Relaxin and the 'Milky Way': The lactocrine hypothesis and maternal programming of development.

Maternal effects on early postnatal development in mammals are mediated, in part, by milk-borne bioactive factors transmitted from mother to nursing offspring. The term 'lactocrine' was coined to describe this mode of signaling. Relaxin (RLX), one of a family of neohormones found in mammals, is detectable in milk from multiple species.

Neonatal lactocrine deficiency affects the adult porcine endometrial transcriptome at pregnancy day 13.

Reproductive performance of female pigs that do not receive sufficient colostrum from birth is permanently impaired. Whether lactocrine deficiency, reflected by low serum immunoglobulin immunocrit (iCrit), affects patterns of endometrial gene expression during the periattachment period of early pregnancy is unknown. Here, objectives were to determine effects of low iCrit at birth on the adult endometrial transcriptome on pregnancy day (PxD) 13.

Effects of colostrum, feeding method and oral IGF1 on porcine uterine development.

Nursing ensures lactocrine delivery of maternally derived, milk-borne bioactive factors to offspring, which affects postnatal development of female reproductive tract tissues. Disruption of lactocrine communication for two days from birth (postnatal day (PND) 0) by feeding milk replacer in lieu of nursing or consumption of colostrum alters porcine uterine gene expression globally by PND 2 and inhibits uterine gland genesis by PND 14. Here, objectives were to determine effects of: (1) nursing or milk replacer feeding from birth; (2) a single dose of colostrum or milk replacer and method of feeding and (3) a single feeding of colostrum or milk replacer, with or without oral supplementation of IGF1, administered at birth on aspects of porcine uterine development at 12-h postnatally.

Maternal lactocrine programming of porcine reproductive tract development.

The lactocrine hypothesis for maternal programming of female reproductive tract development is based on the idea that non-nutritive, milk-borne bioactive factors (MbFs), delivered from mother to offspring during nursing, play a role in determining the trajectory of development with long-term consequences in the adult. Porcine female reproductive tract development is completed postnatally, and the period during which maternal support of neonatal growth derives exclusively from colostrum/milk defines a window of opportunity for lactocrine programming of reproductive tissues. Beyond nutrition, milk serves as a delivery system for a variety of bioactive factors.

Defining age- and lactocrine-sensitive elements of the neonatal porcine uterine microRNA-mRNA interactome.

Factors delivered to offspring in colostrum within 2 days of birth support neonatal porcine uterine development. The uterine mRNA transcriptome is affected by age and nursing during this period. Whether uterine microRNA (miRNA) expression is affected similarly is unknown.

Age and Nursing Affect the Neonatal Porcine Uterine Transcriptome.

The lactocrine hypothesis for maternal programming of neonatal development was proposed to describe a mechanism through which milk-borne bioactive factors, delivered from mother to nursing offspring, could affect development of tissues, including the uterus. Porcine uterine development, initiated before birth, is completed postnatally. However, age- and lactocrine-sensitive elements of the neonatal porcine uterine developmental program are undefined.

Methoxychlor and its metabolite HPTE inhibit cAMP production and expression of estrogen receptors α and β in the rat granulosa cell in vitro.

The major metabolite of the estrogenic pesticide methoxychlor (MXC) HPTE is a stronger ESR1 agonist than MXC and acts also as an ESR2 antagonist. In granulosa cells (GCs), FSH stimulates estradiol via the second messenger cAMP. HPTE inhibits estradiol biosynthesis, and this effect is greater in FSH-treated GCs than in cAMP-treated GCs.

Effects of age, nursing, and oral IGF1 supplementation on neonatal porcine cervical development.

Nursing supports neonatal porcine uterine and testicular development, however, lactocrine effects on cervical development are undefined. Studies were conducted to determine the effects of i) age and the imposition of the lactocrine-null state from birth (postnatal day 0 (PND0)) by milk replacer feeding on cervical histology; ii) imposition of the lactocrine-null state for 2 days from birth on cervical cell proliferation, as reflected by proliferating cell nuclear antigen immunostaining; and iii) a single feeding of colostrum or milk replacer, administered at birth, with or without oral IGF1, on cervical cell proliferation and phosphorylated AKT (pAKT) and B-cell lymphoma 2 (BCL2) protein levels at 12 h postnatal. Cervical crypt depth and height of luminal epithelium (LE) increased with age by PND14, when both responses were reduced in replacer-fed gilts.

Anti-arthritic actions of relaxin, in combination with estrogens, in joint and bone tissue.

The incidence and severity of rheumatoid arthritis decline during pregnancy. However, the role of hormones of pregnancy, including estrogens and relaxin, in attenuating the symptoms of rheumatoid arthritis, including joint inflammation and bone destruction is unknown. In rat adjuvant-induced arthritis, a model for rheumatoid arthritis, relaxin in combination with estrogens, reduced joint inflammation and circulating levels of pro-inflammatory, tumor necrosis factor alpha.

Milk-borne relaxin and reproductive system development.

A window of opportunity for maternal programming of neonatal development is open in the first few days of life as a consequence of nursing. Colostrum (first milk) supports neonatal development by providing a conduit for delivery of milk-borne bioactive factors, exemplified by relaxin, from mother to offspring as proposed in the lactocrine hypothesis. Relaxin, a prototypical milk-borne bioactive factor, is detectable in colostrum from multiple species, including the pig.

Nursing for 48 hours from birth supports porcine uterine gland development and endometrial cell compartment-specific gene expression.

The first 2 wk of neonatal life constitute a critical period for estrogen receptor alpha (ESR1)-dependent uterine adenogenesis in the pig. A relaxin receptor (RXFP1)-mediated, lactocrine-driven mechanism was proposed to explain how nursing could regulate endometrial ESR1 and related gene expression events associated with adenogenesis in the porcine neonate during this period. To determine effects of nursing on endometrial morphogenesis and cell compartment-specific gene expression, gilts (n = 6-8/group) were assigned at birth to be either 1) nursed ad libitum for 48 h, 2) gavage fed milk replacer for 48 h, 3) nursed ad libitum to Postnatal Day (PND) 14, or 4) gavage fed milk replacer for 48 h followed by ad libitum nursing to PND 14.

Nursing during the first two days of life is essential for the expression of proteins important for growth and remodeling of the neonatal porcine cervix.

The neonatal porcine cervix is sensitive to hormones, including relaxin (RLX), from birth. Whether nursing is required to establish the cervical developmental program or to determine cervical developmental trajectory is unknown. The objective of study 1 was to determine effects of age and nursing on expression of molecular markers and mediators of porcine cervical growth and remodeling from birth to postnatal day (PND) 2 and to document effects of RLX treatment during this period on expression of targeted gene products in nursed vs.

Lactocrine programming of female reproductive tract development: environmental connections to the reproductive continuum.

For eutherian mammals a continuum of maternal support insures that development of progeny follows an optimal program. Beginning in utero, such support extends into the early neonatal period when bioactive factors are communicated from mother to offspring in colostrum/milk. Defined as lactocrine signaling, communication of milk-borne bioactive factors from mother to offspring as a consequence of nursing is important for development of somatic tissues, including the female reproductive tract (FRT).

Effects of relaxin and estrogens on bone remodeling markers, receptor activator of NF-kB ligand (RANKL) and osteoprotegerin (OPG), in rat adjuvant-induced arthritis.

Rheumatoid arthritis (RA) is characterized by joint inflammation and bone destruction. The receptor activator of nuclear factor-kappa B ligand (RANKL)-osteoprotegerin (OPG) system is important for maintaining the balance between bone resorption and formation. Both serum RANKL/OPG protein and synovial tissue RANKL/OPG mRNA ratios are elevated in patients with RA.

Milk-borne lactocrine-acting factors affect gene expression patterns in the developing neonatal porcine uterus.

Lactocrine communication of milk-borne bioactive factors (MbFs) from mother to offspring through nursing can affect neonatal development with lasting consequences. Relaxin (RLX), a lactocrine-active peptide found in porcine colostrum, stimulates estrogen receptor-α (ESR1) expression required for uterine development shortly after birth (postnatal day=PND 0). Whether other MbFs or cooperative lactocrine mechanisms affect the neonatal uterine developmental program is unknown.

Transient estrogen exposure from birth affects uterine expression of developmental markers in neonatal gilts with lasting consequences in pregnant adults.

Disruption of estrogen-sensitive, estrogen receptor (ER)-dependent events during porcine uterine development between birth (postnatal day=PND 0) and PND 14 affects patterns of uterine morphoregulatory gene expression in the neonate with lasting consequences for reproductive success. Uterine capacity for conceptus support is reduced in pregnant adult gilts exposed to estradiol valerate (EV) for 14 days from birth. Objectives here were to determine effects of EV exposure from birth through PND 13 on neonatal uterine and adult endometrial markers of growth, patterning, and remodeling.

Relaxin promotes matrix metalloproteinase-2 and decreases Wnt/beta-catenin expression in the neonatal porcine heart.

Relaxin (RLX), reported to play an important role in cardiovascular remodeling, is linked to activation of matrix metalloproteinases (MMPs). Interruption of the cardiac Wnt/beta-catenin signaling system is reported to have antihypertrophic effects. Thus, the objectives of this study were to determine the effects of RLX on the myocardial Wnt/beta-catenin signaling system and MMP expression in the postnatal day 2 (PND 2) porcine heart.

Laser microdissection of neonatal porcine endometrium for tissue-specific evaluation of relaxin receptor (RXFP1) expression in response to perinatal zearalenone exposure.

Porcine neonatal uterine relaxin receptor (RXFP1) expression is tissue compartment specific and estrogen sensitive. Here, procedures were established for laser microdissection, tissue capture, and quantification of the effects of perinatal exposure (14 days pre- to 21 days postnatal) to a selective estrogen receptor modulator of environmental origin, zearalenone (ZEA), on endometrial RXFP1 expression. Total RNA from captured endometrium was used to generate cDNA for quantitative reverse transcription-PCR.

Perinatal zearalenone exposure affects RXFP1, RXFP2, and morphoregulatory gene expression in the neonatal porcine uterus.

The mycotoxin zearalenone (ZEA) is a selective estrogen receptor modulator that can contaminate cereal feeds and lead to reproductive disorders. To determine effects of perinatal ZEA exposure on uterine expression of genes associated with endometrial development in the neonatal gilt, pregnant sows were fed ZEA (1500 microg ZEA/kg of feed/day) or vehicle from 14 days before farrowing through postnatal day (PND) 20-21, when neonatal uterine tissues were collected. At birth, gilts were cross-fostered to generate four ZEA exposure groups (n= 5-6/group): unexposed controls or exposures limited to prenatal, postnatal, or pre- and postnatal (continuous) periods.

Evaluation of systemic relaxin blood profiles in horses as a means of assessing placental function in high-risk pregnancies and responsiveness to therapeutic strategies.

Placental insufficiency is regarded as the primary factor contributing to late-term abortion and perinatal death of foals. Often when problems associated with late-term pregnancy in the horse are manifest the condition is well-advanced and therapeutic intervention may not be effective in rescuing the pregnancy. If a compromised pregnancy due to placental insufficiency could be identified early, the pregnancy might be sustained through medical intervention.

Biological activity of relaxin in porcine milk.

A lactocrine mechanism for delivery of maternally derived relaxin (RLX) into the neonatal circulation as a consequence of nursing has been proposed for the pig. Consistently, immunoreactive porcine RLX was detected in colostrum as well as in the serum of nursing pigs. Concentrations of porcine RLX in milk are highest during early lactation (9-19 ng/mL) and decline to less than 2 ng/mL by postnatal day 14.

Relaxin and maternal lactocrine programming of neonatal uterine development.

In mammals, including the pig (Sus scrofa domesticus), structural patterning and functional programming of uterine tissues involve events that occur shortly after birth. Porcine endometrial development between birth (postnatal day 0 [PND 0]) and PND 15 is estrogen receptor (ER) dependent and estrogen sensitive. The endometrium is relaxin (RLX) receptor (RXFP1) positive and ERalpha negative at birth.

Milk-borne relaxin and the lactocrine hypothesis for maternal programming of neonatal tissues.

The fact that all newborn mammals drink milk extends the time frame of maternal influence on development into neonatal life. While the nutritional and immunological benefits of milk are clear, the role of milk as a conduit for bioactive factors with the potential to affect neonatal development is less well defined. Porcine and canine milk contain immunoreactive relaxin (RLX) that is transmitted into the circulation of nursing offspring.