Growth and development in rats given recombinant human epidermal growth factor(1-48) as neonates.
To assess effects of supraphysiologic doses of human recombinant epidermal growth factor(1-48) (rhEGF(1-48)) on neonatal rats, 10 litters of Wistar rats/treatment group were given 0 (formulated vehicle), 10, 100, or 1000 microg/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 microg/kg during treatment was significantly less than control. Precocious incisor eruption, eye opening, vaginal opening, and preputial separation occurred at 100 and/or 1000 microg/kg. Acquisition of reflexes (negative geotaxis, wire maneuver, acoustic startle reflex, and visual placing) was delayed at 1000 microg/kg. Acquisition of adult locomotion was also delayed at 1000 microg/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. rhEGF(1-48) 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 rhEGF(1-48) and were transient in nature, as severity and incidence diminished with time. An exception was changes observed in the retina at 1000 microg/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.
Henck
J W
JW
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105, USA. henck_judith_w@lilly.com
Reindel
J F
JF
Anderson
J A
JA
D000161:Acoustic Stimulation; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development*; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005835:Genitalia / Q000187:drug effects; D007279:Injections, Subcutaneous; D008934:Mitogens / Q000008:administration & dosage / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010446:Peptide Fragments / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000633:toxicity; D012741:Sexual Maturation / Q000187:drug effects*; D012867:Skin / Q000187:drug effects / Q000473:pathology; D018675:Toxicity Tests; D015430:Weight Gain / Q000187:drug effects
D008934:Mitogens; D010446:Peptide Fragments; D011994:Recombinant Proteins; C102344:epidermal growth factor (1-48); D004815:Epidermal Growth Factor