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Long-Term Effects of Neonatal Phenobarbital Exposure on Aflatoxin B₁ Disposition in Adult Rats¹

Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853

Current evidence in the rat suggests that the activity of various adult hepatic microsomal polysubstrate monooxygenases (PSMO) is programmed by neonatal exposure to hormones or hormonally active compounds. Since most chemical carcinogens are either metabolically activated or detoxified via the PSMO system, it is possible that neonatal exposure to pharmacologically active compounds may subsequently alter carcinogen metabolism in the adult animal. To investigate this question, two studies were conducted to examine the effect of phenobarbital (PB) exposure during the neonatal period on (a) the age-dependent activation of the hepatocarcinogen, aflatoxin B₁ (AFB₁) and (b) hepatic PSMO activities. Lactating rat dams were gavaged with either PB or an equal volume of 0.9% NaCl solution for 7 successive days after parturition. The dose of PB administered to the lactating rats was either 40 or 60 mg/kg for Studies 1 and 2, respectively. Thus, progeny were exposed to PB and its metabolites in the milk via suckling.

Prior to sacrifice, progeny were given i.p. injections with [³H]AFB₁ (1.0 mg/kg) in order to examine the effect of early PB exposure on the level of aflatoxin (AF):DNA adducts. In Study 1 (i.e., PB, 40 mg/kg), early PB exposure did not alter the level of AF:DNA adducts at 28 or 84 days; however, at 168 and 259 days, the level of AF:DNA adducts were increased 19 and 39%, respectively, in males but not in females. Moreover, at 259 days, ethylmorphine N-demethylase activity was increased 160% in males exposed to PB during the neonatal period but not in females.

In Study 2, we also found that neonatal exposure to PB did not alter the levels of AF:DNA adducts or hepatic microsomal PSMO enzyme activities (i.e., ethylmorphine N-demethylase, cytochrome P-450, reduced nicotinamide adenine dinucleotidephosphate-cytochrome c reductase) in 23-day-old weanling animals. However, at 252 days, early PB exposure significantly decreased the level of AF:DNA adducts by approximately 30% without affecting microsomal PSMO enzyme activities. These data are in contrast to our earlier study where a lower dose of neonatal PB (i.e., 40 mg/kg) increased the level of AF:DNA adducts (40%) and ethylmorphine N-demethylase (160%) in 259-day-old males. Presently, the mechanism(s) responsible for these differences is not known.

Thus, the neonatal period appears to be very sensitive to compounds which alter the ontogenetic expression of carcinogen-metabolizing enzymes, and this sensitivity appears to be dose dependent. Interestingly, a similar finding has been reported for neonatal androgen imprinting of steroid metabolizing enzymes. These findings suggest that neonatal exposure to PSMO inducers may be an important determinant of cancer risk, insofar as carcinogen metabolism is involved in the neoplastic process.

¹ This investigation was supported in part by USPHS Grants RO1 CA23913 and T2 E 50705A.

² Present address: University of Texas System Cancer Center, Science Park, Smithville, Texas 78957.

³ To whom request for reprints should be addressed.

Received 2/22/82. Accepted 3/ 7/83.