INDUCTION OF HEPATIC ACUTE-PHASE PROTEIN TRANSCRIPTS - DIFFERENTIAL-EFFECTS OF ACUTE AND SUBCHRONIC DIMETHYLNITROSAMINE EXPOSURE IN-VIVO

Inflammatory responses are accompanied by increased expression of hepa tocyte-derived proteins collectively known as acute phase reactants (A PR). B6C3F(1) female mice were exposed intraperitoneally every 24 hr t o either vehicle (PBS) or DMN (5 mg/kg) for up to six exposures. Follo wing a single treatment (acute), liver tissues were collected at 3, 6, 12, and 24 hr postexposure. The same collection scheme was repeated f ollowing the fourth and sixth exposures (subchronic). Total cellular R NA was isolated and Northern blot analyses were performed using 3'-end radiolabeled oligonucleotides specific for serum amyloid A (SAA), ser um amyloid P (SAP), and albumin (ALB). SAA transcripts were detected 3 hr after acute DMN exposure, peaked at 6 hr, and rapidly declined to vehicle control levels by 12 hr. No SAA transcripts were observed in v ehicle-treated controls. In contrast, SAP transcripts were constitutiv ely expressed in both vehicle and DMN-treated groups throughout the ac ute exposure period. However, at 3 and 6 hr after DMN exposure, elevat ed levels of SAP transcripts were observed before returning to control levels at 12 and 24 hr. Expression of albumin transcripts decreased r apidly following acute DMN exposure and remained suppressed throughout the first 24-hr period measured. Serum levels of complement component -3 (C3) increased 2 hr after a single DMN exposure, whereas decreases in serum albumin levels were first observed at 24 hr post-exposure. Af ter four exposures to DMN, SAA transcripts were detected at all time p eriods measured. Similarly, SAP transcripts in livers of DMN-exposed a nimals were consistently elevated above vehicle controls. Results afte r six exposures to DMN were similar, with SAA and SAP transcripts elev ated at all time points tested. By comparison, repeated vehicle exposu res resulted in a stress-related transient expression of SAA and SAP t ranscripts. Thus, acute and subchronic DMN exposure resulted in differ ential APR transcript expression and may serve as useful biomarkers fo llowing chemical exposure. (C) 1994 Academic Press, Inc.