The transduction of rat submandibular glands by an adenoviral vector carrying the human growth hormone gene is associated with limited and reversible changes at the infusion site.

Adenoviral vectors have been shown to efficiently deliver exogenous genes to salivary glands and have therefore been investigated as tools for the treatment of human disease. The purpose of this study was to evaluate the response of F344 rats to intraductal infusion of the right submandibular salivary gland with an adenoviral vector encoding the gene for human growth hormone (AdCMVhGH). Co-administration of hydroxychloroquine (HCQ) was used to redirect the secretion of human growth hormone (hGH) from saliva into serum. This paper documents the findings of the pathology evaluation of this National Toxicology Program study. The right submandibular salivary gland (infusion site) was the primary target organ, with microscopic lesions characteristic of a mild to moderate insult observed at 3 days post infusion in vector exposed animals. These lesions were characterized by variable degrees of acute glandular inflammation, degeneration and necrosis, with more severe lesions in the higher dose groups. Rats at 28 days post infusion had milder inflammation, degeneration and necrosis compared to day 3 rats, with variable degrees of regeneration. In conclusion, the effects on the salivary glands are reversible as indicated by the milder inflammation and degeneration in the day 28 rats concomitant with mild to moderate regeneration. Therefore, the vector appears relatively innocuous with limited tissue toxicity. [The supplemental data referenced in this paper is not printed in this issue of Toxicologic Pathology. It is available as a downloadable file in the online edition of Toxicologic Pathology, 34(4). In order to access the full article online, you must have either an individual subscription or a member subscription accessed through www.toxpath.org.].

The effects of 4-nonylphenol in rats: a multigeneration reproduction study.

The alkylphenol breakdown products of alkylphenol ethoxylates have been shown in in vitro studies to be weakly estrogenic, but few in vivo data address this issue in mammals. Because estrogens have been found to be most potent during developmental/perinatal exposures, this study maximized developmental exposure to nonylphenol (NP) by treating 3.5 generations of Sprague-Dawley rats to NP in diet at 200, 650, and 2000 ppm to determine the range and severity of any toxicity. Dose rate was higher for younger rats; calculated dose ranges were 9-35, 30-100, and 100-350 mg/kg/d for the low (200NP), middle (650NP), and high (2000NP) dose groups, respectively. There were adult (F0, F1, F2) and postnatal day (pnd) 21 (F1, F2, F3) necropsies; the oldest F3 rats were killed on pnd 55-58. Body weight gain was reduced by 8-10% in the 650NP and 2000NP groups. Vaginal opening was accelerated by approximately 2 days (650NP) and approximately 6 days (2000NP) in F1, F2, and F3 generations. Uterine weights at pnd 21 were increased in 650NP (14%) and 2000NP (50%) F1 females, but not in other generations. Testis descent, anogenital distance, and preputial separation were not consistently changed. No consistent changes were seen in pup number, weight or viability, litter indices, or other functional reproductive measures. Relative ovary weight in F2 adults was decreased at 650NP and 2000NP by 12%; relative ovary was unchanged in other generations. Follicle counts were unchanged in F2 adults. Sperm indices, including CASA measures, were unchanged in F0 and F1 males. In F2 rats, epididymal sperm density was reduced by 8% and 13% at 650NP and 2000NP, respectively. Testicular spermatid count was reduced by 13% in 2000NP F2 males; testis and epididymis weights were unchanged. Erosion of gastric and duodenal mucosa was monitored grossly and microscopically, and never found. Kidney weights were increased in 650NP and 2000NP males, and renal medullary tubular dilatation and cyst formation were noted in all generations of males, and often at the lowest dose tested. These data show that NP had limited effects on the reproductive system in the presence of measurable nephrotoxicity. The F2 sperm effects are either statistical/biological "noise," or imply heretofore unknown pharmacokinetics or toxicodynamics. These sperm data should be interpreted cautiously until the findings are repeated.

Channel patency and neovascularization after transmyocardial revascularization using an excimer laser: results and comparisons to nonlased channels.

BACKGROUND: Transmyocardial revascularization (TMR) has emerged as a promising treatment for ischemic heart disease in patients who are not candidates for coronary bypass surgery or angioplasty. Controversy exists, however, as to whether the use of laser energy is critical for TMR channel patency. We therefore compared by histologic assessment the outcome of lased channels with nonlased channels 30) days after TMR, using a low energy, short-pulse, fiberoptic excimer laser. METHODS AND RESULTS: In each of six sheep, 36 1-mm TMR channels (9 mJ; 240 Hz; 1.55 cm advance/s) were placed in the anterior wall of the left ventricle, and 12 1-mm nonlased channels were created in adjacent segments by advancing the fiberoptic through the left ventricular wall with the laser inactivated. Of the 36 lased channels, 56+/-7.3% were identifiable, and 100% of those identifiable appeared to represent a "channel derivative" with evidence of an endothelialized lumen, whereas none of the nonlased channels had evidence of channel patency. Lased channels had a marked neovascular response (graded on a 0-3 scale) compared with nonlased channels (2.5+/-0.1 versus 1.0+/-0.1; P<.05). Echocardiography performed 1 and 30 days after TMR demonstrated normal global and regional left ventricular function in all animals. Creatinine phosphokinase myocardial band fractions were not significantly increased after TMR. CONCLUSIONS: TMR using the excimer laser results in increased evidence of channel derivatives and neovascularization compared with nonlased channels while preserving normal ventricular function. These findings suggest that laser energy may be an important component of TMR strategy.