What advantages do primate animal models offer over rodent models? Rodent models have historically served as primary tools in studies of human diseases because of their fast generation time, large litter size, easier handling, and small size and because of the ability to perform transgenic studies (i.e., over at least three generations) using them. However, these advantages are accompanied by significant limitations. For example, because of their faster generation time, the evolutionary rate appears more rapid than has occurred among hominids, and more recent data suggest that there are wide structural and physiological differences between humans and rodents (Raaum et al. 2005
). As a second pertinent example, maternal and fetal metabolic physiology comparatively differs among rodents and primates, as demonstrated by the regulation of satiety and appetite being developed postnatally in rodents and prenatally in humans and NHPs (Bouret et al. 2004
; Grayson et al. 2006
; Grove et al. 2003
; Grove and Smith 2003
; Koutcherov et al. 2002
). As a third example, placental structure and function are distinct among primates, which is of importance in light of the essential role of placentation in regulation of fetal nutrient transport and fatty acid and lipid metabolism (Maltepe et al. 2010
). The overall aim of NHP models is to generate an animal model that is robust and that both mimics the gravid physiology unique to primates (generally one uterus, one placenta, and one fetus) and recapitulates human gene function and regulation.
The closest genomic relatives to humans belong to Hominidae
, with clades of humans, chimpanzee, and gorilla being of closest genomic relation (human to chimp bearing greatest sequence similarity), and the more distant clades of orangutan and rhesus still sharing 98% or more identity. The remarkable phenotypic variance is highlighted by recalling the significant eras of divergence, with human to chimpanzee having diverged in the neighborhood of 3.5 to 5 million years ago, whereas orangutan and macaque diverged 14 million years ago and 23 million years ago (Raaum et al. 2005
). Thus, it is intuitive that these NHP models would serve as excellent animal models to study developmental origins of adult diseases because, despite our genomic similarity and recent divergence, our phenotypic variance is profound.
The landscape of fetal programming and the role of epigenomic modifications differ spatially and temporally with tissue and development stage-specific gene expression. For example, investigators delving into the evolution of cognitive capacity have observed well-conserved and predictive patterns of gene expression in the human brain compared with the chimpanzee brain (Caceres et al. 2003
; Enard and Paabo 2004
; Gu and Gu 2003
; Khaitovich et al. 2006
), with early studies suggesting hypermethylation of the cerebrum and thymus occurred with species specificity (Gama-Sosa et al. 1983
). Subsequent studies capable of interrogating discriminate changes have demonstrated that the methylation pattern is conserved between humans and chimpanzees, with prior observed differences in gene expression being at least in part explained by differential methylation (Pai et al. 2011
Which cellular pathways seem to be primarily affected across primate species? Cell cycle–related kinase (CCRK
) gene is involved in cell cycle growth, and transcriptional regulation has been identified to be differentially methylated and expressed in human and chimpanzee brain cortices. The intraspecific differential promoter methylation of CCRK in humans and chimpanzees has been postulated to be connected to interindividual differences in brain development. Thus, the divergence of DNA methylation in CpG islands can be considered as an epigenetic “footprint” of genes crucial for human development compared with NHPs (Farcas et al. 2009
). In a baboon model of reduced maternal nutrient availability, it has been observed that the fetal hepatic PCK1
gene encoding phosphoenolpyruvate caroxykinase 1 has a hypomethylated promoter (Nijland et al. 2010
). In the same model, it has been demonstrated that the juvenile offspring of mothers with reduced maternal nutrient availability exhibit increased fasting glucose, increased fasting insulin, and b cell responsiveness (Choi et al. 2011
). Interestingly, Rodriguez and colleagues (2011)
have demonstrated that exposure to prenatal betamethasone (synthetic glucocorticoid administered in case of premature labor to pregnant women) in maternal baboon model results in sex-specific effects in reversal learning and attention in the juvenile offspring. Maternal nutrient restriction during pregnancy in baboons altered fetal hepatic insulin-like growth factor (Li et al. 2009
). Comparative epigenetic regulation with the closest relative of humans (NHPs) could be the crucial element in improving our understanding of phenotypic differences, cognition development, and susceptibility to adult diseases such as obesity, metabolic syndrome, and cardiovascular disease (.
NHPs have been evaluated to study different aspects of reproductive biology. For instance, baboons, rhesus macaques, pig-tailed macaques, and cynomolgus monkeys have been characterized to study endometriosis, which is a common cause of infertility in women (Hastings et al. 2006
). Leveraging the baboon model to study endometriosis, it has been observed that together the inhibition of histone deacetylase and progesterone lead to expression of glycodelin gene (decreased expression observed in endometriosis) (Jaffe et al. 2007
). Placental methylation for several genes, including APC, SFRP2, CYP24A1, and DNMT1, was conserved in primate species (with variation in distribution and absolute methylation levels) as opposed to nonprimate species (Ng et al. 2010
NHPs have been also been explored as models to study metabolism with respect to enzymatic methylation of arsenic (carconigenic) compounds, which acts as a detoxification mechanism. Out of 17 NHPs, only four species demonstrated hepatic arsenite methyltransferase activity, thereby suggesting further evaluation of alternative detoxification mechanisms in these primates (Wildfang et al. 2001
). The summary of studies performed in other arenas, such as metabolism, reproductive biology, and neurology, are summarized in .