Reducing Pup Litter Size Alters Early Postnatal Calcium Homeostasis and Programs Adverse Adult Cardiovascular and Bone Health in Male Rats

Abstract

The in utero and early postnatal environments play essential roles in offspring growth and development. Standardizing or reducing pup litter size can independently compromise long-term health likely due to altered milk quality, thus limiting translational potential. This study investigated the effect reducing litter size has on milk quality and offspring outcomes. On gestation day 18, dams underwent sham or bilateral uterine vessel ligation surgery to generate dams with normal (Control) and altered (Restricted) milk quality/composition. At birth, pups were cross-fostered onto separate dams with either an unadjusted or reduced litter size. Plasma parathyroid hormone-related protein was increased in Reduced litter pups, whereas ionic calcium and total body calcium were decreased. These data suggest Reduced litter pups have dysregulated calcium homeostasis in early postnatal life, which may impair bone mineralization decreasing adult bone bending strength. Dams suckling Reduced litter pups had increased milk long-chain monounsaturated fatty acid and omega-3 docosahexaenoic acid. Reduced litter pups suckled by Normal milk quality/composition dams had increased milk omega-6 linoleic and arachidonic acids. Reduced litter male adult offspring had elevated blood pressure. This study highlights care must be taken when interpreting data from research that alters litter size as it may mask subtle cardiometabolic health effects.

Molecular mechanisms governing offspring metabolic programming in rodent models of in utero stress

“…Thus, to further address the molecular mechanisms underlying the developmental programming of offspring metabolic health, we recommend that both male and female offspring are studied in future work. Differences in strain, husbandry, control diet composition, severity and duration of the insult, cross fostering techniques and standardisation of litter size postnatally, are also parameters that have been shown to influence metabolic health outcomes [284][285][286][287][288]. For instance, methods to impose "maternal stress" in rodent models of programming range from saline injection, to swimming and physical restraint, which are likely to have differing impacts on raising endogenous corticosterone/cortisol in the mother.…”

Nutrient evaluation of the seed, pulp, flesh, and peel of spaghetti squash

“…This phenomenon indicates that SS could be a rich source of P. In addition, Ca and P are essential components of human bones, and low Ca and P levels have been associated with osteoporosis and chondropathy. Therefore, regular consumption of SS can effectively prevent osteoporotic fractures and reduce fracture risks in the elderly and the weak (Briffa et al, 2019).…”

Rodent models of metabolic disorders: considerations for use in studies of neonatal programming

“…Also, caution must be exercised in the use of exogenous oxytocin to stimulate milk release as this affects the study of litter size. Aside obesity, small litters have also been used in the study of Ca metabolism, the homoeostatic endocannabinoid system (79,86) .…”

“…Most investigations in the lactational period of the nursing dam involve nutritional perturbations. Additional studies examine some other perturbations like maternal disorders, surgical alterations and even exercise on neonatal development (84,86,95) . Pups suckled by diabetic and obese mothers are also common (see Table 2).…”