Evolutionary studies have long emphasized that the genetic architecture of traits holds important microevolutionary consequences. Yet, studies comparing the genetic architecture of traits across species are rare, and discussions of the evolution of genetic systems are made on theoretical arguments rather than on empirical evidence. Here, we compared the genetic architecture of cranial traits in two different mammalian model organisms: the gray short-tailed opossum, Monodelphis domestica, and the laboratory mouse, Mus musculus We show that both organisms share a highly polygenic genetic architecture for craniofacial traits, with many loci of small effect. However, these two model species differ significantly in the overall degree of pleiotropy, N, of the genotype-to-phenotype map, with opossums presenting a higher average N They also diverge in their degree of genetic modularity, with opossums presenting less modular patterns of genetic association among traits. We argue that such differences highlight the context dependency of gene effects, with developmental systems shaping the variational properties of genetic systems. Finally, we also demonstrate based on the opossum data that current measurements for the relationship between the mutational effect size and N need to be re-evaluated in relation to the importance of the cost of pleiotropy for mammals.

IntroductionA variety of factors, including use of tobacco, diet, gender, and genetics impact cancer risk. It is well established that administration of 4‐nitroquinonline 1‐oxide (4NQO) in drinking water mimics the effects of tobacco and leads to development of oral carcinoma in mice. The purpose of this study was to determine whether administration of 4NQO induced liver pathology and to examine the effects of gender, and high and low saturated fat diets (HF and LF, respectively) on the liver histopathology. We hypothesized that 4NQO's carcinogenic effects would cause pathological changes in liver and a HF diet would exacerbate this process.Materials and methodsMale and female C57Bl/6 mice (36 each gender), 5 weeks old, were divided into a low fat (10 kcal% fat; LF) or HF (60 kcal% fat) diet. Within each dietary group, mice were randomly assigned to one of 3 water treatment groups for 17 weeks: water alone (control); propylene glycol in water (1.25%; PG‐H2O); or 4NQO in PG‐H2O (50 mg/ml; 4NQO). After 17 weeks, all mice were given water alone for 6 more weeks. Livers harvested from the euthanized animals were weighed, then fixed in formalin and processed for histological examination. In addition, neutrophils and macrophages were detected by immunocytochemistry (Ly6 and CD68 positive cells, respectively) and counted in a standard area in liver sections. T‐tests were used to confirm no difference between water and PG controls, which were then combined for further statistical analysis using GraphPad Prism 7.0.ResultsAdministration of 4NQO resulted in histopathological changes in liver in all treatment groups. Morphological changes in hepatocytes, the presence of lobular and portal lymphoid cell infiltrates, and periportal fibrosis were observed in hematoxylin and eosin‐stained tissues. In addition, HF diet resulted in severe steatosis and liver enlargement (3× higher liver index in HF males versus all other treatment groups) of male but not female controls. Treatment with 4NQO significantly increased the number of neutrophils in liver, when compared to non‐4NQO‐treated control livers in HF males (208 versus 24.7), HF females (100 versus 29.2), and LF females (80 versus 26.7; for all groups, p<0.05). Also, treatment with 4NQO increased the number of macrophages in HF males, when compared to non‐4NQO‐treated males (121 versus 55, p<0.05). In addition, HF diet exacerbated the effect of 4NQO in males, with 121 neutrophils in HF 4NQO‐treated males versus 94.1 neutrophils in LF 4NQO‐treated males (p = 0.05).ConclusionOral administration of 4NQO, which mimics the effects of tobacco, induces histopathological changes in the liver, and those changes are exacerbated by a HF diet, especially in males.Support or Funding InformationWe recognize the Midwestern University Deans of the College of Dental Medicine and the Basic Science Division for their support of this research. Student research was supported by the Office of Research and Sponsored Programs and the Biomedical Sciences Division.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

No abstract

Risk factors for liver cancer include tobacco use, alcohol consumption, obesity, and male sex. Administration of 4-nitroquinonline-1-oxide (4NQO) in drinking water mimics the effects of tobacco and leads to oral carcinoma in mice. This study compared the effects of diets high and low in saturated fat (HF and LF, respectively), and sex, on liver histopathology in 4NQO-treated mice and controls. We hypothesized that 4NQO would cause histopathological changes in liver, and that a HF diet would increase hepatic pathology when compared to the LF diet. Mice (C57Bl/6, 36/sex), were divided into a low fat (10 kcal% fat; LF) or high fat (60 kcal% fat, HF) diet. Mice were further subdivided into one of 3 water treatment groups for 17 weeks: water (control), vehicle (1.25% propylene glycol in water [PG]), or 4NQO in (50 μg/ml; 4NQO). All mice were subsequently given water alone for 6 more weeks. Upon euthanasia, livers were harvested, fixed, sectioned, and stained with hematoxylin and eosin (H&E). H&E slides were graded for histopathology; frozen liver samples were analyzed for triglyceride content. Trichrome stained sections were graded for fibrosis. CD3+ T cells, CD68+ macrophages, and Ly6+ neutrophils were detected by immunohistochemistry. Compared to water controls, 4NQO-treatment caused mouse liver histopathological changes such as fibrosis, and increases in hepatic neutrophils, T cells, and macrophages. HF diet exacerbated pathological changes compared to LF diet. Male controls, but not females, demonstrated severe steatosis and increased triglyceride content. 4NQO treatment decreased hepatic fat accumulation, even in animals on a HF diet. In conclusion, this murine model of oral cancer may serve as a model to study the effects of tobacco and diet on liver.

No abstract