Impact of neonatal cryptosporidial gastroenteritis on epigenetic programming of rat hepatocytes

Abstract

Inflammation, malnutrition and growth retardation during critical time-windows of development play a powerful role in ontogenetic programming of the life-long risk to many adult diseases (including metabolic syndrome, obesity and diabetes). Cellular mechanisms and the accurate timing and duration of critical periods for the liver remain obscure. To resolve this problem, we developed a postnatal suckling-weanling rat model of mild, moderate, and acute gastroenteritis challenged by a protozoan parasitic spread throughout the whole world, namely Cryptosporidium parvum. The physiological state of the liver was evaluated by hepatocyte ploidy and protein content that were measured by cytophotometry and image analysis on isolated cells. Hepatocyte ploidy is known to irreversibly increase after stress and is associated with the decrease in liver physiological capacity. Hepatocyte hypertrophy reflects cell functional loading. From our results, cryptosporidiosis is able to provoke a burst in premature hepatocyte polyploidization and hypertrophy (in proportion to parasitic load), and thus plays an important role in epigenetic programming of hepatocyte structure and function. We revealed two sensitive periods in liver growth. The first period (the less sensitive) covers the time before the establishment of homoiothermy, i.e. 6-9 days after birth. The second period (the more sensitive) covers the time of weaning when the change of type of nutrition and the peak of hepatocyte polyploidization and differentiation occurs. Thus, our data provide direct evidence that phenomenon of ontogenetic programming is reflected at the cellular level.

Neonatal cardiomyocyte ploidy reveals critical windows of heart development

“…(the peak of parasite prepatent period). Then smears of feces were prepared, fixed in methanol and stained with a 1% aqueous Gentian violet saline [31]. Animals whose stool smears contained 11-20 endogenous stages of parasite in one microscopic field (ob.…”

Respiration characteristics of mitochondria in parental and giant transformed cells of the murine Nemeth—Kellner lymphoma

“…The genome-scale analysis of the expression of housekeeping genes in human and mouse heart and liver revealed a clear link between polyploidization and metabolic shift from aerobic to anaerobic respiration. This created a special metabolic pattern intermediate between aerobic and anaerobic metabolic modes (Anatskaya et al, 2007). Increased NAD-metabolism, immunity and impaired metabolism of lipids are also seen in polyploidy.…”

Somatic polyploidy is associated with the upregulation of c-MYC interacting genes and EMT-like signature

“…Although somatic polyploidy (endopolyploidy) is normally encountered in a few normal mammalian tissues (liver, brain, vascular smooth muscle cells, heart, megakaryocytes, and placenta) [13–19], most solid tumours of any origin develop polyploidy and aneuploidy correlating with poor prognosis [20–27]. The tight association of malignancy with aneuploidy is a surprising fact in view of its essentially anti-proliferative effect [28–31].…”