title: Quantitative histological assessment of xenobiotic-induced liver enzyme induction and pituitary-thyroid axis stimulation in rats using whole-slide automated image analysis.
abstract: Preclinical evaluation of a new compound, RO2910, identified a hypertrophic response in liver, thyroid gland, and pituitary gland (pars distalis). We aimed to develop and validate automated image analysis methods to quantify and refine the interpretation of semi-quantitative histology. Wistar-Han rats were administered RO2910 for 14 days. Liver, thyroid, and pituitary gland tissues were processed for routine histology and immunolabeled with anti-thyroid stimulating hormone (TSH) antibody (pituitary) and anti-topoisomerase II antibody (thyroid). Glass slides were scanned, image analysis methods were developed and applied to whole-slide images, and numerical results were compared with histopathology, circulating hormone levels, and liver enzyme mRNA expression for validation. Quantitative analysis of slides had strong individual correlation with semi-quantitative histological evaluation of all tissues studied. Hepatocellular hypertrophy quantification also correlated strongly with liver enzyme mRNA expression. In the pars distalis, measurement of TSH weak-staining areas correlated with both hypertrophy scores and circulating TSH levels. Whole-slide image analysis enabled automated quantification of semi-quantitative histopathology findings and a more refined interpretation of these data. The analysis also enabled a direct correlation with non-histological parameters using straightforward statistical analysis to provide a more refined dose- and sex-response relationship and integration among affected parameters. These findings demonstrate the utility of our image analysis to support preclinical safety evaluations.
authors: Roche Pharmaceuticals, Nonclinical Safety, Nutley, New Jersey 07110, USA. rosario.garrido@roche.com
authors: Rosario
authors: R
authors: Garrido
authors: Tanja S
authors: TS
authors: Zabka
authors: Jianhua
authors: J
authors: Tao
authors: Mark
authors: M
authors: Fielden
authors: Adrian
authors: A
authors: Fretland
authors: Mudher
authors: M
authors: Albassam
mesh_terms: D000465:Algorithms; D000818:Animals; D001331:Automation; D004790:Enzyme Induction / Q000187:drug effects; D005240:Feasibility Studies; D005260:Female; D006652:Histological Techniques / Q000379:methods*; D006984:Hypertrophy / Q000097:blood / Q000201:enzymology / Q000473:pathology; D007091:Image Processing, Computer-Assisted / Q000379:methods*; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D011920:Rats, Inbred WF; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D013972:Thyrotropin / Q000097:blood; D015262:Xenobiotics / Q000494:pharmacology*
chemical_list: D015262:Xenobiotics; D013972:Thyrotropin