Effects of uteroplacental insufficiency and reducing litter size on maternal mammary function and postnatal offspring growth

Abstract

Human intrauterine growth restriction is often associated with uteroplacental insufficiency and a decline in nutrient and oxygen supply to the fetus. This study investigated the effects of uteroplacental insufficiency and intrauterine growth restriction (Restricted) or reducing litter size for normally grown pups (Reduced Litter) on maternal mammary development and function, milk composition, offspring milk intake, and their resultant effects on postnatal growth. Uteroplacental insufficiency was surgically induced by bilateral uterine vessel ligation on day 18 of gestation in the Wistar Kyoto rat. At birth, a group of sham control rats had their litter size reduced to five (Reduced Litter) to match that of the Restricted group. Cohorts of rats were terminally anesthetized on day 20 of gestation or day 6 of lactation, and a third group was studied throughout lactation. Restricted pups had a lower birth weight (by 16%) and litter size (by 36%) compared with controls, as well as reduced mammary parathyroid hormone-related protein content and milk ionic calcium concentrations associated with reduced total pup calcium. Restricted dams with lower circulating progesterone experienced premature lactogenesis, producing less milk per pup with altered composition compared with controls, further slowing growth during lactation. Reducing litter size of pups born of normal birth weight (Reduced Litter) was associated with decreased pup growth, highlighting the importance of appropriate controls. The present study demonstrates that uteroplacental insufficiency impairs mammary function, compromises milk quality and quantity, and reduces calcium transport into milk, further restraining postnatal growth.

Adolescence and the next generation

“…It is associated with increased risk of neonatal mortality, preterm birth, small for gestational age babies, and low birth weight 34 . The effects extend to the postnatal period with compromised antenatal breast development reducing breast milk quality and quantity 35 and the establishment of attachment bonds 36,37 . Puberty marks a transition to adolescence and a life phase during which girls and boys acquire resources that are essential for becoming parents of the next generation.…”

Uteroplacental insufficiency and reducing litter size alters skeletal muscle mitochondrial biogenesis in a sex-specific manner in the adult rat

“…In previous studies examining these in the rat, control litters were typically culled to reduce the litter size to that of uteroplacental-insufficient litters (12,13,29). We have now shown, however, that reductions in litter size have an adverse impact on mammary function and on postnatal growth of the offspring (20) and may itself independently program later adverse outcomes. Thus, the present study aimed to compare offspring of sham-operated controls of normal litter size and a separate group of reduced litter size, which underwent sham surgery (Reduced Litter), to litters exposed to uteroplacental insufficiency (Restricted).…”

“…A vaginal impedence reader (model MK-10B; Mukomachi Kikai, Osaka, Japan) was used to determine whether females were in the appropriate stage of the estrous cycle for mating, as described previously (20,40,41). The following morning, the presence of sperm in vaginal smears was taken as day 1 of pregnancy.…”

“…The placentally restricted group underwent bilateral uterine vessel (artery and vein) ligation to induce uteroplacental insufficiency, as described previously, and the sham surgery was identical except that the uterine vessels were not ligated (20,40,41). At birth, one-half of the litters from the sham-surgery group (litter size 10 -14 pups) had their litter size randomly reduced to five pups (Reduced Litter) to match the litter size of pups born to uteroplacentally restricted mothers (Restricted) (20,40). The remaining half of the litters from the sham surgery were left with a normal litter size of 10 -14 pups (Control).…”

“…These models restrict placental delivery of substrates to the fetus and also impair mammary development and lactation (20), restricting substrate supply to offspring. This restriction of prenatal and postnatal substrate induces insulin resistance, impaired glucose tolerance, and subsequently diabetes in adult offspring (29,30).…”