In Utero Sources of Skeletal Variation: the Role of Maternal Prenatal Stres

Psychological stress has been demonstrated to predispose pre-menopausal women to osteoporosis (Eskandari et al., 2007). Considering that environmental factors acting in pre-natal life have been known to influence adult health (Barker, 1995a, b, c, d; Gluckman et al., 2005), I hypothesized that psychological stress during pregnancy could result in high levels of cortisol that would affect bone formation in the fetus.;To test this hypothesis I induced immobilization stress to pregnant Wistar rats at different gestational stages: Group 1 mothers were stressed during gestation week 1 (GW1), Group 2 during gestation week 2 (GW2), Group 3 during gestation week 3 (GW3); the Control Group was not stressed in any week. During gestation I monitored dams' cortisol hormone levels through fecal sampling, food intake, and maternal weight gain. After birth the pups were raised in a stress-free environment with adequate access to food and water and minimal human handling.;Histological analysis showed that males have larger bones compared to females starting at the age of 8 weeks for both offspring groups. Controlling for sex, there was no significant difference in trabecular total tissue area or the trabecular bone perimeter between the GW3 offspring and control offspring. The GW3 offspring had a higher bone formation rate as indicated by their higher trabecular bone area at the age of 8 weeks (GW3 = 2.16mm2, controls = 1.27mm2), higher number of osteoblasts, which are the bone forming cells, at the age of 12 weeks (GW3 = 21.66mm, controls = 12.14mm) and a bigger area of the osteoid surface, which is the collagen matrix laid down by osteoblasts that eventually calcifies to form the bone, at the age of 8 weeks (GW3 = 4.98mm, controls = 1.92mm) and 12 weeks (GW3 = 5.50mm, controls = 0.99mm). There was no significant difference in bone resorption rate between the two groups.;This project confirms that stress during pregnancy has negative consequences on both the mother and the offspring. The caloric intake in the mother is reduced, potentially due to the excess cortisol that alters the hypothalamic control of food intake. As a result, the mother does not accrue as many nutrients to support the growing fetuses. Having been nutrient-restricted and exposed to high cortisol levels in utero, the offspring appear to be born with an altered metabolism that results in faster growth and higher weight gain compared to controls. The positive effect of this fast growth is that the offspring born to stressed mothers ended up with a higher bone volume compared to the control offspring.;This study also shows that exposure to high cortisol levels in utero negatively affects the growth plate in offspring. Growth plate analysis showed that at the age of 4 weeks, control offspring had a significantly thicker area of resting and proliferative chondrocytes in the growth plate compared to GW3 offspring. Therefore, the negative effect of prenatal stress was evident in the upper zone of the growth plate even at the age of 4 weeks when the seemingly catch-up growth is expected to have occurred in all measured aspects of bone development. This seems to be the most sensitive part of bone development in relation to prenatal cortisol exposure.;In conclusion, given the negative effects of prenatal stress on the mother and offspring as noted above, this research shows that osteoporosis may have some fetal-origin roots influenced by maternal stress (and elevated cortisol levels). Healthy bones in adulthood require a healthy start. The growth plate is the center for bone growth and any adverse effects during early development would eventually affect the entire skeletal development. A likely result of not attaining the maximum peak bone mass density for which an individual has the genetic potential is a higher risk for osteoporosis. (Abstract shortened by UMI.).