Diverse effects of mild and potent goitrogens on blood-brain barrier nutrient transport

Populations living in goitre endemic areas consume foods rich in a variety of goitrogens of different potencies and some are severely hypothyroid. Recently we observed in Wistar:NIN rats that chronic feeding of KSCN to dams produced only a moderate hypothyroidism and decreased the transport of 2-deoxy-D-glucose (2-DG) across the blood-brain barrier (BBB) in the offspring. The present studies were conducted to assess whether severe hypothyroidism would have greater effect on BBB nutrient transport. It has now been observed that weaning the pups of KSCN fed dams on to KSCN diet for four weeks had no further effect either on their thyroid status or the BBB 2-DG transport. However, feeding KSCN to rats through two generations produced somewhat severe hypothyroidism in F2 pups than that in F1 pups. Interestingly, unlike in F1 pups, the BBB transport of all the three nutrients tested (2-DG, Leu and Tyr) was significantly decreased in F2 pups, albeit to a small extent (10–15%). On the other hand the potent goitrogen: methyl mercaptoimidazole (MMI) even on short term feeding to pregnant dams produced very severe hypothyroidism in the offspring Serum T₄ :0.55±30.09 μg:dl vs 4.96±30.85 in controls . Surprisingly, the BBB transport of 2-DG, Leu, Tyr and also sucrose, the background marker, was significantly increased in these pups (20–30%). The diverse effects of goitrogen-induced moderate and severe hypothyroidism observed here on the BBB nutrient transport probably suggest different mechanisms for iodine deficiency disorders of different aetiologies and hence the need for discrete approaches for their management.     

Effect of maternal iron deficiency on GABA shunt pathway of developing rat brain

Iron deficiency during pregnancy and lactation (35 mg iron/kg diet) produced a significant reduction in liver nonheme iron in dams as well as in fetus and young ones. The body, liver and brain weights of fetus, new-born, and developing pups remained unaffected. However, the body weight and PCV were reduced only in 21-day-old pups. The enzyme activities of GDH, GAD, GABA-transaminase, and NAD(+)-linked ICDH were reduced in 14 and 21-day-old pups. The enzyme activities of NADP(+)-linked ICDH activities remained unaffected in the fetus and developing pups brain. Maternal rehabilitation on iron sufficient diet for 1 week from day 14 to 21 of lactation period did not reverse these changes. The maternal iron deficiency during lactation period alone did not cause any alteration in all parameters assayed, however, there was a reduction in liver non-heme iron of pups on days 14 and 21.     

Selective Alteration in Blood-Brain Barrier and Insulin Transport in Iron-Deficient Rats

Nutritional iron deficiency induced in rats causes a significant reduction in level of brain nonheme iron and is accompanied by selective reduction of dopamine D2 receptor Bmax. Our previous studies have clearly demonstrated that these alterations can be restored to normal by supplementation with ferrous sulfate; however, neither brain nonheme iron level nor dopamine D2 receptor Bmax can be increased beyond control values even after long-term iron therapy. The possibility that iron deficiency can induce the breakdown of the blood-brain barrier (BBB) was examined. A 70 and 100% increase in brain uptake index (BUI) for L-glucose and insulin, respectively, were noted in iron-deficient rats. However, the BUI for valine was decreased by 40%, and those for L-norepinephrine and glycine were unchanged. In addition, it was demonstrated that in normal rats insulin is transported into the brain. The data show that iron deficiency selectively affects the integrity of the BBB for insulin, glucose, and valine transport. Whether the effect of iron deficiency on the BBB is at the level of the capillary endothelial cell tight junction is not yet known. However, this study has shown that an important nutritional disorder (iron-deficiency anemia) has a profound effect on the BBB and brain function.     

Chronic maternal dietary iodine deficiency but not thiocyanate feeding affects maternal reproduction and postnatal performance of the rat

Iodine deficiency disorders affect reproductive performance in the afflicted populations. Environmental iodine deficiency (ID) and goitrogens are important in their aetiology. We observed earlier that chronic maternal dietary ID but not goitrogen feeding altered the blood-brain barrier nutrient transport in adult rats. Whether similar differences exist in their effects on reproduction of dams and postnatal performance of the offspring has been assessed. Inbred, female, weaning WNIN rats were rendered hypothyroid by feeding for 8-12 weeks, a low iodine test diet or a control diet with added potassium thiocyanate (KSCN) (@ 25 mg/rat/day). Following mating with control males, they continued on their respective diets till their pups were weaned. Indices of reproductive performance such as percentage of conception, mortality of dams during pregnancy and parturition, litter size, and survival of pups till weaning were affected markedly by ID but not thiocyanate feeding. Neither ID nor thiocyanate feeding from conception or parturition affected their reproductive performance. Nevertheless, postnatal weight gain of pups was less in all the three ID groups but not thiocyanate fed dams. Rehabilitation of chronically ID pregnant dams from conception or parturition did not improve their pregnancy weight gain, litter size or birth weight of pups but decreased abortion and mortality of mothers during pregnancy and parturition. Rehabilitation improved the pups' postnatal weight gain but the effect was only moderate. Based on the results of the present study it may be suggested that maternal ID but not thiocyanate feeding affects reproductive performance and postnatal performance of their offspring.     

Copper deficient rats and mice both develop anemia but only rats have lower plasma and brain iron levels

Iron homeostasis depends on adequate dietary copper but the mechanisms are unknown. Mice (Mus musculus) and rat (Rattus norvegicus) offspring were compared to determine the effect of dietary copper deficiency (Cu-) on iron status of plasma, liver, brain and intestine. Holtzman rat and Hsd:ICR (CD-1) outbred albino mouse dams were fed a Cu- diet and drank deionized water or Cu supplemented water. Offspring were sampled at time points between postnatal ages 13 and 32. Cu- rat and mouse pups were both anemic, but only rat pups had lower plasma and brain iron levels. Plasma iron was lower throughout the suckling period in Cu- rats but not Cu- mice. Cu- mice derived from dams restricted of Cu only during lactation were also severely anemic without hypoferremia. Intestinal metal analysis confirmed that Cu- pups had major reductions in intestinal concentration of Cu, increased Fe, and normal Zn. However, whole mouse (less the intestine) analysis demonstrated normal content of Fe indicating that the limitation in iron transport by intestinal hephaestin had no consequence to total iron reserves of the mouse. Further research will be needed to determine the reason Cu- mice were anemic since the "ferroxidase" hypothesis does not explain this phenotype.     

1,25-Dihydroxyvitamin D₃ contributes to regulating mammary calcium transport and modulates neonatal skeletal growth and turnover cooperatively with calcium

To assess the interaction of 1,25(OH)(2)D(3) and dietary calcium on mammary calcium transport in lactating dams and skeletal growth and turnover in the neonate, female lactating 1α(OH)ase(+/-) or 1α(OH)ase(-/-) mice were fed either a high-calcium diet containing 1.5% calcium in the drinking water or a "rescue diet." Dietary effects on the expression of molecules mediating mammary calcium transport were determined in the dams, and the effects of milk calcium content were assessed on skeletal growth and turnover in 2-wk-old 1,25(OH)(2)D(3)-deficient pups. Results showed that the reduction of milk calcium levels in the 1α(OH)ase(-/-) dams and the elevation of milk calcium levels in dams fed the rescue diet were associated with the down- or upregulation of calbindin D(9k) and plasma membrane Ca(2+) ATPase isoform 2b expression, respectively, in mammary epithelial cells. The action of ambient calcium in stimulating skeletal growth in the neonates appeared to supercede the direct action of 1,25(OH)(2)D(3), and the response of chondrocytes in the neonates to elevated calcium was more sensitive in hypocalcemic animals. Osteopenia was more apparent in pups nursed by dams with lower milk calcium than in 1,25(OH)(2)D(3)-deficient pups nursed by dams with higher milk calcium. Bone formation parameters were increased significantly in all pups fed by dams on the rescue diet but were still lower in 1α(OH)ase(-/-) pups than in 1α(OH)ase(+/-) pups. Consequently, there is an important contributory role of calcium in conjunction with 1,25(OH)(2)D(3) to mammary calcium transport in lactating dams and skeletal growth and turnover in the neonate.     

Maternal essential fatty acid deficiency depresses serum leptin levels in suckling rat pups

Dietary lipid quantity and quality have recently been shown to affect serum leptin levels in adult rats. Moreover, suckling pups from dams fed a high fat diet had increased serum leptin levels. The aim of the present study was to analyze the influence of essential fatty acid (EFA) deficiency on serum leptin levels in dams and their pups during the suckling period. For the last 10 days of gestation and throughout lactation, pregnant rats were fed a control or an EFA-deficient (EFAD) diet. The levels of leptin and EFA in the serum of the dams and pups were analyzed 1, 2, and 3 weeks after delivery. In parallel, serum levels of glucose and corticosterone were analyzed in the pups. Low serum leptin levels were found in the control lactating dams during the entire lactation period compared with the age-matched nonlactating animals. The leptin concentrations in the lactating dams fed the EFAD diet were lower compared with those fed the control diet. The serum leptin levels of suckling pups from dams on the EFAD diet were markedly decreased compared with controls (P < 0.05). The reduced serum leptin levels could not be explained by nutritional restriction as evaluated by serum levels of glucose and corticosterone. These results indicate the importance of the EFA composition of the maternal diet for serum leptin levels in both dams and pups. EFA deficiency in lactating dams may cause long-term effects on the pups through dysregulation of leptin and leptin-dependent functions. -- Korotkova, M., B. Gabrielsson, L. A. Hanson, and B. Strandvik. Maternal essential fatty acid deficiency depresses serum leptin levels in suckling rat pups. J. Lipid Res. 2001. 42: 359--365.     

EFFECTS OF N-METHYLAMINOETHANOL, AND N,N-DIMETHYL-AMINOETHANOL IN THE DIET OF PREGNANT RATS ON NEONATAL RAT BRAIN CHOLINERGIC AND PHOSPHOLIPID PROFILE

Abstract— Pregnant rats were fed for 15 days predelivery until 15 days postpartum a choline (Ch)-deficient diet (CD diet) or a CD diet supplemented with 0.8% Ch-CI (CS), 1% N -methylaminoethanol (MME) or 1% N,N -dimethylaminoethanol (DME). Gestation and parturition of the pregnant rats proceeded normally. However, all the pups born of dams fed the MME diet, and most of those born of dams fed the DME diet, died within 36 h of birth. No histological or cytological alterations were detected in the brain of the pups. Levels of Ch and acetylcholine (ACh) were elevated in the brain of pups born of dams fed the MME and DME diets, but not the CS diet. The content of total phospholipids in the brain of the pups was not altered by the diet fed to the dams. However, the phosphatidyl-Ch and phosphatidylaminoethanol (PAE) contents in the brain of the MME- and DME-exposed pups were markedly reduced. At the same time, significant amounts of DME, phosphatidyl-N-monomethylaminoethanol (PMME) and of phosphatidyl- N,N -dimethylaminoethanol (PDME) were present in the same brain areas. These results are evaluated and discussed in terms of providing a cause for the death of the MME- and DME-exposed neonatal rats.     

Effects of marginal zinc deficiency on microtubule polymerization in the developing rat brain

One of the possible mechanisms that has been proposed to underlie the deleterious effects of zinc deficiency on brain development is an impairment in the normal formation of the cytoskeletal network. In the current study, in vivo microtubule polymerization was characterized in brain supernatant fluids, from 20-d-old pups whose dams were fed diets containing control (50 micrograms zinc/g) or marginal levels of zinc (10 micrograms zinc/g) throughout pregnancy and lactation. Pup brain and body weights were similar between the groups; however, plasma zinc concentrations were lower (27%) in pups fed the marginal zinc diet than in controls. Tubulin concentrations in 100,000 g brain supernates were similar between the groups; however, tubulin polymerization in the brain supernates was significantly lower in pups fed the marginal zinc diet compared to controls. Primarily, the early events of polymerization were affected; the lag period of the reaction was doubled, and the initial velocity was slower (26%) in supernates from pups fed the marginal zinc diet than in controls. These findings support the idea that some of the negative effects of marginal zinc deficiency on brain development and function may be mediated by an alteration in microtubule formation.     

Spatial memory deficits in maternal iron deficiency paradigms are associated with altered glucocorticoid levels

"The goal of this study was to examine the effect of maternal iron deficiency on the developing hippocampus in order to define a developmental window for this effect, and to see whether iron deficiency causes changes in glucocorticoid levels. The study was carried out using pre-natal, post-natal, and pre + post-natal iron deficiency paradigm. Iron deficient pregnant dams and their pups displayed elevated corticosterone which, in turn, differentially affected glucocorticoid receptor (GR) expression in the CA1 and the dentate gyrus. Brain Derived Neurotrophic Factor (BDNF) was reduced in the hippocampi of pups following elevated corticosterone levels. Reduced neurogenesis at P7 was seen in pups born to iron deficient mothers, and these pups had reduced numbers of hippocampal pyramidal and granule cells as adults. Hippocampal subdivision volumes also were altered. The structural and molecular defects in the pups were correlated with radial arm maze performance; reference memory function was especially affected. Pups from dams that were iron deficient throughout pregnancy and lactation displayed the complete spectrum of defects, while pups from dams that were iron deficient only during pregnancy or during lactation displayed subsets of defects. These findings show that maternal iron deficiency is associated with altered levels of corticosterone and GR expression, and with spatial memory deficits in their pups."     

Dopamine receptor D2 deficiency reduces mouse pup ultrasonic vocalizations and maternal responsiveness

Dopamine signalling facilitates motivated behaviours, and the D2 dopamine receptor (D2R) is important in mother–infant interactions. D2R antagonists disrupt maternal behaviour and, in isolated rat pups, reduce ultrasonic vocalizations (USVs) that promote maternal interaction. Here, we examined the effects of genetic D2R signalling deficiency on pup‐dam interaction with Drd2 knockout (D2R KO) mice. Using heterozygous (HET) cross littermates, the effect of pup genotype on isolation‐induced USVs was quantified. Independent of parental genotype, D2R‐deficient pups emitted fewer USVs than wild type (WT) littermates in a gene dose‐dependent manner. Using reciprocal D2R KO‐WT crosses, we examined how parental genotype affects pup USVs. Heterozygous pups from D2R KO dams produced fewer USVs than HET pups from WT dams. Also, exposure to USV‐emitting pups increased plasma prolactin levels in WT dams but not in D2R KO dams, and KO dams showed delayed pup retrieval and nest building. These findings indicate the importance of the interaction between pup and dam genotypes on behaviour and further support the role of D2R signalling in maternal care.     

Multiple mechanisms account for lower plasma iron in young copper deficient rats

Copper deficiency lowers brain copper and iron during development. The reduced iron content could be due to hypoferremia. Experiments were conducted to evaluate plasma iron and “ferroxidase” hypotheses by determining copper and iron status of Holtzman albino rats following gestational/lactational copper deficiency. Copper deficient (Cu−) dams on treatment for 5 weeks, two of gestation and three of lactation, had markedly lower copper content of milk and mammary tissue, and lower milk iron. Newborn pups from Cu− dams had lower copper and iron concentrations. Compared to Cu+ pups, Cu− pups, analyzed between postnatal age (P) 0 and P26, were smaller, anemic, had lower plasma iron, cardiac hypertrophy, and near zero ceruloplasmin activity. Liver copper in Cu+ pups increased then decreased during development and major reductions were evident in Cu− pups. Liver iron in Cu+ pups decreased with age while nursing but increased after eating solid food. Liver iron was lower in Cu− pups at P0 and P13 and normal at P20 and P26. Small intestinal copper decreased with age in Cu+ pups and was lower in Cu− pups. Intestinal iron levels in Cu− pups were higher than Cu+ pups postweaning in some experiments. Reduction in plasma iron in Cu− pups is likely due to a decreased “ferroxidase” function leading to lower placental iron transport, a lower milk iron diet, and partial block in iron uptake from intestine but is not due to failure to mobilize hepatic iron, in contrast to older rats eating diet with adequate iron.     

Transfer of iodine through the milk in protein-restricted lactating rats

Iodine supply is important to avoid neonatal hypothyroidism. This study evaluated whether protein restriction during lactation affects iodine transfer to the pups through the milk. We studied lactating rats fed an 8% protein-restricted diet (PR), a control 23% protein diet (C), and an energy-restricted diet group (ER). On days 4, 12 and 21, mothers were separated from their pups for 4 h, injected with (131)I IP, and put together with their pups. The animals were killed 2 h later. PR pups had a significant decrease in iodine uptake in the gastric content and duodenal mucosa on the 4th day. On the contrary, at 12 and 21 days radioiodine was increased in the gastric content and in the duodenal mucosa. ER pups had an increase in iodine uptake in the gastric content and in the duodenal mucosa only at the end of lactation. The thyroid iodine uptake in PR pups was significantly decreased on the 4th day and significantly increased on the 21st day compared to control. When injected IP with an equivalent amount of (131)I, the PR pups had a decrease in thyroid iodine uptake on the 4th and 12th day, while ER pups had no significant changes. So, these data suggest that protein restriction during lactation was associated with lower iodine secretion into the milk in the beginning of lactation. However, at the end of lactation, an adaptation process seems to occur leading to a higher transfer of iodine through the milk that compensates the impairment of thyroid iodine uptake in these pups.     

Carnitine depletion in rat pups from mothers given mildronate: a model of carnitine deficiency in late fetal and neonatal life

Mildronate (3-(2,2,2,-trimethylhydrazinium)propionate), is a butyrobetaine analogue that is known to inhibit gamma-butyrobetaine hydroxylase, the enzyme catalyzing the last step of carnitine biosynthesis. When administered to adult rats it determines a systemic carnitine deficiency and may therefore serve as an animal model for human carnitine depletion. The aim of this study was to evaluate the effect of mildronate administration to pregnant and lactating rats on tissue carnitine concentrations in 4- and 13-day-old rat pups. At 14 days of gestation female rats began to receive mildronate in the diet (200 mg/kg/d) and this continued for entire lactation period. Mildronate treatment determined a large reduction of carnitine levels in the milk of lactating dams. Because organ carnitine concentrations in neonatal rats are directly related to dietary supply, pups from mildronate group had significantly depleted levels of total carnitine in serum, heart, liver, muscle, brain and pancreas relative to controls, at 4 and 13 days of age. Correspondingly, an increase in triglyceride levels was observed in liver, heart and muscle of mildronate pups. This is in agreement with a reduction of basal rate of oxidation of [U-(14)C]-palmitate to (14)CO(2) and (14)C-acid-soluble products observed in liver homogenates from carnitine-deficient pups. All functional and biochemical modifications were compatible with a carnitine deficiency status. In conclusion our results describe a model of carnitine depletion in pups, suitable for the investigation of carnitine deficiency in fetal-neonatal nutrition, without any concomitant mildronate-mediated metabolic alterations.     

Oxytocin-induced parturition in copper-deficient guinea pigs.

Dietary copper-deficient guinea pig dams (0.8 microgram Cu/g diet) were administered oxytocin to induce delivery of pups, whereas dietary copper-sufficient guinea pig dams (5.8 micrograms Cu/g diet) had uneventful deliveries with 79% surviving pups. The copper-deficient dams carried the fully-formed fetuses to term but did not go into labor unless 0.5 to 6.2 U oxytocin was administered (i.m.). Birth of live pups from copper-deficient dams increased from 28% overall, to 50% if oxytocin was administered in a timely manner. Many pups died of internal hemorrhages probably the result of defective connective tissue crosslinks requiring copper as a co-factor for lysyl oxidase activity. Dietary copper deficiency may be a factor in depressed parturition in the copper-deficient guinea pig dam that responds to administration of exogenous oxytocin for delivery of pups.     

Maternal zinc deficiency reduces NMDA receptor expression in neonatal rat brain, which persists into early adulthood

Prenatal and early postnatal zinc deficiency impairs learning and memory and these deficits persist into adulthood. A key modulator in this process may be the NMDA receptor; however, effects of zinc deficiency on the regulation of NMDA receptor activity are not well understood. Female Sprague-Dawley rats were fed diets containing 7 (zinc deficient, ZD), 10 (marginally zinc deficient, MZD) or 25 (control) mg Zn/g diet preconception through postnatal day (PN) 20, at which time pups were weaned onto their maternal or control diet. Regulation of NMDA receptor expression was examined at PN2, PN11, and PN65. At PN2, expression of whole brain NMDA receptor subunits NR1, NR2A, and NR2B was lower in pups from dams fed ZD and MZD compared to controls, as analyzed using relative RT-PCR and immunoblotting. At PN11, whole brain and hippocampi NR1, NR2A, NR2B and PSA-NCAM (polysialic acid-neural cell adhesion molecule) expression and the number of PSA-NCAM immunoreactive cells were lower in pups from dams fed ZD compared to controls. Whole brain brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) concentrations were lower in pups from dams fed ZD or both low zinc diets, respectively. Whole brain NR1 expression remained lower in previously zinc-deficient rats at PN65. These data indicate potential mechanisms through which developmental zinc deficiency can impair learning and memory later in life.     

Effects of maternal marginal zinc deficiency on myelin protein profiles in the suckling rat and infant rhesus monkey

In the current study, the effects of marginal Zn deficiency on myelin protein profiles in neonatal rats and rhesus monkeys were investigated. Following mating, rats were fed a Zn-adequate diet,ad libitum (50 μg Zn/g; 50 Zn AL), or a marginal Zn diet (10 μg Zn/g) from day 0 (10 Zn d0) or day 14 (10 Zn d14) of gestation to day 20 postnatal. An additional group of dams was restricted-fed the control diet to the food intake of the 10 Zn d0 group (50 Zn RF). Day 20 pup plasma and liver Zn concentrations in the 10 Zn groups were lower than in the 50 Zn groups. In a parallel experiment, rhesus monkeys were fed a Zn-adequatead libitum diet (100 μg Zn/g) or a marginal Zn diet (4 μg Zn/g diet; MZD) throughout gestation and lactation. Day 30 monkey infant plasma and liver Zn levels were similar in the MZD and control groups. Rat brain and monkey brain cortex weights were similar among the dietary groups. The amount of myelin recovered (mg protein/g brain) from day 20 rat pups from the 10 Zn groups was lower than that recovered from the 50 Zn rat pups. Myelin recovery from the MZD and control monkey infants was similar. When myelin protein profiles were characterized, it was found that the percentages of high-molecular-weight (HMW) proteins and Wolfgram protein were higher, whereas the percentages of small and large basic proteins were lower in myelin from the 10 Zn d0 and 50 Zn RF pups compared to the distribution in the 50 Zn AL rat pups. Results for the 10 Zn d0 and 10 Zn d14 pups were similar for all of the parameters studied. The percentage of HMW proteins was higher and that of basic protein lower in myelin from MZD monkey infants compared to the percentage of these proteins in myelin from controls. Although the interpretation of the rat data is complicated because of the anorexia associated with the Zn deficiency, the observed changes in monkey myelin protein profiles provide strong evidence that maternal Zn deficiency affects myelination in the offspring.     

Maternal treatment with oleoyl-estrone induces resistance to lipid accrual in their descendants

Objective: To determine whether treatment of rat dams with oleoyl‐estrone (OE) has an effect on the offspring's long‐term response to diet restriction during lactation. Methods and Procedures: Control, OE‐treated, and diet‐restricted dams were treated up to day 15 of lactation. Changes in food intake and body weight were recorded for dams and their pups. After weaning, pups received a 4‐week standard diet followed by a 4‐week period of high‐fat diet. Lipid, protein, and energy content of pups plus energy intake and efficiency. Serum metabolites (glucose, urea, and cholesterol) and serum hormones (adiponectin, leptin, insulin, and sexual hormones). Results: Neither pups from dams in the OE‐treated nor in the diet‐restricted group showed significant changes in weight, though these two groups ingested 79% of food ingested by controls. At weaning, the pups from OE‐treated rats were smaller than those of the control or diet‐restricted groups. These pups maintained the differences in size and lipid content during the 4‐week standard‐diet period, whereas pups from diet‐restricted dams showed a sharp decrease in their lipid content. During the 4 weeks of high‐fat diet, the male offspring from OE‐treated dams increased the difference in lipid content in relation to the pups from control dams whereas in females the differences decreased. Female offspring from diet‐restricted dams showed the most marked changes in metabolite and hormone levels in relation to controls. Discussion: Treatment of lactating dams with OE programs the metabolic response of their offspring to resist the challenge of a high‐fat diet that would lead to obesity in adulthood.     

Chronic maternal calcium and 25-hydroxyvitamin D deficiency in Wistar rats programs abnormal hepatic gene expression leading to hepatic steatosis in female offspring

Importance of calcium and vitamin D deficiency is well established in adult dyslipidemia. We hypothesized that maternal calcium and vitamin D deficiency could alter offspring's lipid metabolism. Our objective was to investigate the effect of maternal dietary calcium and vitamin D deficiency on lipid metabolism and liver function of the F1 generation offspring. intergenerational calcium-deficient (CaD) and vitamin D-deficient (VDD) models were developed by mating normal male rats with deficient females and continuing maternal-deficient diets through pregnancy and lactation. Offspring were fed on control diet post-weaning and studied till 30 weeks. Lipid profile, serum glutamate pyruvate transaminase (SGPT), calcium and vitamin D levels were analyzed. Liver fat deposition, omega-3 fatty acids level and mRNA expression levels of peroxisome proliferator-activated receptor-alpha (PPAR-α), sterol regulatory element-binding protein 1c (SREBP-1c), interleukin 6 (IL-6), superoxide dismutase 1 (SOD-1) and uncoupling protein 2 (UCP2) were determined. Low serum vitamin D levels with an increase in SGPT and TG levels in CaD and VDD female offspring were observed. Severe liver steatosis with down-regulation of PPAR-α and UCP2 and up-regulation of SREBP-1c, IL-6 and SOD-1 was observed in the female offspring born to deficient dams. CaD and VDD male offspring showed mild steatosis and down-regulation of UCP2 and SOD-1. We conclude that maternal calcium and vitamin D deficiency programs abnormal lipid metabolism and hepatic gene expression in the F1 generation female offspring leading to hepatic steatosis, despite feeding them on control diet post-weaning.     

Circulating leptin levels in newborn rats: a significant post- natal developmental effect,independent of dietary polyunsaturated fat levels

Leptin expression exhibits developmental and dietary regulation, but it is unknown whether there is an interaction of the regulation by dietary fat and postnatal development. The purpose of this study was to test the effect of different levels of dietary polyunsaturated fat on circulating leptin levels at different post-natal developmental stages. Pregnant (Sprague-Dawley) rats consumed from day 15 of pregnancy through day 9 of lactation a low fat, (11% of energy; LF) polyunsaturated safflower oil diet. From day 9 of lactation, dams and their respective pups were fed low, moderate (40% of energy; MF) or high (67% of energy; HF) polyunsaturated safflower oil diets to full maturation (56 days). Diets were iso-energetic and iso-nitrogenous. Milk fatty acid content reflected the mothers and pups diet, with 15 to 100 fold less C10:0 and 2.6 to 3.3 fold more C18:2 in MF and HF groups compared to LF diet. In newborn rats through post-natal day 56, levels of polyunsaturated fat in mothers' milk and mothers/pups diet had no effect on the levels of circulating leptin. The post-natal development period significantly affected circulating leptin levels (p < 0.001, 15 days = 56 days > 21 days > 28 days). In summary, the developmental postnatal stage regulates leptin levels, independently of the polyunsaturated fat levels in the diet.