Extensive epidemiological and experimental evidence indicates that a sub-optimal environment during fetal and neonatal development in both humans and animals may programme offspring susceptibility to later development of chronic diseases including obesity and diabetes that are the result of altered carbohydrate metabolism. We determined the effects of protein restriction during pregnancy and/or lactation on growth, serum leptin, and glucose and insulin responses to a glucose tolerance test in male and female offspring at 110 days postnatal life. We fed Wistar rats a normal control 20% casein diet (C) or a restricted diet (R) of 10% casein during pregnancy. Female but not male R pups weighed less than C at birth. After delivery, mothers received the C or R diet during lactation to provide four offspring groups: CC (first letter maternal pregnancy diet and second maternal lactation diet), RR, CR and RC. All offspring were fed ad libitum with C diet after weaning. Relative food intake correlated inversely with weight. Offspring serum leptin correlated with body weight and relative, but not absolute, food intake in both male and female pups. Serum leptin was reduced in RR female pups compared with CC and increased in RC males compared with CC at 110 days of age. Offspring underwent a glucose tolerance test (GTT) at 110 days postnatal life. Female RR and CR offspring showed a lower insulin to glucose ratio than CC. At 110 days of age male RR and CR also showed some evidence of increased insulin sensitivity. Male but not female RC offspring showed evidence of insulin resistance compared with CC. Cholesterol was similar and triglycerides (TG) higher in male compared with female CC. Cholesterol and TG were higher in males than females in RR, CR and RC (P < 0.05). Cholesterol and TG did not differ between groups in females. Cholesterol and TG were elevated in RC compared with CC males. Nutrient restriction in lactation increased relative whole protein and decreased whole lipid in both males and females. RC females showed decreased relative levels of protein and increased fat. We conclude that maternal protein restriction during either pregnancy and/or lactation alters postnatal growth, appetitive behaviour, leptin physiology, TG and cholesterol concentrations and modifies glucose metabolism and insulin resistance in a sexand time window of exposure-specific manner.

Compelling epidemiological and experimental evidence indicates that a suboptimal environment during fetal and neonatal development in both humans and animals may programme offspring susceptibility to later development of several chronic diseases including obesity and diabetes in which altered carbohydrate metabolism plays a central role. One of the most interesting and significant features of developmental programming is the evidence from several studies that the adverse consequences of altered intrauterine environments can be passed transgenerationally from mother (F 0 ) to daughter (F 1 ) to second generation offspring (F 2 ). We determined whether when F 0 female rats are exposed to protein restriction during pregnancy and/or lactation their F 1 female pups deliver F 2 offspring with in vivo evidence of altered glucose and insulin metabolism. We fed F 0 virgin Wistar rats a normal control 20% casein diet (C) or a protein restricted isocaloric diet (R) containing 10% casein during pregnancy. F 1 female R pups weighed less than C at birth. After delivery, mothers received C or R diet during lactation to provide four F 1 offspring groups CC (first letter pregnancy diet and second lactation diet), RR, CR and RC. All F 1 female offspring were fed ad libitum with C diet after weaning and during their first pregnancy and lactation. As they grew female offspring (F 1 ) of RR and CR mothers exhibited low body weight and food intake with increased sensitivity to insulin during a glucose tolerance test at 110 days of postnatal life. Male F 2 CR offspring showed evidence of insulin resistance. In contrast RC F 2 females showed evidence of insulin resistance. Sex differences were also observed in F 2 offspring in resting glucose and insulin and insulin : glucose ratios. These sex differences also showed differences specific to stage of development time window. We conclude that maternal protein restriction adversely affects glucose and insulin metabolism of male and female F 2 offspring in a manner specific to sex and developmental time window during their mother's (the F 1 ) fetal and neonatal development.

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The effects of sex hormone-binding globulin (SHBG) on the secretion of human chorionic gonadotrophin (HCG) and cAMP by cultured human cytotrophoblasts were investigated. Cytotrophoblasts obtained from normal term placentae were cultured in serum-free medium with or without the addition of human SHBG. The presence of SHBG in the medium increased the release of HCG and the accumulation of cAMP. Ligand-free SHBG was able to raise both HCG and cAMP concentrations and the maximal response was observed with 1 nM of the steroid-binding globulin. Addition of either oestradiol or 5alpha-dihydro-testosterone (DHT) to cultures previously incubated with SHBG in a final molar ratio of 1:10 resulted in a further increase of HCG and cAMP concentrations. This effect was blocked when cultured placental cells were exposed to SHBG that was previously saturated with DHT or when incubated in the presence of steroids only. The results of the present study provide evidence for the in-vitro regulation of HCG secretion by SHBG and further support the concept that this steroid-binding protein may act as a mediator of steroid action at the cellular level. Finally, the increase in cAMP suggests that SHBG receptor located in the surface of syncytiotrophoblast membranes is coupled to adenylate cyclase as part of the G-protein receptor family. Our results may provide new insights into the biological implications of extracellular steroid-binding proteins as well as new perspectives on the endocrinology of pregnancy.