Studies of the role of ischemia/reperfusion and superoxide anion radical production in the teratogenicity of cocaine

Fantel, Alan G.; Barber, Charles Victor; Carda, M.B.; Tumbic, Ruslan W.; Mackler, Bruce

doi:10.1002/tera.1420460314

Cited by 45 publications

(11 citation statements)

References 28 publications

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“…However, high amounts of ROS have been produced by high oxygen treatment during development of mouse pronuclear stage embryos and could induce the developmental blockage of embryo (Goto et al 1993). Furthermore, high levels of ROS have been implicated as a causative agent in the pathologies of a number of teratogens, including ethanol, cocaine, thalidomide, and diabetes (Fantel et al 1992;Chen and Sulik 1996;Parman et al 1999;Cederberg et al 2001). On the other hand, SOD1 encoded on human chromosome 21 is pathogenetically relevant to several disease states including Down syndrome (trisomy 21) (Gulesserian et al 2001).…”

Section: Discussionmentioning

confidence: 97%

The spatio-temporal expression pattern of cytoplasmic Cu/Zn superoxide dismutase (SOD1) mRNA during mouse embryogenesis

et al. 2007

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The cytoplasmic Cu/Zn-superoxide dismutase (SOD1) represents along with catalase and glutathione peroxidase at the first defense line against reactive oxygen species in all aerobic organisms, but little is known about its distribution in developing embryos. In this study, the expression patterns of SOD1 mRNA in mouse embryos were investigated using real-time RT-PCR and in situ hybridization analyses. Expression of SOD1 mRNA was detected in all embryos with embryonic days (EDs) 7.5-18.5. The signal showed the weakest level at ED 12.5, but the highest level at ED 15.5. SOD1 mRNA was expressed in chorion, allantois, amnion, and neural folds at ED 7.5 and in neural folds, notochord, neuromeres, gut, and primitive streak at ED 8.5. In central nervous system, SOD1 mRNA was expressed greatly in embryos of EDs 9.5-11.5, but weakly in embryos of ED 12.5. At EDs 9.5-12.5, the expression of SOD1 mRNA was high in sensory organs such as tongue, olfactory organ (nasal prominence) and eye (optic vesicle), while it was decreased in ear (otic vesicle) after ED 10.5. In developing limbs, SOD1 mRNA was greatly expressed in forelimbs at EDs 9.5-11.5 and in hindlimbs at EDs 10.5-11.5. The signal increased in liver, heart and genital tubercle after ED 11.5. In the sections of embryos after ED 13.5, SOD1 mRNA was expressed in various tissues and especially high in mucosa and metabolically active sites such as lung, kidney, stomach, and intestines and epithelial cells of skin, whisker follicles, and ear and nasal cavities. These results suggest that SOD1 may be related to organogenesis of embryos as an antioxidant enzyme.

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Section: Discussionmentioning

confidence: 97%

The spatio-temporal expression pattern of cytoplasmic Cu/Zn superoxide dismutase (SOD1) mRNA during mouse embryogenesis

et al. 2007

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“…Elevated reactive oxygen species (ROS) can occur when ROS production is increased and/or the oxidant defense system is decreased. High levels of ROS have been implicated as a causative agent in the pathologies of a number of teratogens, including ethanol, cocaine, thalidomide, and diabetes [33][34][35][36]. Importantly, antioxidant addition has been correlated with decreased ROS concentrations and modulation of the teratogenicity of some agents [24,36,37].…”

Section: Discussionmentioning

confidence: 97%

Copper-Deficient Rat Embryos Are Characterized by Low Superoxide Dismutase Activity and Elevated Superoxide Anions1

Hawk

Lanoue

Keen

et al. 2003

Biology of Reproduction

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The teratogenicity of copper (Cu) deficiency may result from increased oxidative stress and oxidative damage. Dams were fed either control (8.0 microg Cu/g) or Cu-deficient (0.5 microg Cu/g) diets. Embryos were collected on Gestational Day 12 for in vivo studies or on Gestational Day 10 and cultured for 48 h in Cu-deficient or Cu-adequate media for in vitro studies. Superoxide dismutase (SOD), glutathione peroxidase (GPX), and glutathione reductase (GR) activities were measured in control and Cu-deficient embryos as markers of the oxidant defense system. Superoxide anions were measured as an index of exposure to reactive oxygen species (ROS). No differences were found in GPX or GR activities among treatment groups. However, SOD activity was lower and superoxide anion concentrations higher in Cu-deficient embryos cultured in Cu-deficient serum compared to control embryos cultured in control serum. Even so, Cu-deficient embryos had similar CuZnSOD protein levels as controls. In the in vitro system, Cu-deficient embryos had a higher frequency of malformations and increased staining for superoxide anions in the forebrain, heart, forelimb, and somites compared to controls. When assessed for lipid and DNA oxidative damage, conjugated diene concentrations were similar among the groups, but a tendency was observed for Cu-deficient embryos to have higher 8-hydroxy-2'-deoxyguanosine concentrations than controls. Thus, Cu deficiency resulted in embryos with malformations and reduced SOD enzyme activity. Increased ROS concentrations in the Cu-deficient embryo may cause oxidative damage and contribute to the occurrence of developmental defects.

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“…Coherently with a mechanistic involvement of hypoxia, hemorrhagic limb defects have been produced by subjecting fetal rats to a hypoxic environment (24) and, as pointed out in previous investigations (3)(4)(5)(6)(7)(8), by exposing fetuses to vasoactive agents capable of uteroplacental perfusion reduction, including epinephrine (25,26), cocaine (27), calcium-channel blockers (28,29), phenytoin (30), and uterine vascular clamping (31,32). Limb defects were also produced by multiple brief exposures of cultured rat embryos to hypoxia (33). On the other hand, maternal hyperoxia has been found to prevent hereditary congenital limb amputations and associated hemorrhages in the rabbit (34), and to reduce in the mouse the occurrence of craniofacial teratogenicity of phenytoin (35), an antiepileptic agent whose embryotoxicity has been causally linked to episodes of interrupted oxygen supply and possible generation of reactive oxygen species during reoxygenation (36).…”

Section: Tiboni Et Almentioning

confidence: 99%

The Nitric Oxide Synthesis Inhibitor Nω-Nitro-L-Arginine Methyl Ester (L-NAME) Causes Limb Defects in Mouse Fetuses: Protective Effect of Acute Hyperoxia

2003

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In the present study the relationship between exposure to the nitric oxide synthesis inhibitor N -nitro-L-arginine methyl ester (L-NAME) and the induction of limb defects, with respect to stage specificity and dose dependency, was investigated in the mouse. ICR (CD-1) mice were dosed s.c with L-NAME at 50 or 90 mg/kg on gestation d 12, 13, 14, 15, or 16. A group of animals treated with vehicle on gestation d 14 served as control. Uterine contents were evaluated for teratogenesis on gestation d 18. A treatment-related disruption of limb development was noted. The effect was dose dependent and phase specific. L-NAME became teratogenically operational on gestation d 13 and elicited its maximum effect on gestation d 14, whereas no significant teratogenicity was observed when exposure occurred after gestation d 15. In utero exposure to L-NAME also reduced embryo viability relative to controls. When the higher dose was injected on gestation d 16, a significant number of dams delivered preterm. In a parallel study, the ability of hyperoxia to prevent limb teratogenesis was investigated. To this aim, a group of L-NAMEtreated animals (90 mg/kg s.c. on gestation d 14) were exposed to 98 to 100% O 2 for 12 h. L-NAME-treated mice breathing room air served as positive controls. In response to hyperoxia, a significant decrement of L-NAME-induced limb defects was found. This study characterizes for the first time the teratogenic capacity of L-NAME in the mouse. Results obtained with hyperoxia fit the hypothesis that hypoxic tissue damage may play a contributory role in L-NAME-induced limb defects. NO is a colorless gaseous molecule involved in the regulation of diverse important physiologic processes, including vascular tone, platelet reactivity, smooth muscle contractility, neurotransmission, and the cytotoxic action of immune cells (1). NO is generated endogenously during the conversion of L-arginine to citrulline by a family of enzymes known as NOS. At least three isoforms of NOS have been isolated, including the constitutive eNOS and neuronal NOS isoforms, and the inducible isoform, iNOS (1). Pharmacologic manipulation of NOS activity can be achieved by several classes of NOS inhibitors including L-arginine analogs, which act by denying NOS its substrate in a competitive manner (2).The L-arginine analog L-NAME, a nonselective inhibitor of NOS, has been shown to be teratogenic when administered to rats (3-8). Limb reduction defects with associated characteristic areas of macroscopic hemorrhage were the most common phenotypic alterations noted (3-8). L-NAME is not the only L-arginine analog known to cause dysmelia, as N -nitro-Larginine also induced limb defects (9). Notably, disruptions similar to those induced by L-arginine analogs have been noted in knockout mice lacking eNOS (10, 11). The current state of knowledge on L-NAME teratogenicity also includes the following facts: 1) the period of fetal vulnerability has an onset relatively late in gestation (3-5); 2) both oral (3-6) and parenteral (5) treatments are effective;...

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Studies of the role of ischemia/reperfusion and superoxide anion radical production in the teratogenicity of cocaine

Cited by 45 publications

References 28 publications

The spatio-temporal expression pattern of cytoplasmic Cu/Zn superoxide dismutase (SOD1) mRNA during mouse embryogenesis

The spatio-temporal expression pattern of cytoplasmic Cu/Zn superoxide dismutase (SOD1) mRNA during mouse embryogenesis

Copper-Deficient Rat Embryos Are Characterized by Low Superoxide Dismutase Activity and Elevated Superoxide Anions1

The Nitric Oxide Synthesis Inhibitor Nω-Nitro-L-Arginine Methyl Ester (L-NAME) Causes Limb Defects in Mouse Fetuses: Protective Effect of Acute Hyperoxia

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