Iron deficiency during pregnancy and lactation modifies the fatty acid composition of the brain of neonatal rats.

Iron deficiency is common in pregnant and lactating women and is associated with reduced cognitive development of the offspring. Since iron affects lipid metabolism, the availability of fatty acids, particularly the polyunsaturated fatty acids required for early neural development, was investigated in the offspring of female rats fed iron-deficient diets during gestation and lactation. Subsequent to the dams giving birth, one group of iron-deficient dams was recuperated by feeding an iron-replete diet. Dams and neonates were killed on postnatal days 1, 3 and 10, and the fatty acid composition of brain and stomach contents was assessed by gas chromatography. Changes in the fatty acid profile on day 3 became more pronounced on day 10 with a decrease in the proportion of saturated fatty acids and a compensatory increase in monounsaturated fatty acids. Long-chain polyunsaturated fatty acids in the n-6 family were reduced, but there was no change in the n-3 family. The fatty acid profiles of neonatal brain and stomach contents were similar, suggesting that the change in milk composition may be related to the changes in the neonatal brain. When the dams were fed an iron-sufficient diet at birth, the effects of iron deficiency on the fatty acid composition of lipids in both dam's milk and neonates' brains were reduced. This study showed an interaction between maternal iron status and fatty acid composition of the offspring's brain and suggests that these effects can be reduced by iron repletion of the dam's diet at birth.

Dietary iron absorption during early postnatal life.

Inadequate iron levels during early life can have adverse consequences for the developing infant. Iron deficiency during this critical period of growth can affect brain development and cognitive function, problems that can be lifelong despite subsequent correction of the iron deficit. Therefore, it is critical that the suckling infant has sufficient iron for their developmental needs. Much of the iron used in the immediate post-natal period is stored iron that was acquired from the mother in the final trimester of pregnancy, however, despite having low iron levels, breast milk can also make a significant contribution to infant iron needs. This reflects the ability of the suckling infant to absorb dietary iron far more efficiently than is possible after weaning. The mechanisms underlying this enhanced iron absorption are poorly understood. The iron export protein ferroportin is essential for this process, as it is in adults, however, the role of other molecules normally involved in iron absorption following weaning is less clear. The composition and distribution of iron in breast milk may be important, as could the contribution of more distal parts of the gastrointestinal tract. This review discusses the potential role of each of the above components in intestinal iron absorption during suckling and highlights the need for further research into this important process.

Gestation and breastfeeding in schistosomotic mice differentially alters the expression of histone deacetylases (HDACs) in adult offspring

BACKGROUND Breastfeeding or gestation in schistosomotic mothers can cause long-term alterations in the immune response of offspring. OBJECTIVES Evaluate the expression of histone deacetylases (HDACs) (all classes), the production of cytokines by T and B lymphocytes and macrophages, and the frequency of CD4+CD25+FoxP3+-cells in adult offspring born and/or suckled by schistosomotic mothers. METHODS We harvested splenocytes from offspring born to (BIM), suckled by (SIM), or born to/suckled by (BSIM) schistosomotic mothers and animals from noninfected mothers (Control) at seven-weeks old and cultured them with/without Concanavalin A. HDAC expression was evaluated by real-time quantitative polymerase chain reaction (qPCR), and cytokines and membrane markers were evaluated by fluorescence-activated cell sorting (FACS). FINDINGS Compared to Control, BIM mice showed increased expression of HDAC9 and frequency of CD4+IL-10+-cells. The SIM group had increased expression of HDAC1, HDAC2, HDAC6, HDAC7, HDAC10, Sirt2, Sirt5, Sirt6, and Sirt7. The BSIM group only had increased HDAC10 expression. The SIM and BSIM groups exhibited decreased frequencies of CD4+IL-4+-cells and CD4+CD25+FoxP3+-cells, along with a higher frequency of CD14+IL-10+-cells and an increase in CD45R/B220+IL-10+-cells. The BSIM group also showed a high frequency of CD4+IL10+-cells. MAIN CONCLUSIONS Breastfeeding induced the expression of HDACs from various classes involved in reducing inflammatory responses. However, gestation enhanced the expression of a single HDAC and breastfeeding or gestation appears to favour multiple IL-10-dependent pathways, but not cells with a regulatory phenotype.

N-acetylcysteine attenuates intrauterine growth retardation-induced hepatic damage in suckling piglets by improving glutathione synthesis and cellular homeostasis.

PURPOSE: The objective of the present study was to test the hypothesis that N-acetylcysteine (NAC) may play beneficial roles against intrauterine growth retardation (IUGR)-induced hepatic damage in suckling piglets. METHODS: Fourteen IUGR and seven normal birth weight (NBW) neonatal male piglets were selected. Piglets were weaned at 7 days of postnatal age and fed the control formula milk (NBW-CON and IUGR-CON groups) or the control formula milk supplemented with 1.2 g/kg NAC (IUGR-NAC group) for 14 days (n = 7). The plasma and liver samples were analyzed for the parameters related to hepatic damage, redox status, apoptosis, and autophagy. RESULTS: Compared with the NBW-CON group, IUGR-CON group exhibited increased activities of plasma aminotransferases, increased numbers of apoptotic hepatocytes, as well as higher concentrations of protein carbonyl, malondialdehyde (MDA), microtubule-associated protein 1 light chain 3 beta, and phospholipid-conjugated form (MAP1LC3B-II), along with a decrease in the content of reduced glutathione (GSH). NAC treatment increased GSH content and GSH-to-oxidized GSH ratio in the liver of IUGR-NAC group, most likely owing to the improved activities of γ-glutamine-cysteine ligase, γ-glutamine-cysteine synthetase, and glutathione reductase. The hepatic protein carbonyl and MDA contents were decreased in the IUGR-NAC group compared with the IUGR-CON group. In addition, NAC-treated piglets had an increased content of B cell lymphoma/leukemia 2 protein, whereas a decreased expression level of MAP1LC3B-II in the liver. CONCLUSIONS: NAC may have beneficial effects in improving GSH synthesis and cellular homeostasis in the liver of IUGR suckling piglets.

Perfil bioquímico sérico de bezerros de origem leiteira aleitados com dietas líquidas alternativas / Serum biochemistry profile of dairy calves fed with alternative liquid diets

O perfil metabólico é utilizado como monitoramento rotineiro para o diagnóstico de transtornos metabólicos, deficiências nutricionais e como preventivo de transtornos subclínicos, além da pesquisa de problemas de saúde e de desempenho de um rebanho. Neste contexto, o objetivo do presente trabalho foi avaliar a influência de diferentes dietas líquidas contendo soro de queijo e colostro sobre os perfis dos metabólitos séricos de bezerros durante a fase de aleitamento. Foram utilizados 24 bezerros mestiços provenientes de rebanhos leiteiros da região, distribuídos em delineamento inteiramente casualizado com três tratamentos e oito repetições: LI = Leite integral (controle); LS = 50% Leite integral + 50% de Soro de queijo in natura; SC = 70% de Soro de queijo in natura + 30% Colostro. Semanalmente foram coletadas amostras de sangue por punção jugular externa, no período da manhã, antes do fornecimento da dieta líquida e duas horas após a ingestão desta. As concentrações dos parâmetros séricos avaliados diferiram entre os tratamentos, porém sem comprometer o desempenho dos animais. Desse modo, a utilização de soro de queijo associado ao colostro apresenta-se como forma viável de redução de custos com aleitamento de bezerros, visto que possíveis déficits causados pelas diferenças nutricionais das dietas líquidas são supridos pelos alimentos sólidos, não afetando os perfis dos metabólitos séricos relacionados ao status protéico e energético.(AU)

Metabolic profile is used as routine monitoring for the diagnosis of metabolic disorders, nutritional deficiencies, and as a preventive of subclinical disorders, in addition to research health issues and performance of a herd. In this context, the aim of this study was to evaluate the influence of different liquid diets containing whey cheese and colostrum on the serum biochemistry profile of calves. Twenty-four crossbred calves from dairy herds in the region, distributed in a completely randomized design with three treatments and eight replicates: LI = Whole milk (control); LS = 50% Whole milk + 50% cheese whey in nature; SC = 70% of cheese whey in natura + 30% Colostrum. Weekly blood samples by jugular puncture were collected in the morning, before the supply of liquid diet and two hours after eating this. The serum concentrations of the evaluated parameters differ between treatments, but without compromising animal performance. Thus, the use of whey associated with colostrum presents itself as a viable cost reduction with feeding calves, since possible nutritional deficits caused by differences in liquid diets are supplied by solid food form, not affecting the profiles of the metabolites related to serum protein and energy status.(AU)

Caracterización del metabolismo óseo mineral en pacientes con enfermedad renal crónica en hemodiálisis en el Servicio de Salud Metropolitano Sur, Santiago de Chile / Bone mineral metabolism in patients with chronic kidney disease on dialysis in Southern Metropolitan Santiago

Background: Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) is a condition of dialysis patients associated with both morbidity and mortality. Management is based on clinical guidelines with goals that are hard to comply with. Aim: To describe and compare biochemical variables associated with this disorder in two different time periods. Material and Methods: Revision of medical records of 814 patients (49% females) dialyzed during 2009 and 1018 patients (48% females), dialyzed during 2012 in Southern Metropolitan Santiago. Information about serum calcium, phosphorus, parathyroid hormone (PTH) and albumin was retrieved. Results: Median PTH values in 2009 and 2012 were 222.5 and 353.5 pg/ml respectively (p < 0.05). The figures for serum calcium corrected by albumin were 9.0 and 8.5 mg/dl respectively (p < 0.05). The figures for phosphorus were 4.7 and 5.0 mg/dl respectively (p < 0.05). The Calcium x Phosphorus product was 41.4 and 42.5 mg²/dl² (p < 0.05). Of note, the proportion patients with serum calcium below recommended levels (< 8.4 mg/dl) increased from 16% to 40% from 2009 to 2012. The proportion of patients with biochemical variables within recommended ranges was lower in 2012 than in 2009. Conclusions: There was a low proportion of patients with bone metabolism parameters within ranges recommended by clinical guidelines. These parameters were worst in 2012.

Effect of phytate reduction of sorghum, through genetic modification, on iron and zinc availability as assessed by an in vitro dialysability bioaccessibility assay, Caco-2 cell uptake assay, and suckling rat pup absorption model.

Improved iron and zinc availability from sorghum, a commonly consumed staple, will benefit many malnourished communities in rural Africa burdened with high prevalence of iron and zinc deficiency. This research compared the effect of genetic phytate reduction in sorghum on iron and zinc bioaccessibility and uptake measured by in vitro dialysability and Caco-2 cell uptake assays to that of iron and zinc absorption measured by a suckling rat pup model. The phytate reduction (80-86%) in these sorghums significantly increased zinc availability. The Caco-2 cell method, but not the dialysability assay, proved useful in estimating zinc absorption. The measured increase in iron availability differed between the methods, possibly due to the effect of varying mineral (Ca, Fe, Zn, P) contents of the sorghums. This effect was most prominent in the iron uptake results. More research is needed to determine the effect of naturally occurring variations in mineral contents of sorghum on the iron uptake by Caco-2 cells.

Contribution of FcRn binding to intestinal uptake of IgG in suckling rat pups and human FcRn-transgenic mice.

Immunoglobulin G (IgG) is transcytosed across intestinal epithelial cells of suckling mammals by the neonatal Fc receptor (FcRn); however, the contribution of FcRn vs. FcRn-independent uptake to serum IgG levels had not been determined in either rat pups or human (h)FcRn-expressing mice (Tg276 and Tg32). In isoflurane-anesthetized rodents, serum levels were determined after regional intestinal delivery of human monoclonal antibodies (hIgG) with either wild-type (WT) Fc sequences or variants engineered for different FcRn binding affinities. Detection of full-length hIgG was by immunoassay; intestinal hFcRn and hIgG localization was by immunocytochemistry. High (µg/ml) serum levels of hIgG were detected after proximal intestinal delivery (0.1-10 mg/kg) in 2-wk-old rats. Human FcRn was visualized in epithelial cells of Tg276 mice, but low serum hIgG levels (<10 ng/ml) were obtained. In rat pups, intraintestinal hIgG1 WT administration resulted in dose-related and saturable uptake, whereas uptake of a low FcRn-binding affinity variant was nonsaturable. There were no differences in hIgG levels from systemic and hepatic portal vein serum samples, and intense hIgG immunostaining was noted in villi enterocytes and within lymphatic lacteal-like vessels. This study demonstrated that FcRn-mediated uptake in rat pups accounted for ~80% of serum hIgG levels and that IgG enters the circulation via the lymph and not the hepatic portal vein. The remaining uptake though the immature intestine is nonreceptor mediated. Intestinal epithelial cell hFcRn expression occurred in Tg276 mice, but receptor-mediated transport of IgG was not observed. The suckling rat pup intestine is a mechanistic model of FcRn-IgG-mediated transcytosis.

Depletion of glutathione does not affect electron transport chain complex activity in brain mitochondria: Implications for Parkinson disease and postmortem studies.

Glutathione is an important antioxidant in the brain that appears to be decreased, in conjunction with mitochondrial complex I activity, in Parkinson disease patients. In postmortem analysis, measurement of glutathione levels and complex I activity can be delayed up to 20h. We investigated whether depletion of glutathione in the preweanling rat induces a reduction in complex I activity in brain mitochondria and the effects that postmortem delay has on glutathione levels and electron transport chain activity. After injection with the glutamate-cysteine ligase inhibitor, buthionine sulfoximine (L-BSO), glutathione levels were decreased by 53% compared to the control values in whole-brain homogenates. During postmortem delay of 24h, in which animals were kept at 4°C, the levels of glutathione decreased in the control group by 58% and in the L-BSO-treated group by 79%. However, during this period, there were no changes in mitochondrial electron transport chain complex I, II-III, or IV activity in either group. These results suggest that a preexisting deficiency of glutathione or a loss of glutathione during postmortem delay does not influence mitochondrial respiratory chain activity in the brain.

Efeitos da dieta rica em linhaça na lactação sobre a composição corporal e função tireóidea da prole na idade adulta / Effects of maternal flaxseed diet during lactation on body composition and thyroid function in adult animals

A Linhaça (Linum Usitatissimum) apresenta diversas substâncias com alegados efeitos benéficos que favorecem a diminuição da adiposidade, glicemia e melhoram o perfil lipidêmico e o sistema cardiovascular. Neste trabalho, investigamos na prole 21 e 180 dias de vida o efeito do consumo materno da semente de linhaça durante a lactação sobre os parâmetros associados a composição corporal, a homeostase glicêmica, lipídica e protéica, a leptinemia, adiponectinemia e insulinemia, a função tireoideana e a via de sinalização da leptina no eixo hipotálamo-hipófise-tireóide. As ratas lactantes foram separadas em dois grupos: controle (C) - recebendo ração a base de caseína (20%) e linhaça (L) - recebendo ração adicionada de 25% da semente de linhaça, contendo 18,9% de proteína (sendo 13,9% de caseína e 5% de linhaça) durante a lactação. O sacrifício das proles ocorreu aos 21 e 180 dias de idade, para determinação de: glicemia, albuminemia, proteínas totais, hematócrito, hemoglobina, colesterol total e triglicerídeos, insulina, leptina, adiponectina, TSH, T4 livre e T3 total. Os animais foram completamente eviscerados para obtenção da carcaça e análise da composição corporal. O consumo alimentar e a massa corporal (MC) foram aferidos diariamente durante a lactação e de 4 em 4 dias após a lactação até a idade adulta. As ratas lactantes do grupo L não apresentaram diferença na massa corporal e consumo alimentar. Durante a lactação a prole L apresentou maior ganho de peso corporal e após ao desmame observamos um aumento transitório de massa corporal até a idade adulta. Aos 21 dias, observamos na prole do grupo L menor gordura total e subcutanea, colesterol total, triblicerideo, albumina, insulina, T3 total e atividade de D1 no fígado; e aumento da área dos adipocitos no tecido subcutaneo, leptina, TSH e expressão de Ob-R, STAT3 e p-STAT3 na hipofise (p<0,05). Aos 180 dias, o grupo L apresentou menor glicemia, adiponectina, T4 livre, atividade de D1 e D2 na tireóide...

Flaxseed (Linum usitatissimum) presents high number of substances with alleged beneficial effects that decrease the adiposity, glocuse levels and improved lipid profile and cardiovascular system. In this study, we investigated in the offspring at 21 and 180 days old the effect of maternal consumption of flaxseed during lactation on the parameters associated with body composition, glucose homeostasis, lipid and protein, leptinemia, adiponectinemia and insulinemia, thyroid function, and leptin signaling pathway in the hypothalamus-pituitary-thyroid axis in the offspring at 21 and 180 days old. Lactating rats were divided into: (1) Controls (C), diet containing 20% casein; (2) FLaxseed (F), diet with additional 25% of flaxseed, containing 18.9% protein (13.9% from casein and 5% from flaxseed). The offspring were sacrificed at 21 and 180 days of age to determinate: glycemia, albumin, leptin, adiponectin, TSH, free T4 and total T3. The animals were completely eviscerated to obtain the carcass by body composition analysis. The maternal food intake and body mass were measured daily during the lactation, and after weaning were monitored once every 4 days until they were 180 days old. The dams of F group presented no changes in body mass and food intake. During the lactation the F offspring showed higher body mass and after weaning they presented a higher transitory body mass until 180 days old. At 21 days old, F group showed lower total and subcutaneous fat mass, total cholesterol, triacylglycerol, albumin, insulin, total T3 and D1 liver activity; and higher subcutaneous adipocytes area, leptin, TSH and Ob-R, STAT3 and p-STAT expression in pituitary (p<0,05). At 180 days old, F group presented lower glycemia, adiponectin, free T4 and D1 and D2 activity in thyroid; and higher visceral and subcutaneous adipocytes area, insuli, Ob-R expression in thyroid and D2 activity in brown adipose tissue (p<0,05). In conclusion, maternal flaxseed diet during lactation...

A single postnatal injection of oxytocin rescues the lethal feeding behaviour in mouse newborns deficient for the imprinted Magel2 gene.

The onset of feeding at birth is a vital step for the adaptation of the neonate to extra uterine life. Prader-Willi syndrome (PWS) is a complex neurogenetic disorder caused by the alteration of several imprinted contiguous genes including MAGEL2. PWS presents with various clinical manifestations, including poor suckling behaviour and feeding problems in neonates. Hypothalamic defects have been proposed, but the pathophysiological mechanisms remain poorly understood. Here, we report that a Magel2-deficient mouse with 50% neonatal mortality had an altered onset of suckling activity and subsequent impaired feeding, suggesting a role of MAGEL2 in the suckling deficit seen in PW newborns. The hypothalamus of Magel2 mutant neonates showed a significant reduction in oxytocin (OT). Furthermore, injection of a specific OT receptor antagonist in wild-type neonates recapitulated the feeding deficiency seen in Magel2 mutants, and a single injection of OT, 3-5 h after birth, rescued the phenotype of Magel2 mutant pups, allowing all of them to survive. Our study illustrates the crucial role of feeding onset behaviour after birth. We propose that OT supply might constitute a promising avenue for the treatment of feeding difficulties in PW neonates and potentially of other newborns with impaired feeding onset.

Introduction of distillate rosemary leaves into the diet of the Murciano-Granadina goat: transfer of polyphenolic compounds to goats' milk and the plasma of suckling goat kids.

The effect of the introduction of distilled rosemary leaves into the diet of the Murciano-Granadina goat on the polyphenolic profile of the goats' milk during the physiological stages of gestation and lactation was studied. The inclusion of rosemary leaves into the animal diet modified neither animal productivity (milk yield) nor milk quality. The following components were found in increased concentration (P < 0.05) in the goats' milk after the introduction of rosemary leaves into their diet: flavonoids hesperidin, naringin, and genkwanin; gallic acid; and phenolic diterpenes carnosol and carnosic acid. With regard to the transfer of polyphenols to the plasma of the suckling goat kid, a statistically significant increase (P < 0.05) in rosmarinic acid, carnosic acid, and carnosol concentrations was detected. From this point of view, distillate rosemary leaves can be proposed as an ingredient in ruminant feed because they both alter neither the yield nor the quality of Murciano-Granadina goats' milk and allow for an increased concentration of polyphenolic components in the goats' milk and in the plasma of the suckling goat kid.

Role of beta-hydroxybutyric acid in the central regulation of energy balance.

Although the phenomenon of beta-hydroxybutyric acid (BHBA) impact on satiety and thermogenesis has been described in the past decades, the underlying molecular mechanisms involved remain unresolved. Other metabolites such as glucose, fatty or branched chain amino acids are known to activate the AMP kinase pathway leading to an increase of anorexic and a decrease of orexigenic neuropeptides in the hypothalamus, one of the central regulators of energy homeostasis. Since BHBA is utilized as an energy source by the brain particularly in suckling newborns and under starving conditions, it is supposed to be a further central signal and energy providing substrate involved in the regulation of food intake. Moreover, BHBA might present a therapeutic approach for treating neuronal diseases because of its neuroprotective properties. Therefore, the purpose of this review is to summarize the known central effects of BHBA and to point out the importance of the identification of cellular pathways triggered in response to BHBA.

Effect of the oral administration of monosodium glutamate during pregnancy and breast-feeding in the offspring of pregnant Wistar rats / Efeito da administração de glutamato monossódico durante a gestação e amamentação na prole de ratas Wistar prenhes

PURPOSE: Determine the effects of the MSG (monosodium glutamate) in the offspring of pregnant rats through the comparison of the weight, NAL (nasal-anal length) and IL (Index of Lee) at birth and with 21 days of life. METHODS: Pregnant Wistar rats and their offspring were divided into 3 groups: GC, G10 and G20. Each of the groups received 0 percent, 10 percent and 20 percent of MSG, respectively from coupling until the end of the weaning period. RESULTS: Neither weight nor NAL were different among the groups at birth. The group G20 at birth had an IL lower than the group GC (p<0,05) and with 21 days of life presented weight and NAL lower than the groups G10 and this lower than the GC (p<0,01). Otherwise the G20 at 21 days of life had the IL similar to the other two groups. The weight profit percentage from birth to the 21st day of life was lower in the G20 regarding the other two groups (p<0,01). The G20 had a NAL increase percentage from birth to the 21st day of life lower than the G10 and this lower than the GC (p<0,01). CONCLUSIONS: MSG presented a dose-dependent relation in the variables weight and NAL. It caused a decrease in the growth pattern as well as in the weight gain pattern until the 21st day of life. The IL of the group 20 percent had an increased in relation to the control group after 3 weeks of follow up.

OBJETIVO: Avaliar o efeito do glutamato monossódico (GMS) nos fetos de ratas prenhes por meio da comparação do peso, comprimento nasal-anal (CNA) e índice de Lee (IL) ao nascimento e com 21 dias de vida. MÉTODOS: Foram utilizadas ratas prenhes da linhagem Wistar distribuídas em três grupos: grupo controle (GC), G10 e G20. Estes, respectivamente, foram alimentados com ração contendo 0, 10 e 20 por cento de GMS desde o período de acasalamento até o final da amamentação. RESULTADOS: O peso e o CNA não foram diferentes entre os grupos ao nascimento. O grupo G20, ao nascimento, teve IL menor que o grupo GC (p < 0,05) e, aos 21 dias de vida, apresentou peso e CNA menores que o grupo G10, o qual foi menor que o GC (p < 0,01). O grupo G20, aos 21 dias de vida, teve IL semelhante aos outros dois grupos. O percentual de ganho de peso do nascimento ao 21º dia de vida foi menor no G20 em relação aos outros dois grupos (p < 0,01). O grupo G20 teve percentual de aumento de CNA do nascimento ao 21º dia de vida menor que o grupo G10, e este menor que o grupo GC (p < 0,01). CONCLUSÕES: O GMS nas concentrações de 10 e 20 por cento na ração de ratas prenhes Wistar apresentou uma relação dose-dependente nas variáveis peso e CNA. Houve diminuição no padrão de ganho de peso e de aumento de CNA do nascimento ao 21º dia de vida com uso de GMS. O IL na prole do grupo G20 aumentou em relação ao do grupo GC após 3 semanas de acompanhamento.

Developmental changes in glycolipids and synchronized expression of nutrient transporters in the mouse small intestine.

Small intestinal epithelial cells are rich in characteristic glycosphingolipids (GSLs) that are composed of phytosphingosine and alpha-hydroxy fatty acid, but the physiological roles of GSLs in the small intestine remain unclear. Here, we report the developmental changes in GSL composition in the mouse small intestine (duodenum through ileum) and their relationship with the temporal mRNA expression of nutrient transporters. Up to 2 weeks after birth, the major GSLs were hexosylceramide (HexCer), GM3, GM1 and GD1a. After 2 weeks of age, HexCer and asialo GM1 became the major GSLs. The ceramide moiety of both HexCer and asialo GM1 was composed mainly of phytosphingosine and alpha-hydroxy fatty acid, from birth through adulthood. Immunohistochemically, GM1 localized in the cytoplasm, and asialo GM1 localized exclusively in the apical microvillous membrane of small intestinal epithelial cells. The shift from sialylated GSLs to asialo GM1 was achieved by the combinational and tissue-specific transcriptional down-regulation of GM3 synthase and GM1-beta-galactosidase at around 2 weeks of age. The temporal mRNA expression of various nutrient transporters also showed significant changes at around 2 weeks of age, including the up-regulation of the sodium/glucose cotransporter and the oligopeptide transporter, as well as the down-regulation of amino acid transporters. These synchronized changes in the mRNA expression of nutrient transporters with GSL composition during suckling-to-weanling transition suggest the contributions of GSLs to morphologic and functional development in the membrane of mouse small intestinal epithelial cells.

The effect of dietary selenium supplementation on cadmium absorption and retention in suckling rats.

Selenium (Se) reduces cadmium (Cd) toxicity in adult animals, but its effects in newborn animals are still unknown. This study investigated Cd (as CdCl2) absorption, distribution, and retention in suckling rats receiving oral Se supplementation (as Na2SeO3) in equimolar doses (8 µmol Cd and/or Se per kg b.w./day). Selenium was given either before and during Cd exposure (Sepre + Cd group; pretreatment group) or only during Cd exposure (Se + Cd group). Rats were treated from postnatal day (PND) 6-14 as follows: controls (H2O, PND 6-14), Se (PND 10-14), Cd (PND 10-14), Sepre + Cd (Se PND 6-14 + Cd PND 10-14) and Se + Cd (Se + Cd PND 10-14). Selenium supplementation, especially pre-treatment, decreased Cd levels in the blood, brain, liver and kidney of suckling rats. Selenium levels in plasma, brain, and kidney also decreased. These findings suggest that higher Se intake could efficiently reduce Cd retention during the suckling period.

Intestinal regulation of copper homeostasis: a developmental perspective.

Stable-isotope studies in human infants and adults have shown that copper homeostasis occurs, but the contribution of the small intestine to this regulation is still not well understood. Copper first needs to be reduced to the cuprous form, most likely by Steap proteins on the apical membrane. Copper is subsequently absorbed by Ctr1 and then transferred in the enterocyte by the chaperone Atox1 to reach ATP7A for export from the cell. The role of ATP7B, shown to be present in the small intestine, is still poorly understood. In situations of high copper exposure, Ctr1 is endocytosed, metallothionein is induced, and ATP7A moves to a more basolateral localization. However, the ontogeny of regulation of copper homeostasis has received little attention. In rat pups, tissue copper and total-body (67)Cu retention decrease throughout postnatal development, whereas liver (67)Cu retention, serum copper, and ceruloplasmin activity increase. Total (67)Cu absorption decreases and intestinal (67)Cu retention increases with increased copper intake. During early infancy (day 10), copper supplementation increases intestinal copper and metallothionein gene expression, and Ctr1 protein levels increase, whereas Atp7A and Atp7B are unaffected. However, during late infancy (day 20), intestinal copper concentrations are unaffected by supplementation, but Ctr1, ATP7A, and Atp7B protein levels are higher than in controls. Thus, maturation of small intestine copper transport occurs through increased abundance and altered localization of Ctr1, Atp7A, and Atp7B. The mechanisms behind this maturation, including both transcriptional and posttranscriptional regulation, require further studies.

Pharmacokinetics, distribution, metabolism, and excretion of deferasirox and its iron complex in rats.

Deferasirox (Exjade, ICL670, CGP72670) is an iron-chelating drug for p.o. treatment of transfusional iron overload in patients with beta-thalassemia or sickle cell disease. The pharmacokinetics and disposition of deferasirox were investigated in rats. The animals received single intravenous (10 mg/kg) or p.o. (10 or 100 mg/kg) doses of 14C-radiolabeled deferasirox. Biological samples were analyzed for radioactivity (liquid scintillation counting, quantitative whole-body autoradioluminography), for deferasirox and its iron complex [high-performance liquid chromatography (HPLC)/UV], and for metabolites (HPLC with radiodetection, liquid chromatography/mass spectrometry, 1H and 13C NMR, and two-dimensional NMR techniques). At least 75% of p.o.-dosed deferasirox was absorbed. The p.o. bioavailability was 26% at the 10 mg/kg dose and showed an overproportional increase at the 100 mg/kg dose, probably because of saturation of elimination processes. Deferasirox-related radioactivity was distributed mainly to blood, excretory organs, and gastrointestinal tract. Enterohepatic recirculation of deferasirox was observed. No retention occurred in any tissue. The placental barrier was passed to a low extent. Approximately 3% of the dose was transferred into the breast milk. Excretion of deferasirox and metabolites was rapid and complete within 7 days. Key clearance processes were hepatic metabolism and biliary elimination via multidrug resistance protein 2. Deferasirox, iron complex, and metabolites were excreted largely via bile and feces (total > or = 90%). Metabolism included glucuronidation at the carboxylate group (acyl glucuronide M3) and at phenolic hydroxy groups, as well as, to a lower degree, cytochrome P450-catalyzed hydroxylations. Two hydroxylated metabolites (M1 and M2) were administered to rats and were shown not to contribute substantially to iron elimination in vivo.

Critical role of cyclooxygenase-2 activation in pathogenesis of hydronephrosis caused by lactational exposure of mice to dioxin.

Congenital hydronephrosis is a serious disease occurring among infants and children. Besides the intrinsic genetic factors, in utero exposure to a xenobiotic, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has been suggested to induce hydronephrosis in rodents owing to anatomical obstruction in the ureter. Here, we report that hydronephrosis induced in mouse pups exposed lactationally to TCDD is not associated with anatomical obstruction, but with abnormal alterations in the subepithelial mesenchyma of the ureter. In the kidneys of these pups, the expressions of a battery of inflammatory cytokines including monocyte chemoattractant protein (MCP)-1, tumor necrosis factor alpha (TNFalpha) and interleukin (IL)-1beta were up-regulated as early as postnatal day (PND) 7. The amounts of cyclooxygenase (COX)-2 mRNA and protein as well as prostaglandin E2 (PGE(2)) were conspicuously up-regulated in an arylhydrocarbon-receptor-dependent manner in the TCDD-induced hydronephrotic kidney, with a subsequent down-regulation of the gene expressions of Na+ and K+ transporters, NKCC2 and ROMK. Daily administration of a COX-2 selective inhibitor to newborns until PND 7 completely abrogated the TCDD-induced PGE(2) synthesis and gene expressions of inflammatory cytokines and electrolyte transporters, and eventually prevented the onset of hydronephrosis. These findings suggest an essential role of COX-2 in mediating the TCDD action of inducing hydronephrosis through the functional impairment rather than the anatomical blockade of the ureter.

Maternal caffeine intake affects acetylcholinesterase in hippocampus of neonate rats.

Transcriptional factors and signalling molecules from intracellular metabolism modulate a complex set of events during brain development. Neurotransmitter and neuromodulator synthesis and their receptor expressions vary according to different stages of brain development. The dynamics of signalling systems is often accompanied by alterations in enzyme expression and activity. Adenosine is a neuromodulator that controls the release of several neurotransmitters, including acetylcholine, which is an important neurotransmitter during brain development. Caffeine is a non-specific antagonist of adenosine receptors and can reach the immature brain. We evaluated the effects of rat maternal caffeine intake (1g/L) on acetylcholine degradation and acetylcholinesterase expression from hippocampus of 7-, 14- and 21-day-old neonates in caffeine-treated and control groups. Caffeine was not able to change the age-dependent increase of acetylcholinesterase activity or the age-dependent decrease of acetylcholinesterase expression. However, caffeine promoted an increase of acetylcholinesterase activity (42%) without modifications on the level of acetylcholinesterase mRNA transcripts in 21-day-old rats. Considering the high score of phosphorylatable residues on acetylcholinesterase, this profile can be associated with a possible regulation by specific phosphorylation sites. These results highlight the ability of maternal caffeine intake to interfere on cholinergic neurotransmission during brain development.