Sex differences in transgenerational alterations of growth and metabolism in progeny (F₂) of female offspring (F₁) of rats fed a low protein diet during pregnancy and lactation

Abstract

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.

Transgenerational epigenetic effects of the endocrine disruptor vinclozolin on pregnancies and female adult onset disease

“…These results support the findings of a transgenerational epigenetic disease phenotype in animals exposed during embryonic gonadal development to the environmental toxicant vinclozolin (Anway et al 2005, 2006a, 2006b, Chang et al 2006. These findings also are consistent with the hypothesis that the multi-generational effects of exposure to diethylstilbestrol, dexamethasone, or caloric restriction during pregnancy (Blatt et al 2003, Drake et al 2005, Zambrano et al 2005) are in part due to epigenetic alterations. The ability of an environmental toxicant to promote a variety of different disease states for multiple generations supports the idea that a novel mechanism for disease etiology exists involving epigenetic transmission.…”

“…The fetal basis of adult onset disease has been well documented (Gluckman & Hanson 2004, Reynolds et al 2007, but the molecular mechanisms involved are poorly understood and do not appear to involve DNA sequence mutations. In addition to environmental compound exposure, caloric restriction during pregnancy (Zambrano et al 2005) and fetal exposure to diethylstilbestrol or dexamethasone (Blatt et al 2003, Drake et al 2005 can cause abnormalities in the F1 and F2 generations. Both the F1 generation embryo and F2 generation germ line are directly exposed when an F0 generation pregnant mother is exposed.…”

Sexual dimorphism in environmental epigenetic programming

“…In rats, feeding a diet rich in lard to pregnant females leads to gender-related cardiovascular dysfunction in normally fed offspring as blood pressure was found to be high in the female but not in the male offspring [72]. A maternal low-protein diet (LPD) during pregnancy and lactation modifies the growth and metabolism of the progeny (F2) of the female offspring (F1) [73,74]. Maternal undernutrition, restricted to the preimplantation period in rat development, causes blastocyst abnormalities and the programming of postnatal hypertension.…”

Decreased basal insulin secretion from pancreatic islets of pups in a rat model of maternal obesity

“…the degree and type of metabolic alteration observed across tissues and species (McCormick et al 1995, Zambrano et al 2005. The sex differences in the effects of MO on beta cells may be partially related to increases in oxidative stress in male islets (Plata et al 2014) and protection by estrogens (estradiol) in female pancreatic tissue, as shown by Yokomizo and colleagues (2014).…”