Effects of formaldehyde on xenotransplanted human respiratory epithelium.
A laboratory animal model that permits the exposure of xenotransplanted human respiratory epithelium to formaldehyde was used to study the effects of formaldehyde alone or in combination with the ultimate carcinogenic metabolite of benzo[a]pyrene, benzo[a]pyrene diol epoxide. Epithelial cells obtained from autopsies of full-term human fetuses or infants less than one year old were isolated, amplified in primary cultures, and then inoculated into rat tracheas from which the epithelial layer had been removed. These tracheas then were sealed and transplanted subcutaneously into irradiated athymic nude mice. Four weeks after transplantation, the tracheal lumen was completely covered by epithelium, most of which was of the mucociliary respiratory type. At this stage, tracheal transplants containing tracheobronchial epithelium from 20 different human infant donors were exposed to silastic devices containing 0, 0.5, 1, or 2 mg of formaldehyde. The tracheal transplants were examined histologically 2, 4, 8, or 16 weeks after transplantation. Before being killed, all animals were injected with a single pulse of tritiated thymidine. Important epithelial alterations were seen in the transplants treated with formaldehyde, with a maximum effect visible two weeks after exposure. In most cases, the highest dose of 2 mg produced numerous areas of epithelial erosion and inflammation; however, this effect was not as evident with the lower doses. All doses produced areas of hyperplastic epithelium alternating with areas of atrophic epithelium. Although the differences in predominance of different types of epithelium were not clearly dependent on dose, the labeling index showed dose dependence between two and four weeks after the initiation of exposure. The maximum mean labeling index was three to four times higher than normal, although in some focal hyperplastic-metaplastic lesions the labeling index increased up to 20 times. These studies show that formaldehyde, although toxic at higher doses, is able to elicit at lower doses a proliferative response of the human infant tracheobronchial epithelium that is not preceded by a massive toxic effect. Similar studies were performed using xenotransplanted human adult nasal respiratory epithelium (Study 2). The response pattern was very similar to that of the xenotransplanted human tracheobronchial epithelium from human infants (Study 1). In Study 3, using cells obtained from 11 human infant tracheobronchial epithelia, the formaldehyde applied simultaneously or sequentially with benzo[a]pyrene diol epoxide did not induce epithelial alterations different from those observed with formaldehyde treatments alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Klein-Szanto
A J
AJ
Fox Chase Cancer Center, Institute for Cancer Research, Philadelphia, PA 19111.
Ura
H
H
Momiki
S
S
Bonfil
D
D
Litwin
S
S
D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity; D001980:Bronchi / Q000033:anatomy & histology / Q000187:drug effects*; D003043:Cocarcinogenesis; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects / Q000637:transplantation; D005557:Formaldehyde / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009666:Nose / Q000033:anatomy & histology / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D012044:Regression Analysis; D013997:Time Factors; D014132:Trachea / Q000033:anatomy & histology / Q000187:drug effects* / Q000473:pathology; D014134:Tracheal Neoplasms / Q000139:chemically induced* / Q000473:pathology; D014183:Transplantation, Heterologous
D005557:Formaldehyde; D001564:Benzo(a)pyrene