[MJ.] trols, To study possible alterations in EGF binding, 12sI-EGF was injected i.v. in newborn rats. 12sI-EGF bound in all the organs investigated. The binding is listed in decreasing order: liver, gut, skin, kidney, and lungs. In the pups from EGF-immunized rats, the lungs and the skin bound a significantly higher amount than the controls. This could represent an upregulation of the EGF receptor in response to the lack of EGF. Postnatally, the pups from EGF-immunized mothers grew faster and were on par with controls within 1 wk. We found no differences concerning tooth eruption, ear opening, and eye opening. In extension of present knowledge concerning the tissue localization of EGF and its receptor and concerning the pharmacologic effects of EGF, our study demonstrates an effect of EGF deficiency. This supports a role for EGF in the epigenetic regulation of the development of the lungs, the skin, and the liver. (Pediatr Res 37: 175-181, 1995) Abbreviations EGF, epidermal growth factor SP-A, surfactant protein A TGF-a, transforming growth factor-aWe have used rats with epidermal growth factor (EGF) autoantibodies to study the role of EGF deficiency during perinatal development. The study was focused on organs known to contain EGF or its receptor. Compared with controls, the offspring of autoimmune rats had a higher perinatal mortality and a lower birth weight. The weight of the lungs was particularly low in the offspring of EGF-immunized rats, and morphologically the lungs from the surviving pups seemed atelectatic and had alveolar duct dilatation, which indicates mild respiratory distress syndrome. Judged from immunohistochemical studies, the amount of surfactant protein-A was decreased, suggesting a delayed lung maturation. The offspring of EGF-immunized rats had dry and wrinkled skin. The skin was thin and the hair follicles were immature. This suggests a role for EGF in the growth and development of the skin. The liver/body weight ratio was lower in pups from EGF-immunized rats. This difference was, however, not significant (p = 0.07), but flow cytometric analyses showed a significantly lower proportion of the liver cells from newborn EGF-deficient pups to be in S-phase and indicated that these cells were larger than liver cells from conThe epigenetic regulation of fetal and neonatal development is assumed to take place within a milieu of growth factors. This hypothesis is mainly deduced from the localization of growth factors and growth factor receptors and from studies of their pharmacologic effects. Limited information is available about the effects of growth factor deficiency. Based on studies in which EGF has been injected into the mother, the fetus, or the neonate, EGF is believed to be involved in the development of the integument (1, 2), the lungs (3, 4), the liver (5), and the digestive tract (6). At present it has not been established whether these effects reflect a physiologic or a pharmacologic role of the peptide. One of the difficulties faced is that EGF is produced in multiple organs...

Epidermal growth factor (EGF) in pharmacologic doses is able to induce growth and development in the fetus and the newborn. To investigate the opposite situation, the effects of insufficient amounts of EGF during development, we wanted to establish an in vivo model with a state of EGF deficiency. This was attempted by induction of autoimmunity to EGF in rats. Twenty rats were immunized with EGF. Fifteen of these developed autoantibodies against EGF, which, as judged by Scatchard analysis, had a median apparent affi nity constant of 14 X 10 9 L Imol and a median concentration of binding sites of 20 X 10-9 mol/L, The antibodies recognized purified EGF from the submandibular glands (6 kD) and from urine (45 kD) and further native EGF in saliva and urine. The cross-reactivity toward transforming growth factor-a was below 3%. Binding of EGF by antibodies inhibited its binding to the EGF-receptor by approximately 97% in vitro. Investigation of in vivo metabolism of EGF is a 53-amino acid peptide, discovered by Stanley Cohen (1), wit h an ability to accelerate ey elid opening and incisor eruption in newborn mice . Its human counterpart w as iso lat ed from urine and initially named urogastrone, be cause it co uld inhibit gastric acid sec retio n (2) . Today it is known th at EGF is produced in several organ s, including the submandibul ar glands, the respiratory sys tem , th e kidneys, and the digestiv e tract (3, 4). Its receptor has been identified in most organs stud ied (5) . EGF is abl e to induce g row th and differentiation, antibody-bound 125I_EGF confirmed these results, that is, the antibodies were able to inactivate EGF. The adult rats were unaffected by the induction and presence of autoantibodies, and the EGF-containing organs did not show any histologic signs of inflammation or tissue damage. Furthermore, as judged by immunohistochemistry, no major changes in the distribution and tissue concentration of EGF were seen in the adult rat. These results show that it is possible to induce homologous antibodies that can inhibit the binding of EGF to its receptor and further suggest that circulatory EGF is of no physiologic importance in the healthy, adult rat. (Pediatr Res 37: 169-174, 1995) Abbreviations EGF, epidermal growth factor NGF, nerve growth factor TGF-a, transforming growth factor-a and at an early stage it w as suggested that it participates in the regulation of fetal dev elopment (6 , 7)_ Most results concerning a possible ph ysiologic role for EGF have been obtained by injecti on of pharmacologic dos es of the peptide. Because EGF is sy nthesized in several org ans and is believed to act locally, it is impossible to induce EGF defici enc y by surgery . A different approa ch is to induce an immunologic EGF deficiency. Thi s techniqu e was introduced by Gorin and Johnson (8), who immunized rats with mou se NGF and show ed that the offspring had the predicted developmental defects, whereas the adult immunized rats were unaffected. Concerning EGF, only passive immunization, in a heterologous system...