Perinatal programming and neuroendocrine function

Sammanfattning: Perinatal growth and development are dependent on a sufficient metabolic, hormonal and nutritional environment. Suboptimal conditions during specific perinatal developmental windows can lead to permanent programming of physiological systems in the fetus or newborn, with implications for adult health. Epidemiological studies have shown that impaired intrauterine growth and development correlate with an increased risk of developing insulin resistance, hypertension, obesity and cardiovascular disease at adult age. The aim of this study was to examine in a rat model if exposition to endotoxin or hormones perinatally can affect neuroendocrine and metabolic function in the adult offspring. The programming effects of testosterone to newborn female pups were examined. Neonatal testosterone was shown to result in adult female rats with increased insulin resistance. Increased muscle weight and centralization of adipose tissue were seen. Circulating levels of testosterone and progesterone were lower in T-exposed rats. The long-term implications of prenatal exposure to high leptin, a hormone suggested to be involved in fetal growth and development, were explored. Prenatal leptin exposure resulted in reduced skeletal growth, bone formation and adipose tissue in the offspring. Male offspring showed increased response to stress and female offspring had high circulating testosterone levels. The programming effects of exposure to endotoxin (LPS), both prenatally and postnatally were examined. LPS exposure in utero led to male offspring exhibiting obesity, insulin resistance and high levels of estradiol and progesterone. Leptin levels were increased, as were food intake. The HPA-axis response to stress was attenuated and the glucocorticoid receptor was upregulated in hippocampus. Female offspring exposed to LPS in utero had increased corticosterone and testosterone and increased adrenal weight, but showed no effects on body composition and insulin sensitivity. Postnatal LPS exposition left male offspring unaffected whereas female offspring showed increased sensitivity to insulin, had increased muscle weight and decreased intraabdominal fat. Furthermore, they showed increased basal and stress-induced corticosterone levels. Increased basal ACTH levels and adrenal hypertrophy were also seen. LPS exposure is known to stimulate HPA axis with subsequent increased corticosterone secretion in rats. Female pups were exposed to corticosterone postnatally and the programming effects were examined in adulthood. Corticosterone-exposed animals were lean, had reduced food intake and low levels of leptin. Furthermore, as seen after postnatal LPS exposure, corticosterone-exposed animals showed increased sensitivity to insulin. They also had low basal and stress-induced corticosterone levels.To conclude, these results show in a rat model, that perinatal exposition to endotoxin or abnormal levels of hormones, may lead to long-lasting consequences for health in the adult offspring. Body composition, insulin sensitivity and neuroendocrine function are factors that can be programmed perinatally. Depending of timing of exposure and nature of exposure, the long-term outcome varies. A difference in sensitivity between genders also seems to prevail.