Reproduction in Domestic Animals

274 FF Bartol, AA Wiley and CA BagnellCourse of developmentDevelopmentalprogram affectedDCriticalPeriodTimeDevelopmentaltrajectory affectedFig. 1. Potential effects of an organizationally disruptive event on thedevelopmental program and trajectory. Depicted is a scheme in whicha disruptive event (D) is encountered during a critical organizationalperiod early in development. The normal developmental program isdepicted by the solid line, with a range of developmental eventsassociated with normal outcomes indicated by the hatched area.Consequences of disruption may include: (1) alteration of the normaldevelopmental program without effects on the developmental trajectory(dashed line); or (2) alteration of both the developmental programand trajectory with long-term consequences for adult phenotype(dotted line)Here, data are reviewed to show that the basic elementsof a signalling system activated by a milk-borne morphoregulatorygrowth factor (MbF) exemplified byrelaxin (RLX) are present in the pig at birth. Collectively,data support the ‘lactocrine hypothesis’ for maternalprogramming of FRT tissues whereby milk-borne RLX,absorbed into the neonatal circulation during the firstdays of post-natal life, acts directly through its ownreceptor to induce and ⁄ or support oestrogen receptor-a(ER) expression and activation in a manner necessary toinsure normal FRT programming and an optimal developmentaltrajectory for FRT tissues in the pig.Reproductive Tract Development andConsequences of Developmental DisruptionClassic data indicating that pre-natal exposure ofhuman foetuses to the synthetic oestrogen diethylstilbestrolalters the developmental program of FRT tissuesand sets the stage for cervicovaginal cancer and othercomplications (Herbst et al. 1979; Iguchi and Sato 2000)drew attention to the fact that disruption of hormonesensitivedevelopmental events can have serious consequencesfor reproductive performance and health.Studies catalysed by these observations provided importantinsights into the roles of the steroid hormonesuperfamily of receptors and related ligands in normaland aberrant FRT programming. For the uterus, lossof-functionstudies showed that ER expression isrequired for normal growth, while both the progesteronereceptor (PR) and ER are required for normal uterinefunction (Conneely et al. 2001; Emmen and Korach2003). Neither ER nor PR expression is necessary tosupport primary uterine patterning events in pre- orperinatal life. However, aberrant activation of these andrelated receptor systems during critical organizationalperiods can affect the developmental program withsignificant functional consequences in both rodents andungulates (Bartol et al. 1999; Gray et al. 2000; Iguchiand Sato 2000; Huang et al. 2005). In laboratoryanimals, perinatal oestrogen exposure produced lesionsin adult uteri that included altered steroid receptorconcentrations and responsiveness; changes in oestrogenmetabolism and protein synthesis; persistent inductionor deregulation of gene expression; deregulation ofprotooncogene expression affecting epithelial proliferationand apoptosis; a myriad of structural lesions and,classically, general hypoplasia of FRT tissues andorgans (Iguchi and Sato 2000; Huang et al. 2005).Complementary data involving ungulate models indicateclearly that adult uterine phenotype can beprogrammed by targeted disruption of both steroidand peptide hormone-sensitive post-natal organizationalevents (Bartol et al. 1999, 2006; Carpenter et al. 2003;Tarleton et al. 2003).Events associated with normal and, particularly,oestrogen-induced disruption of neonatal uterine developmentin the pig have been reviewed (Bartol et al.1993; Yan et al. 2006b) and concepts related to maternaland ⁄ or environmental programming of reproductive⁄ somatic tissues in the pig are illustrated in Fig. 2.Data for the porcine uterus show that disruption ofFRT development during the early post-natal period hasboth morphological and functional consequences. Radialpatterning of the porcine uterine wall is incompleteat birth (PND 0), when tissues are ER-negative (Bartolet al. 1993; Tarleton et al. 1998). Early post-natal eventsassociated with development of these tissues includedifferentiation of glandular epithelium (GE) from luminalepithelium (LE), proliferation of nascent endometrialglands, and onset of regular ER expression instroma and GE, but not in LE (Spencer et al. 1993a;Yan et al. 2006a; b; Masters et al. 2007). When administeredfor 14 days from birth, the ER antagonist ICI182,780 retards development of the uterine wall andinhibits gland genesis in the neonatal endometrium(Tarleton et al. 1999). Thus, the ER is both a marker ofGE differentiation and a mediator of radial patterningin the neonatal porcine uterus.Aberrant activation of the neonatal ER system byadministration of oestradiol valerate (EV) to gilts fromPND 0–13, while acutely uterotrophic (Spencer et al.1993b), alters patterns of morphoregulatory geneexpression in the developing endometrium (Bartol et al.2006) and is ultimately both antiuterotrophic andantiembryotrophic (Bartol et al. 1993; Tarleton et al.2001, 2003). The hypoplastic, neonatally EV-exposedadult porcine uterus does not respond normally tosignals associated with the periattachment stage of earlypregnancy. Compared to unexposed controls on gestationalday 12 (GD 12), uterine luminal fluid proteincontent was reduced, uterine growth responses to earlypregnancy were inhibited, and endometrial gene expressionpatterns were altered in neonatally EV-exposed,pregnant adult gilts (Tarleton et al. 2003; Chen et al.2007). Treatment effects on the adult endometrialproteome for GD 12 were also pronounced (Bartolet al. 2006), and embryo survival in neonatallyEV-exposed gilts was reduced by 22% when assessedon GD 45 (Bartol et al. 1993). Thus, disruption ofoestrogen-sensitive, ER-dependent developmentalevents between birth and PND 14 has marked andlasting effects on uterine form and function in the pig. ItÓ 2008 The Authors. Journal compilation Ó 2008 Blackwell Verlag