Gender, age and dose effects of neonatally administered aspartate on the sexually dimorphic plasma growth hormone profiles regulating expression of the rat sex-dependent hepatic CYP isoforms.

Newborn male and female rat pups were injected with either 2 mg or 4 mg monosodium aspartate (MSA)/g body weight or diluent on alternate days for the first 9 days of life. Both doses of the amino acid had profound effects on the sexually dimorphic growth hormone secretory profiles in adulthood. There were no measurable levels of growth hormone in any of the plasma samples obtained during 8 continuous hr of serial blood collections from the adult males and females treated neonatally with 4 mg of MSA. Male rats treated with half the dose of the amino acid (i.e., 2 mg MSA/g) exhibited typical masculine profiles of growth hormone release, except that the amplitudes of the ultradian pulses were reduced to 10-20% of normal male levels. Otherwise, like normal males, the peaks occurred about every 3-4 hr and the intervening 2.5-hr troughs had undetectable levels of growth hormone. In a similar sense, females treated with 2 mg of MSA maintained their sexually dimorphic pattern of plasma growth hormone, i.e., frequent pulses of hormone followed by short-lived troughs. However, the peaks rarely exceeded 20 ng/ml and the troughs usually fell to a measurable 8 to 10 ng/ml resulting in an approximate 75% reduction in the mean plasma concentration. Growth hormone- and gender-dependent expression of CYP2C7, 2C11, 2C12, 2C13, 2A1, 2A2, and 3A2 (mRNAs, proteins, and catalytic activities) were generally unaffected by neonatal exposure to 2 mg of MSA. In contrast, the higher 4-mg dose of the amino acid completely or near completely suppressed male-specific CYP2C11, 2C13, 2A2, and 3A2 expression while inducing small increases in female-specific CYP2C12 and female-predominant CYP2A1 in the treated males. Females exposed to the 4 mg MSA dose exhibited less severe isoform changes characterized by small reductions in CYP2C12 and 2C7 levels. Whereas expression levels of most of the CYP isoforms in both sexes were lowest in the pubertal (47-day-old) rats, and occasionally higher in the adults (207-day-old) as compared with the early postpubertal (70-day-old) rats, the effects of neonatal MSA were the same at all ages studied. Since each of the CYP isoforms are regulated by different "signaling elements" in the sexually dimorphic plasma growth hormone profiles, it is possible to correlate MSA-induced alterations in CYP expression levels to specific changes in the gender-dependent growth hormone profiles.