Lactocrine programming of postnatal reproductive tract development

Abstract Text: Lactocrine signaling occurs when bioactive factors are communicated from mother to offspring as a consequence of nursing.  In the pig (Sus scrofa), relaxin was identified as a prototypical lactocrine-active factor in colostrum.  Administration of exogenous relaxin from birth (postnatal day [PND] = 0) increased neonatal uterine estrogen receptor-α (ESR1) expression.  Using multispectral immunofluoresecence imaging, expression of ESR1 is detectable in nascent endometrial glandular epithelium and stroma within two days of birth, and supports uterine gland genesis.  Imposition of a lactocrine-null condition for two days from birth by substitution of porcine milk replacer for colostrum retarded endometrial development and uterine gland genesis. Compared to nursed gilts, replacer-feeding from birth reduced stromal ESR1 expression and endometrial cell proliferation and increased endometrial relaxin receptor expression by PND 2.  Effects of transient imposition (48 h) of the lactocrine-null state on endometrial morphology were pronounced by PND 14, when cell proliferation, reflected by patterns of proliferating cell nuclear antigen immunostaining, and development of nascent endometrial glands were markedly reduced.  Collectively, the observations suggested a lactocrine-driven mechanism regulating establishment of the uterine developmental program and endometrial adenogenesis in the neonatal pig.  The lactocrine hypothesis for maternal programming of reproductive tract development predicts that neonates deprived of colostrum will have reduced uterine capacity to support conceptus development as adults due to disruption of the uterine developmental program shortly after birth.  Results of a retrospective study involving 381 gilts indicated that lifetime fecundity (number of piglets born alive over approximately four parities per gilt) was reduced in animals that consumed minimal amounts of colostrum as indicated by low serum immunocrit values on PND 0.  To the extent that the first two days of neonatal life constitute a critical period for establishment of the uterine developmental program, effects of replacer feeding for two days from birth on global patterns of uterine gene expression were evaluated using whole uterine transcriptome analysis via RNA sequencing (RNA-seq).  Analyses were performed on uteri (n = 4/group) obtained on PND 2 from gilts that were either nursed (PND 2N) or fed porcine milk replacer from birth (PND 2R).  Using RNA-seq, 896 genes were determined to be differentially expressed (> 2-fold) between the PND 2N and PND 2R groups.  Thus, disruption of lactocrine signaling has profound effects on neonatal uterine gene expression. The results indicate that lactocrine support is required to establish a normal uterine developmental program in the neonatal pig.

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