Animal Models of Human Disease: Severe and Mild Lead Encephalopathy in the Neonatal Rat

Abstract

Inorganic lead produces cerebral dysfunction and clinically definable encephalopathies in man. To date there have been few studies on the biochemical changes in brain following exposure to inorganic lead. Studies correlating toxicity with behavioral and brain neurochemical changes following lead exposure have been hindered because adult laboratory animals are resistant to the central nervous system effects of lead poisoning. Such studies have been impeded by lack of suitable experimental models until Pentschew and Garro showed that brain lesions develop In neonatal rats when a pregnant rat newly delivered of her litter is placed on a 4% lead carbonate containing diet. Lead passes into the developing sucklings via maternal milk. Lead-poisoned newborns have pronounced retardation of growth and during the fourth week of ilfe develop the severe signs of lead encephalopathy, namely, extensive histological lesions of the cerebellum, brain edema, and paraplegia. There is an approximate 85-fold increase in the lead concentration of both the cerebellum and cerebral cortex relative to controls, but edema and gross vascular changes are confined to the cerebellum. Ingested lead had little effect on RNA, DNA, and protein concentrations of developing rat cerebellum and cerebral cortex. However, there was a reduction of between 10 and 20% in the DNA content of the cerebellum around 3 weeks of age in the lead-exposed sucklings. This suggests a failure of cell multiplication in this part of the brain.A critical evaluation of this experimental approach indicated that under similar dietary conditions experimental lactating rats eat 30% less food than controls resulting in: (a) sustained loss in body weight of nursing mothers and that (b) offsprings who develop paraplegia and cerebellar damage do so after gaining access to lead containing diet.We have studied mothers' food consumption and body weight changes and blood, milk, and brain lead content; and newborns' body and brain weight changes, blood and brain lead content, and brain serotonin (5HT), norepinephrine (NE), dopamine (DA), and -y-aminobutyric acid (GABA). We have found that a lactating mother rat eating 5% lead acetate (2.73% Pb) produced milk containing 25 ppm lead. When the mothers' diet is changed at day 16 from 5% PbAc to one containing 25 ppm Pb, and neonates allowed free access to the solid diet, the sucklings still have retarded body growth but do not develop paraplegia or grossly apparent vascular damage of the cerebellum. However, during the fourth week these animals exhibit a less severe form of "encephalopathy" consisting of hyperactivity, tremors, and stereotype behavior. Pair-fed controls coetaneous to experimental groups do not display such activities. There was no change in brain 5HT, GABA, or NE, but a 15-20% decrease in brain DA. Change in DA relative to other monoamines suggests a relationship between CNS dysfunction due to lead and DA metabolism in the brain.The experimental design as discribed provides a model of CNS dysfunction due to lead exposure w...

THE EFFECTS OF POSTNATAL LEAD EXPOSURE ON Purkinje cell DENDRITIC DEVELOPMENT IN THE RAT

“…As expected from previous descriptions of experimental lead encephalopathy (Pentschew & Garro, 1966;Thomas et al, 1971;Michaelson, 1973;Clasen et al, 1974;Goldstein, Asbury & Diamond, 1974;Press, 1977) the pups suckled by mothers receiving the lead-containing diet showed a significant reduction by 30 days in their growth rate (Figure 3), by 28% in the lead-fed pups. Many of the pups also showed the abnormally ruBed coat and broad-based gait described by Michaelson (1973) and Michaelson & Sauerhoff (1974) ,and a number developed urinary incontinence during the fourth week of life. However, in contrast to previous reports, only one out of the thirty-six pups surviving to 30 days developed paraplegia, the paralysis becoming apparent on day 25 postpartum.…”

“…In the present experiment the method of network analysis (Berry, Hollingworth, Anderson & Flinn, 1975;Berry & Bradley, 1976a) was used to study the dendritic networks of Purkinje cells from the cerebella of 30-day-old, lead-exposed rats, in an attempt to determine whether such treatment does produce alterations of dendritic growth and branching. The cerebellum of rodents is particularly susceptible to the effects of lead (Pentschew & Garro, 1966;Michaelson, 1973;Michaelson & Sauerhoff, 1974;Press, 1977), changes in the morphology of the Purkinje cell bodies being apparent from 21 days post partum in rats lead-poisoned from birth (Thomas et al, 1971). Thus, if lead does affect the growth of neuronal processes it seems probable that the morphology of the Purkinje cell dendritic networks would show evidence of this.…”

Comparative Toxicity and Tissue Distribution of Lead Acetate in Weanling and Adult Rats

“…The lowest mean blood lead value at which elevations in FEP were measured was 21 pug/dl in the group of weanling animals exposed to lead acetate once per week. Considerable information has been obtained in experimental animals on the effects on the nervous system of exposure to lead (10,12,33). These observations suggest that the blood lead concentration associated with a significant elevation in FEP is lower for weanling rats than for adult animals.…”

The Morphological Effects of Lead on the Developing Central Nervous System

“…This loss in weight gain is induced by lead at a variety of doses and exposures, and similar changes can be evoked using lower doses and long exposures, or high doses for short periods of time. In an elegant study using pair-fed controls Michaelson & Sauerhoff (1974) showed this loss in weight-gain to be a consequence of reduced food intake by the maternal rat. Carmichael, Winder & Lewis (1981) found that doses of lead in maternal drinking water above 100ppm (0.2%) produced growth retardation (an index of somatic toxicity) in the offspring as well as reduced weight and liquid intake in the mother.…”