to a disturbance of the hypothalamus–pituitary–gonad axis and/or direct effect on the ovaries and adrenals. http://dx.doi.org/10.1016/j.toxlet.2013.05.378
P13-22 Quantum mechanical, in vitro and in vivo evidence of the involvement of non-bonding nitrogen interactions in valine derived -amino chalcogenides Waseem Hassan ∗ , Senthil Narayanaperumal, Kashif Gul, Rogério de Aquino Saraiva, Antonio L. Braga, Oscar E.D. Rodrigues, João Batista Teixeira da Rocha ∗ Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, CEP 97105-900, RS, Brazil Global reactivity descriptors (electronic affinity, ionization potential, hardness, electronegativity, and electrophilicity) for valine derived diselenides and sulfides were calculated using the generalized gradient approximation (GGA) of Perdew, Burke, and Ernzerhof (PBE) and a double-numeric-plus polarization (DNP) method. Geometry optimizations were performed and the obtained geometries were verified to show only real infrared frequencies. HOMO and LUMO calculations confirmed the existence and involvement of significant non bonding interactions which
Abstracts / Toxicology Letters 221S (2013) S59–S256
P13-19 Polyphenolic compounds from Aronia melanocarpa berries protect from hydrogen peroxide accumulation in the bone tissue of cadmium-exposed rats Alicja Roszczenko ∗ , Malgorzata M. Brzóska, Joanna Rogalska
P13-21 Protein kinase C inhibition induced steroid hormonal perturbation in rat in vivo Schadt Heiko, Dincer Zuhal, Schwald Marianne, Dietz Audrey, Ledieu David, Cordier Andre, Papoutsi Maria, Junker Walker Ursula, Spence Fiona, Chibout Salah-Dine, Wolf Armin, Pognan Francois
Department of Toxicology, Medical University of Bialystok, Poland Oxidative/antioxidative status of the bone tissue plays a crucial role in its physiology and pathology. During bone resorption reactive oxygen species (ROS), including particularly hydrogen peroxide and superoxide anion, are generated. ROS inhibit osteoblasts differentiation and mediate osteoclasts formation stimulating further processes of bone resorption. Recent data indicate that oxidative stress is involved in the mechanisms of damaging cadmium action in the bone tissue. The aim of the present study was to investigate whether enhanced consumption of polyphenolic compounds, characterized by antioxidative properties, may protect from cadmium-induced ROS production and accumulation in the bone tissue. The concentration of hydrogen peroxide and the activities of antioxidative enzymes involved in its detoxification (catalase and glutathione peroxidase) as well as total antioxidative status and total oxidative status were determined in the bone tissue at the femoral distal end (trabecular bone region) of the female Wistar rats administered 0.1% water extract of polyphenols from the berries of Aronia melanocarpa or/and cadmium in diet (1 and 5 mg/kg) for 24 months. The administration of polyphenolic compounds under the exposure to cadmium improved the bone antioxidative capacity and importantly protected from this heavy metal-induced hydrogen peroxide accumulation and development of oxidative stress. The results show that polyphenolic compounds may prevent from cadmium-induced hydrogen peroxide accumulation and development of oxidative stress in the bone tissue, and in this way protect from skeleton damage under exposure to this heavy metal. http://dx.doi.org/10.1016/j.toxlet.2013.05.376
P13-20 Protective efficacy of selenite against lead-induced neurotoxicity in Caenorhabditis elegans Vivian Hsiu-Chuan Liao ∗ , Wen-Hsuan Li, Yeu-Ching Shi, I.-Ling Tseng Department of Bioenvironmental Systems Engineering, National Taiwan University, No. 1 Roosevelt Road, Sec. 4, Taipei 106, Taiwan Background: Selenium is an essential micronutrient that has a narrow exposure window between its beneficial and toxic effects. This study investigated the protective potential of selenite (IV) against lead (Pb(II))-induced neurotoxicity in Caenorhabditis elegans. Principal findings: The results showed that Se(IV) (0.01 M) pretreatment ameliorated the decline of locomotion behaviors (frequencies of body bends, head thrashes, and reversal) of C. elegans that are damaged by Pb(II) (100 M) exposure. The intracellular ROS level of C. elegans induced by Pb(II) exposure was significantly lowered by Se(IV) supplementation prior to Pb exposure. Finally, Se(IV) protects AFD sensory neurons from Pb(II)induced toxicity. Conclusions: Our study suggests that Se(IV) has protective activities against Pb(II)-induced neurotoxicity through its antioxidant property. http://dx.doi.org/10.1016/j.toxlet.2013.05.377
Preclinical Safety, Novartis Institutes for Biomedical Research, Basel, Switzerland Steroid hormones are critical endogenous mediators synthesized and secreted into the bloodstream by endocrine glands, such as the adrenal cortex or gonads. They mediate a wide variety of physiological functions. Since protein kinase C (PKC) is involved in the regulation and signal transduction of various hormones, its inhibition could potentially affect steroid hormone regulation. To investigate this hypothesis, a 2-week oral mechanistic study was conducted in rats with special focus on histopathology, genomic investigations and hormone measurements. After treatment with 100 mg/kg/day or 200 mg/kg/day of a protein kinase C inhibitor for 2 weeks, androstenedione and testosterone were both decreased in plasma, adrenals and testes of male animals. In female rats, a reduction of estrogens and its precursor androstenedione was observed in ovaries, whereas progesterone was increased in ovaries and adrenals, yet decreased in plasma. Luteinizing Hormone, which is released by the anterior pituitary and regulates sex hormones, was decreased in blood and could consequently have triggered the reduction of androgens, estrogens and plasma progesterone. However, as progesterone levels were elevated in ovaries, the PKC inhibitor might have an additional direct effect in the corpora lutea independently of the LH reduction which could have led to the observed disturbances in estrous cycle. In both gender, aldosterone was elevated in plasma and adrenals which was associated with adrenal gland cortical vacuolation. In summary, these data support possible PKCi induced hormonal imbalances in the rat, likely due to a disturbance of the hypothalamus–pituitary–gonad axis and/or direct effect on the ovaries and adrenals. http://dx.doi.org/10.1016/j.toxlet.2013.05.378
P13-22 Quantum mechanical, in vitro and in vivo evidence of the involvement of non-bonding nitrogen interactions in valine derived -amino chalcogenides Waseem Hassan ∗ , Senthil Narayanaperumal, Kashif Gul, Rogério de Aquino Saraiva, Antonio L. Braga, Oscar E.D. Rodrigues, João Batista Teixeira da Rocha ∗ Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, CEP 97105-900, RS, Brazil Global reactivity descriptors (electronic affinity, ionization potential, hardness, electronegativity, and electrophilicity) for valine derived diselenides and sulfides were calculated using the generalized gradient approximation (GGA) of Perdew, Burke, and Ernzerhof (PBE) and a double-numeric-plus polarization (DNP) method. Geometry optimizations were performed and the obtained geometries were verified to show only real infrared frequencies. HOMO and LUMO calculations confirmed the existence and involvement of significant non bonding interactions which