Impaired Cardiac Functional Reserve and Left Ventricular Hypertrophy in Adult Sheep After Prenatal Dexamethasone Exposure

Dodic, Miodrag; Samuel, Chrishan S.; Moritz, Karen M.; Wintour, E. M.; Morgan, John G.; Grigg, Leeanne; Wong, Janet

doi:10.1161/hh1901.097086

Cited by 90 publications

(97 citation statements)

References 47 publications

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“…The secretion of insulin, the counterbalancing hormone for glucagon, proceeds through activation of AC (Gao et al 2002), so the heterologous augmentation of AC signaling caused by CPF exposure is likely to amplify the physiologic effect of a superimposed deficiency in the glucagon response. It is now recognized that diseases that occupy a distinct cluster-hypertension, obesity, and diabetes-may have significant dependence on prenatal stress and/or toxicant exposures (Dodic et al 1999(Dodic et al , 2001Nyirenda and Seckl 1998;Power and Jefferis 2002;Slikker and Schwetz 2003;Toschke et al 2002). The present results point to the possibility that otherwise subtoxic, nonsymptomatic developmental exposure may provide predisposition to these types of diseases, with a specific component of delayed-onset effects.…”

Section: Discussionmentioning

confidence: 55%

“…The "Barker Hypothesis" originally drew a connection between fetal growth retardation and the subsequent incidence of coronary artery disease and diabetes (Barker 2003;Phillips 2002), and there is also significant literature on the long-term consequences of prenatal stress and the role of glucocorticoid hormones (Dodic et al 1999(Dodic et al , 2001Nyirenda and Seckl 1998). More recently, there are suggestions that environmental toxicants may play an important contributory role in such disorders as hypertension, diabetes, and obesity, beyond neural contributions (Power and Jefferis 2002;Slikker and Schwetz 2003;Toschke et al 2002).…”

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confidence: 99%

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Developmental effects of chlorpyrifos extend beyond neurotoxicity: critical periods for immediate and delayed-onset effects on cardiac and hepatic cell signaling.

Meyer

Seidler

Slotkin

2004

Environ Health Perspect

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The fetal and neonatal neurotoxicity of chlorpyrifos (CPF) and related insecticides is a major concern. Developmental effects of CPF involve mechanisms over and above cholinesterase inhibition, notably events in cell signaling that are shared by nonneural targets. In the present study, we evaluated the immediate and long-term effects of CPF exposure of rats during different developmental windows [gestational days (GD) 9-12 or 17-20, postnatal days (PN) 1-4 or 11-14] on the adenylyl cyclase (AC) signaling cascade in the heart and liver. In addition to basal AC activity, we assessed the responses to direct AC stimulants (forskolin, Mn 2+ ); to isoproterenol and glucagon, which activate signaling through specific membrane receptors; and to sodium fluoride, which activates the G-proteins that couple the receptors to AC. Few immediate effects on AC were apparent when CPF doses remained below the threshold for systemic toxicity. Nevertheless, CPF exposures on GD9-12, GD17-20, or PN1-4 elicited sex-selective effects that emerged by adulthood (PN60), whereas later exposure (PN11-14) elicited smaller, nonsignificant effects, indicative of closure of the window of vulnerability. Most of the effects were heterologous, involving signaling elements downstream from the receptors, and thus were shared by multiple inputs; superimposed on this basic pattern, there were also selective alterations in receptor-mediated responses. These results suggest that the developmental toxicity of CPF extends beyond the nervous system, to include cell signaling cascades that are vital to cardiac and hepatic homeostasis. Future work needs to address the potential implications of these effects for cardiovascular and metabolic disorders that may emerge long after the end of CPF exposure.

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Section: Discussionmentioning

confidence: 55%

mentioning

confidence: 99%

Developmental effects of chlorpyrifos extend beyond neurotoxicity: critical periods for immediate and delayed-onset effects on cardiac and hepatic cell signaling.

Meyer

Seidler

Slotkin

2004

Environ Health Perspect

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“…Oophorectomized offspring (group SA, nϭ6; group DA, nϭ5) have been studied extensively before being killed at 7 years of age for tissue collection. [11][12][13]21 Both male and female animals from the first cohort had basal blood pressure measurements. Blood pressure response to testosterone was studied after basal blood pressure measurements only in males from the same cohort.…”

Section: Animalsmentioning

confidence: 99%

“…12 By 7 years of age, these animals had developed left ventricular hypertrophy with reduced cardiac functional reserve. 13 In these studies, only female offspring were studied. However, in many models, the programming effects of the prenatal treatment are only seen in male offspring, 14 or they were more pronounced in male offspring compared with female offspring.…”

mentioning

confidence: 99%

Programming Effects of Short Prenatal Exposure to Dexamethasone in Sheep

et al. 2002

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Abstract-Recent studies have linked fetal exposure to a suboptimal intrauterine environment with adult hypertension. The aims of the present study were to see whether prenatal dexamethasone administered intravenously to the ewe between 26 to 28 days of gestation (1) resulted in high blood pressure in male and female offspring and whether hypertension in males was modulated by testosterone status, and (2) altered gene expression for angiotensinogen and angiotensin type 1 (AT 1 ) receptors in the brain in late gestation and in the adult. Basal mean arterial pressure (MAP) at 2 years of age was significantly higher in wethers exposed to prenatal dexamethasone (group D; 106Ϯ5 mm Hg, nϭ9) compared with the control group (group S; 91Ϯ3 mm Hg, nϭ8; PϽ0.01). Infusion of testosterone for 3 weeks had no effect on MAP in either treatment group. Key Words: brain Ⅲ glucocorticoids Ⅲ hypertension, experimental Ⅲ sheep E pidemiological evidence suggests that babies born small for gestational age have an increased incidence of adultonset diseases or dysfunction, including syndrome X (hypertension, non-insulin-dependent diabetes mellitus, and hyperlipidemia). [1][2][3] It is hypothesized that a suboptimal intrauterine environment during a critical stage of development permanently alters, or "programs," the development of fetal tissues. This may ensure the short-term survival of the fetus but also may bring adverse consequences in postnatal life.Animal models using maternal undernutrition or restriction of specific dietary components (iron, protein), either throughout pregnancy or during parts of gestation, have confirmed that restriction of fetal growth leads to elevated blood pressure in the progeny of rats. 4 -6 A second type of animal model has examined the long-term/programming effects caused by prenatal glucocorticoid exposure. When adult rats were exposed to large doses of carbenoxolone (an 11␤-hydroxysteroid dehydrogenase [HSD] inhibitor, which blocks placental inactivation of endogenous glucocorticoids) throughout gestation, offspring were of low birth weight and had high blood pressure. 7-9 The synthetic glucocorticoid dexamethasone, which is poorly metabolized by placental 11␤-HSD, given throughout rat pregnancy resulted in offspring with high blood pressure. 10 In the sheep, we 11 have shown that exposure to dexamethasone, for 2 days very early in gestation (at a mean age of 27 days of the 150-day gestation period) results in hypertensive female offspring by 3 to 4 months of age. This hypertension amplifies with age and is associated with an increased cardiac output. 12 By 7 years of age, these animals had developed left ventricular hypertrophy with reduced cardiac functional reserve. 13 In these studies, only female offspring were studied. However, in many models, the programming effects of the prenatal treatment are only seen in male offspring, 14 or they were more pronounced in male offspring compared with female offspring. 4 These studies proposed that programming, at least in some models, may be gender specific....

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“…A comparação dos valores por nós obtidos com aqueles considerados referência para ovinos, 37,2% (Moses & Ross 1987), 42% (Dodic et al 2001) e 40% (Rabbani et al 2006), permite clara evidenciação do comprometimento da função cardíaca induzido pelo MF. Achados similares (FE = 32,4% e 29,5%) foram recentemente descritos em ovinos intoxicados com 20g/kg de M. rigida (Lago et al 2009).…”

Section: Discussionunclassified

Avaliações clínico-patológicas e laboratoriais da intoxicação experimental por monofluoroacetato de sódio em ovinos

et al. 2010

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O objetivo deste trabalho foi verificar se a administração de doses únicas e de frações diárias da dose letal de monofluoroacetato de sódio (MF) a ovinos induzem a clássica degeneração hidrópico-vacuolar (DHV) dos túbulos uriníferos contornados distais observada no rim de bovinos intoxicados por plantas brasileiras que causam "morte súbita" (PBCMS). MF foi administrado, por via oral, em doses únicas de 0,5 e 1,0mg/kg, cada dose para dois ovinos, e em doses subletais repetidas diariamente de 0,1mg/kg/dia, por quatro dias, e 0,2mg/kg/dia por seis dias, cada dose para um ovino. Todos os ovinos que receberam MF morreram, exceto um que recebeu 0,5mg/kg e não mostrou sintomas. A evolução da intoxicação variou de 3min a 33h5min. Clinicamente os animais apresentaram taquicardia, respiração abdominal, tremores musculares, ligeira perda de equilíbrio, por vezes cambaleavam, deitavam e apoiavam a cabeça no flanco. Na fase final, os ovinos caíam em decúbito lateral, esticavam os membros, faziam movimentos de pedalagem, apresentavam opistótono e morriam. O exame ecocardiográfico evidenciou dilatação cardíaca e redução da fração de encurtamento sistólico. A análise dos níveis séricos de uréia e creatinina revelou moderada a acentuada azotemia. MF provocou "morte súbita" em todos os ovinos que mostraram sintomas. À necropsia verificaram-se aurículas e veias jugulares, cavas, ázigos e pulmonares moderadamente ingurgitadas e, em alguns animais, edema pulmonar. O exame histopatológico revelou, em todos os ovinos, leve a acentuada DHV das células epiteliais dos túbulos contornados distais, associada à picnose nuclear. Adicionalmente, verificaram-se discreta vacuolização e, por vezes, necrose de coagulação de hepatócitos. Não encontramos referências a esse tipo peculiar de lesão, exceto das descrições sobre lesões renais associadas à ingestão de PBCMS e de recentes estudos em bovinos intoxicados com MF. Este trabalho demonstra, em ovinos, que tanto doses letais únicas quanto subdoses diárias de MF induzem a DHV dos túbulos uriníferos contornados distais associada à picnose nuclear.

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Impaired Cardiac Functional Reserve and Left Ventricular Hypertrophy in Adult Sheep After Prenatal Dexamethasone Exposure

Cited by 90 publications

References 47 publications

Developmental effects of chlorpyrifos extend beyond neurotoxicity: critical periods for immediate and delayed-onset effects on cardiac and hepatic cell signaling.

Developmental effects of chlorpyrifos extend beyond neurotoxicity: critical periods for immediate and delayed-onset effects on cardiac and hepatic cell signaling.

Programming Effects of Short Prenatal Exposure to Dexamethasone in Sheep

Avaliações clínico-patológicas e laboratoriais da intoxicação experimental por monofluoroacetato de sódio em ovinos

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