Journal Article

Growth and Development in Rats Given Recombinant Human Epidermal Growth Factor<sub>1-48</sub> as Neonates

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

in Toxicological Sciences

Volume 62, issue 1, pages 80-91
Published in print July 2001 | ISSN: 1096-6080
Published online July 2001 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/62.1.80
Growth and Development in Rats Given Recombinant Human Epidermal Growth Factor1-48 as Neonates

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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.

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

Journal Article.  7194 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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