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 hepatocyte-derived proteins collectively known as acute phase reactants (APR). B6C3F₁ female mice were exposed intraperitoneally every 24 hr to either vehicle (PBS) or DMN (5 mg/kg) for up to six exposures. Following a single treatment (acute), liver tissues were collected at 3, 6, 12, and 24 hr postexposure. The same collection scheme was repeated following the fourth and sixth exposures (subchronic). Total cellular RNA was isolated and Northern blot analyses were performed using 3'-end radiolabeled oligonucleotides specific for serum amyloid A (SAA), serum 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 vehicle-treated controls. In contrast, SAP transcripts were constitutively expressed in both vehicle and DMN-treated groups throughout the acute exposure period. However, at 3 and 6 hr after DMN exposure, elevated levels of SAP transcripts were observed before returning to control levels at 12 and 24 hr. Expression of albumin transcripts decreased rapidly 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. After four exposures to DMN, SAA transcripts were detected at all time periods measured. Similarly, SAP transcripts in livers of DMN-exposed animals were consistently elevated above vehicle controls. Results after six exposures to DMN were similar, with SAA and SAP transcripts elevated at all time points tested. By comparison, repeated vehicle exposures resulted in a stress-related transient expression of SAA and SAP transcripts. Thus, acute and subchronic DMN exposure resulted in differential APR transcript expression and may serve as useful biomarkers following chemical exposure.