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Toxicological Sciences 62, 80-91 (2001)
Copyright © 2001 by the Society of Toxicology

REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY

Growth and Development in Rats Given Recombinant Human Epidermal Growth Factor1-48 as Neonates

J. W. Henck,1, J. F. Reindel and J. A. Anderson

Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105

To assess effects of supraphysiologic doses of human recombinant epidermal growth factor1-48 (rhEGF1-48) on neonatal rats, 10 litters of Wistar rats/treatment group were given 0 (formulated vehicle), 10, 100, or 1000 µg/kg daily by subcutaneous injection on postnatal days (PND) 1 through 6. Clinical signs, body weight, acquisition of developmental landmarks and reflexes, and behavior were monitored during treatment and for 5 weeks thereafter (to PND 42). A subset of animals was euthanized weekly from PND 7–28 and necropsied. Selected tissues were examined microscopically. Body weight gain at 1000 µg/kg during treatment was significantly less than control. Precocious incisor eruption, eye opening, vaginal opening, and preputial separation occurred at 100 and/or 1000 µg/kg. Acquisition of reflexes (negative geotaxis, wire maneuver, acoustic startle reflex, and visual placing) was delayed at 1000 µg/kg. Acquisition of adult locomotion was also delayed at 1000 µg/kg. These effects were transient, as locomotor activity at PND 28 and 42 did not differ from control. Effects on acoustic-startle responding persisted in females to final assessment on PND 42. Habituation to repeated acoustic stimuli was impaired, as well as response inhibition following a prepulse acoustic stimulus. rhEGF1-48 induced structural changes in the skin, retina, kidney, oral and nasal mucosa, lung, and liver. Many of these changes were consistent with the expected mitogenic activity of rhEGF1-48 and were transient in nature, as severity and incidence diminished with time. An exception was changes observed in the retina at 1000 µg/kg (rosettes/folds and focal defects in the outer nuclear/photoreceptor layers) that were still present 3 weeks after termination of treatment. Acceleration of developmental landmarks; suppression of reflexes, behavior, and somatic growth; and mitogenic responses in epidermal tissues have been reported in rodents treated with epidermal growth factor (EGF) derived from various mammalian species. These results demonstrate that a 48-amino acid fragment of human EGF produced by recombinant technology also induces such effects.

Key Words: rhEGF1-48 toxicity; human epidermal growth factor1-48; neonates; rats; development; behavior..


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