Reproduction in Domestic Animals

Reprod Dom Anim 43 (Suppl. 2), 273–279 (2008); doi: 10.1111/j.1439-0531.2008.01174.xISSN 0936-6768Epigenetic Programming of Porcine Endometrial Function and the LactocrineHypothesisFF Bartol 1 , AA Wiley 1 and CA Bagnell 21 Departments of Animal Sciences and Anatomy, Physiology and Pharmacology, Cellular and Molecular Biosciences Program, Auburn University,Auburn, AL, USA; 2 Department of Animal Sciences, Endocrinology and Animal Biosciences Program, Rutgers University, New Brunswick, NJ, USAContentsEpigenetic programs controlling development of the femalereproductive tract (FRT) are influenced by the effects ofnaturally occurring bioactive agents on patterns of geneexpression in FRT tissues during organizationally criticalperiods of foetal and perinatal life. Aberrations in suchimportant cellular and molecular events, as may occur withexposure to natural or manmade steroid or peptide receptormodulatingagents, disrupt the developmental program andcan change the developmental trajectory of FRT tissues,including the endometrium, with lasting consequences. In thepig, as in other mammals, maternal programming of FRTdevelopment begins pre-natally and is completed postnatally,when maternal effects on development can becommunicated via signals transmitted in milk. Studiesinvolving relaxin (RLX), a prototypic milk-borne morphoregulatoryfactor (MbF), serve as the basis for ongoingefforts to identify maternal programming events that affectuterine and cervical tissues in the neonatal pig. Data supportthe lactocrine hypothesis for delivery of MbFs to neonatesas a specific consequence of nursing. Components of amaternally driven lactocrine mechanism for RLX-mediatedsignalling in neonatal FRT tissues, including evidence thatmilk-borne RLX is delivered into the neonatal circulationwhere it can act on RLX receptor (RXFP1) -positiveneonatal tissues to affect their development, are in place inthe pig. The fact that all newborn mammals drink milkextends the timeframe of maternal influence on neonataldevelopment across many species. Thus, lactocrine transmissionof milk-borne developmental signals is an element ofthe maternal epigenetic programming equation that deservesfurther study.IntroductionIn the pig (Sus scrofa domesticus), as in other mammals,development of the female reproductive tract (FRT)begins pre-natally but is completed post-natally (Yinand Ma 2005; Bartol et al. 2006). Structural patterning(morphogenesis) and functional programming (cytodifferentiation)of epithelial-mesenchymal tissues derivedfrom the Mu¨llerian ducts, including the oviducts, uterus,cervix and anterior vagina, are coupled processessupported by the progressive generation of increasinglycomplex and specific cellular relationships and interactions(Gray et al. 2001; Yin and Ma 2005). Over time,these interactions drive the evolution of organizationallycritical, temporally and spatially unique morphoregulatorygene expression domains that define micro-environmentalconditions which, in turn, direct and specifycell fate, dictate patterns of development, and determinecell and tissue identity and functionality. For a giventissue, this complex sequence of events defines thedevelopmental program and, in so doing, establishes adevelopmental trajectory for cells and tissues that willeventually dictate phenotype (Burggren 1999).Genetic potential for developmental success is definedat conception. Thereafter, if development proceedsalong a normal course through embryonic, foetal andperinatal life, a normal phenotypic trajectory is establishedand an optimal phenotypic outcome is realized(Fig. 1). However, developmental programs can bedisrupted by a host of epigenetic factors of both biotic(physiological, endocrinological, metabolic) and abiotic(anthropogenic ⁄ macro-environmental) origin (Burggren1999; Bartol 2002). Disruption of the developmentalprogram during organizationally critical periods, whencells and tissues are uniquely sensitive to aberrantstimuli, alters micro-environmental conditions requiredfor normal development. Divergence from the normaldevelopmental program can be sufficient to alter thedevelopmental trajectory and, ultimately, the phenotypeof a cell, tissue or organ (Fig. 1) (Bartol et al. 1999;Bartol 2002; Nathanielsz 2006). A wealth of evidenceindicates that exposure to organizationally disruptiveconditions during perinatal life can have lasting effectson both the form and function of FRT tissues (Yin andMa 2005; Bartol et al. 2006). Factors required toestablish a normal developmental program and toinsure an optimal developmental trajectory for FRTtissues remain incompletely defined.The term epigenetics, coined by Waddington in the1940s, was originally defined to describe the interactionsof genes with their environment which give rise tophenotype (Waddington 1940). This definition hasevolved to describe the study of changes in geneexpression that occur without a change in DNAsequence (Jirtle and Skinner 2007). The term is nowused broadly in reference to the ‘inheritance of informationbased on gene expression levels rather than ongene sequence’ (Junien 2006). Thus, factors that affectdevelopmentally critical gene expression events, particularlythose with lasting and potentially heritableconsequences, constitute epigenetic elements of thedevelopmental program (Jirtle and Skinner 2007).‘Maternal programming’ refers to maternally drivenepigenetic events with the potential to affect both thedevelopmental program and trajectory of embryonic,foetal and ⁄ or perinatal tissues (Szyf et al. 2005; Nathanielsz2006; Wells 2007). It is likely that maternaleffects on development do not end with parturition, butextend into the early neonatal period. During this time,colostrum (first milk) serves as the conduit for communicationof organizationally important developmentalsignals from mother to offspring.Ó 2008 The Authors. Journal compilation Ó 2008 Blackwell Verlag