Effect of Neonatal Androgen and Estrogen Injection on Liver Tumor Induction byN-Hydroxy-N-2-fluorenylacetamide and on the Metabolism of the Carcinogen in Rats

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Abstract
Male and female Fischer stain rats were injected neonatally with a single dose of testosterone propionate or estradiol benzoate in cottonseed oil. After weaning they were placed on a semisynthetic diet with or without the carcinogen N-hydroxy-N-2-fluorenylacetamide (N-OH-FAA) for 16 weeks. Necropsies were performed after an additional 10 weeks on control diet. In male rats, the liver tumor incidence was not affected by testosterone injection but was reduced appreciably by estradiol. In female rats, testosterone enhanced the carcinogenicity, while estradiol had a biphasic action, augmenting carcinogenesis in a few rats but generally reducing it in most of them. In males, functional gonads contribute to the carcinogenic process in the liver but are not essential. A functional pituitary, reflected in adrenal, gonadal and perhaps other endocrine participation, appears more crucial. The metabolism of N-OH-FAA was studied in these experimental situations. A single dose of carcinogen showed a sex-associated pattern of metabolites giving higher plasma and lower urinary values in males than in females. The lower urinary excretion in the male was expressed chiefly by lower excretion of glucosiduronic acids and particularly of the conjugate of N-OH-FAA. Neonatal injection of testosterone in females and estradiol in males led to similar values of urinary N-OH-FAA glucuronide, intermediate between those of control males or females. Under subacute conditions of N-OH-FAA administration the sex-connected differences tended to disappear, and the characteristic pronounced increase in the glucosiduronic acid fraction, and in particular that of the conjugate of N-OH-FAA, was seen. The demonstrated alteration in metabolic patterns of the carcinogen does not fully account for the development of liver neoplasia as a function of hormonal status. Endocrine factors must therefore play additional roles in the induction of liver cancer by aromatic amine derivatives.