Radiation effects on growth are altered in rats by prednisone and methotrexate.

CNS therapy for childhood leukemia has adverse effects upon growth and cognition. The cause of these deficits is unknown. In a rat model, we determined which agent, or combination of agents, in CNS therapy affected growth. Young Sprague-Dawley rats were exposed to cranial irradiation (1000 cGy), methotrexate (2 or 4 mg/kg, intraperitoneally), or prednisolone (18 or 36 mg/kg, intraperitoneally) alone or in two- or three-agent combinations. Matched control groups received appropriate sham radiation, intraperitoneal saline, or both. Body weight was recorded from 14 through 150 d of age. After the rats were killed at 150 d, body length was recorded and the head and left femur were removed to determine body and craniofacial proportions. Cranial irradiation alone, but not methotrexate or prednisolone alone, stunted growth permanently and altered craniofacial proportions. When these agents were combined, methotrexate and prednisolone modified the growth response to cranial irradiation. Methotrexate given before cranial irradiation prevented radiation stunting in males. This protection was lost when the dose of methotrexate was increased, when prednisolone was added to the combination, or when females were studied. The protection in males was effective against both growth and behavioral deficits. These results indicate that the physical and behavioral side effects of CNS therapy are better understood in the context of dose, sex, and interactions of the agents.

An animal model to study toxicity of central nervous system therapy for childhood acute lymphoblastic leukemia: effects on growth and craniofacial proportion.

Many long term survivors of childhood acute lymphoblastic leukemia have short stature, as well as craniofacial and dental abnormalities, as side effects of central nervous system prophylactic therapy. An animal model is presented to assess these adverse effects on growth. Cranial irradiation (1000 cGy) with and without prednisolone (18 mg/kg i.p.) and methotrexate (2 mg/kg i.p.) was administered to 17- and 18-day-old Sprague-Dawley male and female rats. Animals were weighed 3 times/week. Final body weight and body length were measured at 150 days of age. Femur length and craniofacial dimensions were measured directly from the bones, using calipers. For all exposed groups there was a permanent suppression of weight gain with no catch-up growth or normal adolescent growth spurt. Body length was reduced for all treated groups, as were the ratios of body weight to body length and cranial length to body length. Animals subjected to cranial irradiation exhibited microcephaly, whereas those who received a combination of radiation and chemotherapy demonstrated altered craniofacial proportions in addition to microcephaly. Changes in growth patterns and skeletal proportions exhibited sexually dimorphic characteristics. The results indicate that cranial irradiation is a major factor in the growth failure in exposed rats, but chemotherapeutic agents contribute significantly to the outcome of growth and craniofacial dimensions.

Prenatal exposure to phenytoin and its effect on postnatal growth and craniofacial proportion in the rat.

Neonatal rats exposed prenatally to phenytoin (PHT) have been reported to have craniofacial abnormalities and growth retardation [Lorente et al.: Teratology 24:169-180, 1981]. This study reports on the persistence of these effects in the adult rat. Pregnant Sprague-Dawley rats were intubated on gestational days 9, 11, and 13 with 1,000 mg/kg PHT suspended in 1% carboxymethylcellulose (CMC). Six male and six female exposed offspring (PHT) and an equal number of control animals (CMC) were weighed through postnatal day 135, at which point they were killed and the skeletons were prepared for analysis. The PHT-exposed animals had reduced weights at all time points with the males more severely affected. A normal adolescent growth spurt was not observed in the exposed group. Absent or rudimentary lacrimal bones and nasolacrimal canals were note in all PHT-exposed rats. This contributed to the recessed positioning of the eyes that was grossly apparent. In addition, shorter and broader frontal bones in the PHT animals led to the appearance of hypertelorism. Ratios of craniofacial dimensions obtained by direct measurement of the skulls showed that the PHT offspring were significantly different in proportion from their control counterparts. The PHT skulls were smaller for body size with reduced facial height and broader midfacial regions. A unique craniofacial pattern was observed in the experimental offspring. Normal sexual dimorphism in craniofacial pattern was not expressed in the PHT group. These studies suggest that prenatal phenytoin exposure in the rat may interfere with the full expression of normal dimorphism based on gender and confirms the toxic effect of this drug on postnatal growth, adult body proportion, and craniofacial geometry.