Maternal endotoxemia, fetal anomalies, and central nervous system damage: A rat model of a human problem

Ornoy, Asher; Altshuler, Geoffrey

doi:10.1016/s0002-9378(16)33298-7

Cited by 64 publications

(31 citation statements)

References 9 publications

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“…A recent clinical study suggests that low birth weight is associated with lower adult bone and muscle mass which indicate that the risk of osteoporosis in later life might be programmed by genetic or environmental influences during gestation (Gale et al 2001). Furthermore, a low birth weight and leanness at birth have been shown to be associated with insulin resistance in children and adolescents (Ornoy & Altshuler 1976, Hofman et al 1997, Robinson et al 2000. A recent study has shown that prenatal exposure to Dex leads to increased fat depots in the adult rat.…”

Section: Introductionmentioning

confidence: 99%

Affected skeletal growth but normal bone mineralization in rat offspring after prenatal dexamethasone exposure

Swolin-Eide¹,

Dahlgren²,

Nilsson³

et al. 2002

Journal of Endocrinology

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Events occurring early in life or prenatally are able to play important roles in the pathogenesis of diseases in adult life. Different sorts of stress or hormonal influences, during particular periods of pregnancy, may result in persisting or transient changes in physiology. Glucocorticoids are used for the treatment of a variety of diseases, to promote organ maturation and to prevent preterm delivery. Glucocorticoids are also known to affect skeletal growth and adult bone metabolism. The aim of the present study was to investigate whether exposure to dexamethasone (Dex) during fetal life has any effect on skeletal growth and/or bone mineral density in adult rat offspring.Pregnant rats were given injections of either Dex (100µg/kg) or vehicle on days 9, 11 and 13 of gestation. Dex-exposed male but not female rat offspring showed transient increases in crown-rump length and tibia and femur lengths at 3-6 weeks of age. In contrast, the cortical bone dimensions were altered in 12-week-old female but not male Dex-exposed offspring. The areal bone mineral densities of the long bones and the spine, as determined by dual X-ray absorptiometry, and trabecular as well as cortical volumetric bone mineral density, as measured using peripheral quantitative computerized tomography, were unchanged in both male and female Dex-exposed offspring.In conclusion, prenatal Dex exposure affects skeletal growth in a gender-specific manner, while the mineralization of bones is unaffected in both male and female offspring.

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Section: Introductionmentioning

confidence: 99%

Affected skeletal growth but normal bone mineralization in rat offspring after prenatal dexamethasone exposure

Swolin-Eide¹,

Dahlgren²,

Nilsson³

et al. 2002

Journal of Endocrinology

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“…LPS is a potent inflammatory agent and has been used to mimic infection because it initiates most components of an inflammatory response. Exposure to LPS in neonatal rats (13), kittens (1), and monkeys (13), as well as in fetal rats (14,15) and rabbits (16,17), leads to cerebral white matter damage, including PVL. However, in these studies, fetuses and neonates were not catheterized and hence physiologic data associated with brain injury would have been difficult to obtain; furthermore, cerebral injury was not observed in all animals exposed to LPS in these paradigms.…”

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confidence: 99%

White Matter Injury after Repeated Endotoxin Exposure in the Preterm Ovine Fetus

Duncan

2002

Pediatric Research

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Intrauterine infection has been linked to neurologic injury in preterm infants. However, a reproducible model of white matter injury in the preterm fetus in a long gestation species that can be monitored in utero is currently unavailable. Thus, our objective was to determine the effects of bacterial endotoxin (lipopolysaccharide, LPS) on physiologic and inflammatory responses and brain structure in the preterm ovine fetus. At 0.7 of gestation, six catheterized fetuses received three to five intravenous injections of LPS (1 g/kg) over 5 d; seven fetuses served as controls. Fetal responses were monitored and brain tissue examined 10 -11 d after the initial LPS injection. After LPS on d 1 and 2, fetuses became transiently hypoxemic and hypotensive and blood IL-6 levels were increased, but these responses were smaller or absent after subsequent LPS exposures. Neural injury was observed in all LPS-exposed fetuses, most prominently in the cerebral white matter. Injury ranged from diffuse subcortical damage to periventricular leukomalacia, and in the brainstem the cross-sectional area of the corticospinal tract was reduced by 30%. Thus, repeated exposure of the preterm ovine fetus to LPS causes neuropathology resembling that of cerebral palsy and provides a robust model for exploring the etiology, prevention, and treatment of white matter damage. It has been hypothesized that infection during pregnancy, for example, bacterial vaginosis, urinary tract infection, or chorioamnionitis, can lead to preterm fetal brain injury (1-4). Furthermore, it has been hypothesized that such injury might result from an inflammatory cascade initiated via mediators from the mother, placenta, or membranes (3). These hypotheses have been supported by clinical evidence that maternal infection is associated with both preterm birth and neonatal neurologic injury (5), and with increased levels of pro-inflammatory cytokines in amniotic fluid (6) and fetal blood (7). White matter damage is the most common form of brain injury and includes necrosis and cystic lesions in white matter adjacent to the lateral ventricles, usually referred to as PVL. The proinflammatory cytokines TNF-␣ (8) and IL-6 (9) have been identified within PVL (8)

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“…The teratologic potential of endotoxin has been evaluated in fetal rats and rabbits (15,24). These studies demonstrate an increased incidence of central nervous system anomalies (hydrocephalus, microcephaly, anopthalmia) after endotoxin exposure; however, the paucity of cerebral white matter in the fetal rat brain renders the animal a poor experimental model to study a disorder that has a predilection for white matter injury (12).…”

Section: Resultsmentioning

confidence: 99%

Systemic and Neuropathologic Effects of E. coli Endotoxin in Neonatal Dogs

1983

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Summarytional 2 0 4 samples of arterial blood were obtained hourly forThe acute systemic and neuropathologic effects of E. coli endotoxin were determined in neonatal dogs. Administration of sublethal (LDo), moderate (LD50), or lethal (LDlo0) doses of endotoxin produced significant arterial hypotension, metabolic (lactic) acidosis, and hypoglycemia. Neuropathologic changes consisted of widespread inflammation in both grey and white matter; however, necrotic lesions were found only in forebrain white matter.determination ofplasma glucose and lactate levels by fluorometric analysis according to the method of Lowry and Passoneau (19). Body temperature was monitored by means of a rectal thermocouple (Yellow Springs) and maintained by a servo-controlled heating lamp. After insertion of the catheter, halothane was withdrawn and the animals allowed to spbntaneously breathe room air. The wound was sutured and periodically infiltrated with xylocaine, 1%. A low (LDo), moderate (LD~o), or high (LDIoo) Bacterial infections in the human infant are an important cause of subsequent mental retardation, cerebral palsy, and epilepsy (18,22,23,25). The morbidity and mortality associated with perinatal bacterial infections have been attributed to bacterial endotoxin, a lipopolysaccharide component of the bacterial cell wall. Because administration of endotoxin to laboratory animals mimics human septicemia (1,4,8,14), the systemic and neuropathologic disturbances induced by endotoxin are of considerable interest.Studies by Gilles et al. (12) have shown that administration of E. coli endotoxin to newborn kittens produces extensive brain injury. The acute systemic changes occurring during neonatal endotoxemia have not been described in detail. We, therefore, undertook a series of experiments in neonatal dogs to determine the acute neuropathologic changes occurring during endotoxemia as well as the critical physiologic and and metabolic parameters (blood pressure, heart rate, arterial blood gases, glucose, and lactate levels), which might be associated with those neuropathologic changes. Although these systemic parameters have not been studied during endotoxemia in the neonatal dog, they have been shown to be important predictors of mortality in the endotoxintreated adult dog (5,9,17,20). MATERIALS AND METHODSDose-response curve. Mongrel dogs, 1-10 days of age, were selected because their state of neurologic development at birth resembles that of the human infant of approximately 34-40 wk gestation (16). Trials were conducted in 16 animals to determine the dose of E. coli endotoxin that would result in 0, 50, and 100% mortality when injected subcutaneously. A lyophilized preparation of endotoxin from E. coli 055:B5 (Difco Laboratories) was chosen because this organism is a pathogen for human neonates, may be transmitted by nursery personnel (28), and has been previously used in neuropathologic experiments (12).Systemic responses to graded endotoxemia. The physiologic and metabolic responses of the animals were examined before and after ...

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Maternal endotoxemia, fetal anomalies, and central nervous system damage: A rat model of a human problem

Cited by 64 publications

References 9 publications

Affected skeletal growth but normal bone mineralization in rat offspring after prenatal dexamethasone exposure

Affected skeletal growth but normal bone mineralization in rat offspring after prenatal dexamethasone exposure

White Matter Injury after Repeated Endotoxin Exposure in the Preterm Ovine Fetus

Systemic and Neuropathologic Effects of E. coli Endotoxin in Neonatal Dogs

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