Effects of  -lipoic acid supplementation on maternal diabetes-induced growth retardation and congenital anomalies in rat fetuses

Ghafli, M.H.M. Al; Padmanabhan, R.; Kataya, Hazem Hasan; Berg, Bertel

doi:10.1023/b:mcbi.0000028747.92084.42

Cited by 41 publications

(38 citation statements)

References 54 publications

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“…Maternal diabetes entails embryo maldevelopment, leading to increased perinatal pathological situations, such as microsomias and congenital malformations (3,26), that are obvious from earlier stages of pregnancy according to our results and other previous works (10,49). Along these lines, we observed both an increased percentage of malformed embryos (4-fold increase on gestational day 13) and retarded growth in normal embryos from diabetic mothers.…”

Section: Discussionsupporting

confidence: 89%

Responses of mitochondrial biogenesis and function to maternal diabetes in rat embryo during the placentation period

Alcolea¹,

Lladó²,

García-Palmer³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Alcolea MP, Lladó I, García-Palmer FJ, Gianotti M. Responses of mitochondrial biogenesis and function to maternal diabetes in rat embryo during the placentation period. Am J Physiol Endocrinol Metab 293: E636-E644, 2007; doi:10.1152/ajpendo.00120.2007.-Mitochondria are cellular organelles that have been reported to be altered in diabetes, being closely related to its associated complications. Moreover, mitochondrial biogenesis and function are essential for proper embryo development throughout the placentation period, occurring during organogenesis, when a great rate of congenital malformations have been associated with diabetic pregnancy. Thus, the aim of the current work was to investigate the effect of the diabetic environment on mitochondrial function and biogenesis during the placentation period. For this purpose, we studied the oxidative phosphorylation system (OXPHOS) enzymatic activities as well as the expression of genes involved in the coordinated regulation of both mitochondrial and nuclear genome (PGC-1␣, NRF-1, NRF-2␣, mtSSB, and TFAM) and mitochondrial function (COX-IV, COX-I, and ␤-ATPase) in rat embryos from control and streptozotocininduced diabetic mothers. Our results reflected that diabetic pregnancy retarded and altered embryo growth. The embryos from diabetic mothers showing normal morphology presented a reduced content of proteins regulated through the PGC-1␣ mitochondriogenic pathway on gestational day 12. This fact was accompanied by several responses that entailed the activation of OXPHOS activities on the same day and the recovery of the content of the studied proteins to control levels on day 13. As a result, the mitochondria of these embryos would reach a situation close to control on day 13 that could allow them to follow the normal mitochondriogenic schedule throughout a gestational period in which the mitochondrial differentiation process is critical. Nevertheless, malformed embryos from diabetic mothers seemed to show a lower adaptation capability, which could exacerbate their maldevelopment.peroxisome proliferator-activated receptor-␥ coactivator-1␣; nuclear respiratory factors; mitochondrial transcription factor A; oxidative phosphorylation system THE ALTERED EMBRYO-FETAL DEVELOPMENT induced by the oxida-

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Section: Discussionsupporting

confidence: 89%

Responses of mitochondrial biogenesis and function to maternal diabetes in rat embryo during the placentation period

Alcolea¹,

Lladó²,

García-Palmer³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…After the animals were killed, it was observed that the uteruses of diabetic female rats that did not deliver offspring revealed the presence of resorptions sites, indicating that chronic hyperglycemia in the intrauterine environment caused by maternal diabetes negatively affected offspring development and survival since the moment of conception. A recent study also reported an elevation in the rates of embryo resorption and fetal death among the offspring of diabetic female rats (26).…”

Section: Discussionmentioning

confidence: 87%

Reproductive physiology, and physical and sexual development of female offspring born to diabetic dams

Spadotto

Damasceno

Godinho

et al. 2012

Arq Bras Endocrinol Metab

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Objectives: The objective of this study was to evaluate physical and sexual development and reproductive physiology in female rat offspring that developed in hyperglycemia conditions in utero and during lactation. Materials and methods: Maternal diabetes was induced in female rats by a single IV injection of streptozotocin before mating. Female offspring development was evaluated by means of the following parameters: physical development; age of vaginal opening and first estrus; weight and histological evaluation of uterus and ovaries; duration of the estrous cycle, sexual behavior, and fertility after natural mating. Results: In the female offspring, maternal diabetes caused delays in initial physical development; diminution in ovary weight and number of follicles; and inferior reproductive performance compared with the control group. Conclusions: The exposure to hyperglycemia in uterus and during lactation caused delays in physical and sexual development, and affected the reproductive physiology of female rats negatively. Arq Bras Endocrinol Metab. 2012;56(2):96-103 Keywords Sexual behavior; physical development; diabetes; female reproductive physiology; female rat; streptozotocin RESUMO Objetivos: O objetivo deste estudo foi avaliar o desenvolvimento físico e sexual e a fisiologia reprodutiva de ratas que se desenvolveram em condições hiperglicêmicas in utero e lactação. Materiais e métodos: Para induzir o diabetes nas ratas, foi utilizada estreptozotocina em dose única via intravenosa antes do acasalamento. A prole feminina foi avaliada por meio dos seguintes parâmetros: o desenvolvimento físico; a idade de abertura vaginal e do primeiro estro, peso e avaliação histológica do útero e ovários; a duração do ciclo estral, o comportamento sexual e a fertilidade após acasalamentos naturais. Resultados: O diabetes materno provocou, na prole feminina, retardo no desenvolvimento físico; diminuição do peso dos ovários e do número de folículos; a performance reprodutiva foi inferior à do grupo controle. Conclusões: Concluiu-se que a exposição aos meios intrauterino e lactacional hiperglicêmicos provocou retardo no desenvolvimento físico e sexual e prejudicou a fisiologia reprodutiva de ratas. Arq Bras Endocrinol Metab. 2012;56(2):96-103

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“…Supplementing the maternal diet with LA failed to rescue Lias Ϫ/Ϫ mice from embryonic lethality, although it is likely that LA can cross the placenta efficiently, since Al Ghafli et al have demonstrated that LA supplementation (20 mg kg Ϫ1 , given intraperitoneally) improved the survival of embryos in rats with diabetes induced by streptozotocin during the pregnancy (1).…”

Section: Discussionmentioning

confidence: 99%

Endogenous Production of Lipoic Acid Is Essential for Mouse Development

Maeda

2005

Molecular and Cellular Biology

116

102

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␣-Lipoic acid (LA) is a cofactor for mitochondrial ␣-ketoacid dehydrogenase complexes and is one of the most potent, natural antioxidants. Reduction of oxidative stress by LA supplementation has been demonstrated in patients with diabetic neuropathy and in animal models. To determine how normal development or pathological conditions are affected by genetic alterations in the ability of mammalian cells to synthesize LA and whether dietary LA can circumvent its endogenous absence, we have generated mice deficient in lipoic acid synthase (Lias). Mice heterozygous for disruption of the Lias gene develop normally, and their plasma levels of thiobarbituric acid-reactive substances do not differ from those of wild-type mice. However, the heterozygotes have significantly reduced erythrocyte glutathione levels, indicating that their endogenous antioxidant capacity is lower than those of wild-type mice. Homozygous embryos lacking Lias appear healthy at the blastocyst stage, but their development is retarded globally by 7.5 days postcoitum (dpc), and all the null embryos die before 9.5 dpc. Supplementing the diet of heterozygous mothers with LA (1.65 g/kg of body weight) during pregnancy fails to prevent the prenatal deaths of homozygous embryos. Thus, endogenous LA synthesis is essential for developmental survival and cannot be replaced by LA in maternal tissues and blood.R-␣-Lipoic acid (6,8-thioctic acid) (LA) is a crucial cofactor that is required for the activity of the multienzyme complexes involved in the decarboxylation of ␣-ketoacids, important steps in energy metabolism. These complexes include pyruvate dehydrogenase complex (PDC), ␣-ketoglutarate dehydrogenase complex, branched chain ␣-ketoacid dehydrogenase complex (32), and a glycine cleavage system (11). LA is covalently attached via an amide bond to specific lysine residues of the E2 subunits of these complexes. LA is universally present in prokaryotes and eukaryotes (28), and previous investigations have shown that it is synthesized by lipoic acid synthase from octanoic acid and a sulfur source (23,25). Mouse lipoic acid synthase is encoded by the nuclear gene Lias.LA, one of the most potent natural antioxidants, has received considerable attention as a general dietary supplement for the past 15 years (3). Many lines of evidence have shown that both LA and its reduced form, dihydrolipoic acid (DHLA), have multifunctional antioxidant activities with the following characteristics (29). First, LA/DHLA are amphiphilic and readily cross the blood-brain barrier and cell membranes. Second, LA/DHLA possess metal-chelating activity. Third, LA is reduced to DHLA by several antioxidant enzymes that are expressed constitutively in most types of cells. In addition, because of its strong negative redox potential, DHLA can recycle other antioxidants, such as vitamin C, vitamin E, glutathione, coenzyme Q10, and ubiquinone (14,15,21,29,33).A growing body of evidence implicates oxidative stress as an important pathogenic element in a variety of diseases, including atheroscle...

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Effects of -lipoic acid supplementation on maternal diabetes-induced growth retardation and congenital anomalies in rat fetuses

Cited by 41 publications

References 54 publications

Responses of mitochondrial biogenesis and function to maternal diabetes in rat embryo during the placentation period

Responses of mitochondrial biogenesis and function to maternal diabetes in rat embryo during the placentation period

Reproductive physiology, and physical and sexual development of female offspring born to diabetic dams

Endogenous Production of Lipoic Acid Is Essential for Mouse Development

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