Mice Deficient in Glycerol-3-Phosphate Acyltransferase-1 Have a Reduced Susceptibility to Liver Cancer

The risk of hepatocellular carcinoma increases with the persistence of non-alcoholic fatty liver disease. Triacylglycerol synthesis is initiated by glycerol-3-phosphate acyltransferase (GPAT). Of four isoforms, GPAT1 contributes 30–50% of total liver GPAT activity, and we hypothesized that it might influence liver susceptibility to tumorigenesis. C57Bl/6 mice deficient in GPAT1 were backcrossed 6 times to C3H mice. After exposure to the carcinogen diethylnitrosamine (DEN) and the tumor promoter phenobarbital, male Gpat1−/− mice, compared with controls (Gpat1+/+), had 93% fewer macroscopically visible nodules per liver at 21 weeks of age and 39% fewer at 34 weeks of age. Microscopically, control mice had increased numbers of foci of altered hepatocytes, particularly the basophilic subtype, as well as more, and malignant, liver neoplasms than did the Gpat1−/− mice. At 21 weeks of age, 50% (4/8) of control mice (50%) had hepatocellular adenomas with an average multiplicity (tumors per tumor-bearing-animal) of 4.3, while none occurred in 8 Gpat1−/− mice. At 34 weeks of age, all 15 control mice (100%) had hepatocellular adenomas with an average multiplicity of 5.2 compared to an incidence of 93% in Gpat1−/− mice and multiplicity of 3.1. HCCs were observed in 13% of control mice and in only 6% of Gpat1−/− mice. These data show that alterations in the formation of complex lipids catalyzed by Gpat1 reduce susceptibility to DEN-induced liver tumorigenesis

Effects of prenatal exposure to a low dose atrazine metabolite mixture on pubertal timing and prostate development of male Long-Evans rats

The present study examines the postnatal reproductive development of male rats following prenatal exposure to an atrazine metabolite mixture (AMM) consisting of the herbicide atrazine and its environmental metabolites diaminochlorotriazine, hydroxyatrazine, deethylatrazine, and deisopropylatrazine. Pregnant Long Evans rats were treated by gavage with 0.09, 0.87, or 8.73 mg AMM/kg body weight (BW), vehicle, or 100 mg ATR/kg BW positive control, on gestation days 15-19. Preputial separation was significantly delayed in 0.87 mg and 8.73 mg AMM-exposed males. AMM-exposed males demonstrated a significant treatment-related increase in incidence and severity of inflammation in the prostate on postnatal day (PND) 120. A dose-dependent increase in epididymal fat masses and prostate foci were grossly visible in AMM-exposed offspring. These results indicate that a short, late prenatal exposure to mixture of chlorotriazine metabolites can cause chronic prostatitis in male LE rats. The mode of action for these effects is presently unclear

A comprehensive analysis of common genetic variation in prolactin (PRL) and PRL receptor (PRLR) genes in relation to plasma prolactin levels and breast cancer risk: the Multiethnic Cohort

<p>Abstract</p> <p>Background</p> <p>Studies in animals and humans clearly indicate a role for prolactin (PRL) in breast epithelial proliferation, differentiation, and tumorigenesis. Prospective epidemiological studies have also shown that women with higher circulating PRL levels have an increase in risk of breast cancer, suggesting that variability in PRL may also be important in determining a woman's risk.</p> <p>Methods</p> <p>We evaluated genetic variation in the PRL and PRL receptor (PRLR) genes as predictors of plasma PRL levels and breast cancer risk among African-American, Native Hawaiian, Japanese-American, Latina, and White women in the Multiethnic Cohort Study (MEC). We selected single nucleotide polymorphisms (SNPs) from both the public (dbSNP) and private (Celera) databases to construct high density SNP maps that included up to 20 kilobases (kb) upstream of the transcription initiation site and 10 kb downstream of the last exon of each gene, for a total coverage of 59 kb in PRL and 210 kb in PRLR. We genotyped 80 SNPs in PRL and 173 SNPs in PRLR in a multiethnic panel of 349 unaffected subjects to characterize linkage disequilibrium (LD) and haplotype patterns. We sequenced the coding regions of PRL and PRLR in 95 advanced breast cancer cases (19 of each racial/ethnic group) to uncover putative functional variation. A total of 33 and 60 haplotype "tag" SNPs (tagSNPs) that allowed for high predictability (R_h²≥ 0.70) of the common haplotypes in PRL and PRLR, respectively, were then genotyped in a multiethnic breast cancer case-control study of 1,615 invasive breast cancer cases and 1,962 controls in the MEC. We also assessed the association of common genetic variation with circulating PRL levels in 362 postmenopausal controls without a history of hormone therapy use at blood draw. Because of the large number of comparisons being performed we used a relatively stringent type I error criteria (p < 0.0005) for evaluating the significance of any single association to correct for performing approximately 100 independent tests, close to the number of tagSNPs genotyped for both genes.</p> <p>Results</p> <p>We observed no significant associations between PRL and PRLR haplotypes or individual SNPs in relation to breast cancer risk. A nominally significant association was noted between prolactin levels and a tagSNP (tagSNP 44, rs2244502) in intron 1 of PRL. This SNP showed approximately a 50% increase in levels between minor allele homozygotes vs. major allele homozygotes. However, this association was not significant (p = 0.002) using our type I error criteria to correct for multiple testing, nor was this SNP associated with breast cancer risk (p = 0.58).</p> <p>Conclusion</p> <p>In this comprehensive analysis covering 59 kb of the PRL locus and 210 kb of the PRLR locus, we found no significant association between common variation in these candidate genes and breast cancer risk or plasma PRL levels. The LD characterization of PRL and PRLR in this multiethnic population provide a framework for studying these genes in relation to other disease outcomes that have been associated with PRL, as well as for larger studies of plasma PRL levels.</p

An Agent-Based Model of a Hepatic Inflammatory Response to Salmonella: A Computational Study under a Large Set of Experimental Data

Citation: Shi, Z. Z., Chapes, S. K., Ben-Arieh, D., & Wu, C. H. (2016). An Agent-Based Model of a Hepatic Inflammatory Response to Salmonella: A Computational Study under a Large Set of Experimental Data. Plos One, 11(8), 39. doi:10.1371/journal.pone.0161131We present an agent-based model (ABM) to simulate a hepatic inflammatory response (HIR) in a mouse infected by Salmonella that sometimes progressed to problematic proportions, known as "sepsis". Based on over 200 published studies, this ABM describes interactions among 21 cells or cytokines and incorporates 226 experimental data sets and/or data estimates from those reports to simulate a mouse HIR in silico. Our simulated results reproduced dynamic patterns of HIR reported in the literature. As shown in vivo, our model also demonstrated that sepsis was highly related to the initial Salmonella dose and the presence of components of the adaptive immune system. We determined that high mobility group box-1, C-reactive protein, and the interleukin-10: tumor necrosis factor-a ratio, and CD4+ T cell: CD8+ T cell ratio, all recognized as biomarkers during HIR, significantly correlated with outcomes of HIR. During therapy-directed silico simulations, our results demonstrated that anti-agent intervention impacted the survival rates of septic individuals in a time-dependent manner. By specifying the infected species, source of infection, and site of infection, this ABM enabled us to reproduce the kinetics of several essential indicators during a HIR, observe distinct dynamic patterns that are manifested during HIR, and allowed us to test proposed therapy-directed treatments. Although limitation still exists, this ABM is a step forward because it links underlying biological processes to computational simulation and was validated through a series of comparisons between the simulated results and experimental studies

Hepatic Gene Expression Changes throughout the Day in the Fischer Rat: Implications for Toxicogenomic Experiments

There is increasing use of transcriptional profiling in hepato-toxicity studies in the rat. Understanding hepatic gene expression changes over time is critical, since tissue collection may occur throughout the day. Furthermore, when comparing results from different data sets, times of dosing and tissue collection may vary. Circadian effects on the mouse hepatic transcriptome have been well documented. However, limited reports exist for the rat. In one study approximately 7 % of the hepatic genes showed a diurnal expression pattern in a comparison of rat liver samples collected during the day versus livers collected at night. The results of a second study comparing rat liver samples collected at multiple time points over a circadian day suggest only minimal variation of the hepatic transcriptome. We studied temporal hepatic gene expression in 48 untreated F344/N rats using both approaches employed in these previous studies. Statistical analysis of micro