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 m g monosodium aspartate (MSA)/g body weight or diluent on alternate day s for the first 9 days of life, Both doses of the amino acid had profo und effects on the sexually dimorphic growth hormone secretory profile s in adulthood, There were no measurable levels of growth hormone in a ny of the plasma samples obtained during 8 continuous hr of serial blo od collections from the adult males and females treated neonatally wit h 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 horm one release, except that the amplitudes of the ultradian pulses were r educed 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 troug hs had undetectable levels of growth hormone, In a similar sense, fema les treated with 2 mg of MSA maintained their sexually dimorphic patte rn of plasma growth hormone, i.e., frequent pulses of hormone followed by short-lived troughs, However, the peaks rarely exceeded 20 ng/ml a nd 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 gen erally unaffected by neonatal exposure to 2 mg of MSA, In contrast, th e higher 4-mg dose of the amino acid completely or near completely sup pressed male-specific CYP2C11, 2C13, 2A2, and 3A2 expression while ind ucing small increases in female-specific CYP2C12 and female-predominan t CYP2A1 in the treated males, Females exposed to the 4 mg MSA dose ex hibited less severe isoform changes characterized by small reductions in CYP2C12 and 2C7 levels, Whereas expression levels of most of the CY P 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 dimorph ic plasma growth hormone profiles, it is possible to correlate MSA-ind uced alterations in CYP expression levels to specific changes in the g ender-dependent growth hormone profiles.