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A wide variety of in utero insults are associated with an increased incidence of metabolic disorders in the offspring and
in subsequent generations. We have shown that fetal and neonatal exposure to nicotine results in endocrine and metabolic changes
in the offspring that are consistent with those observed in type 2 diabetes. This study examines whether fetal and neonatal
exposure to nicotine has transgenerational effects in the F2 offspring. Female Wistar rats were given either saline or nicotine
(1 mg/kg/d) during pregnancy and lactation to create saline- and nicotine-exposed female F1 progeny. These F1 females were
then bred to produce F2 offspring. We examined glucose homeostasis, serum lipids and fat pad weights, mitochondrial enzyme
activity in skeletal muscle and blood pressure in these F2 offspring between 13 and 15 weeks of age. Offspring of nicotine-
versus saline-exposed mothers had elevated fasting serum insulin concentrations and an enhanced total insulin response to
the glucose challenge. This apparent insulin resistance was unrelated to changes in skeletal muscle mitochondrial volume or
activity. The offspring of nicotine-exposed mothers also had elevated blood pressure. These data demonstrate that adverse
effects of fetal and neonatal exposure to nicotine can influence aspects of metabolic risk in subsequent generations. 相似文献
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Vieau D 《World journal of diabetes》2011,2(9):133-136
Data indicate that perinatal nutritional insults not onlyhave short-term consequences on the growth velocity of the fetus/neonate but also sensitize to the development of metabolic adult diseases.The pathophysiological mechanisms involved in the so-called "Developmental Origin of Health and Adult Diseases" are still largely unknown and depend on the type of alteration (nutritional,psychological,endocrine disruptors,etc.),its intensity and duration,species,sex and the time during which it is applied.Perinatal stress,via disturbances of both hy-pothalamo-pituitary-adrenal (HPA) axis and sympathoadrenal-system (SAS),as well as brain-adipose axis and pancreas alterations could play a crucial role.Interestingly,it has been demonstrated that perinatal insults may be transmitted transgenerationally,suggesting that these long-term consequences may be inherited via epigenetic mechanisms.Finally,since the placenta has been demonstrated to be sensitive to perinatal nutritional manipulations,the identification of placental markers may thus represent an important new avenue to identify the more susceptible babies prone to developing meta-bolic diseases. 相似文献
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As an important environmental pollutant, the heavy metal cadmium has a significant negative impact on the stability of the ecological environment and on organismal health. Previous studies have shown that cadmium chloride can damage the nervous, skeletal, endocrine, and reproductive systems, but to our knowledge, the effects of cadmium on the behavior, neurotransmitter levels, and neuronal development in the offspring of exposed animals have not been reported. In the present study, sexually-mature zebrafish were exposed to cadmium chloride at different concentrations for 60 days, and in this background, behavior, neurotransmitters level, neuro-development and neurotransmitter metabolism was investigated in the F1 offspring. The results showed that exposure of the parental zebrafish to cadmium chloride resulted swimming speed and distance of F1 offspring significantly reduced; the levels of neurotransmitters, such as dopamine, serotonin, and acetylcholine is disrupted. neuro-development and neurotransmitter metabolism related genes expression pattern was altered, which cause zebrafish F1 offspring developmental neurotoxicity. These findings provide further insights into the harm posed by cadmium chloride to the aquatic ecosystems. 相似文献
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Kunifumi Inawaka Mayumi Kawabe Satoru Takahashi Yoshitaka Tomigahara Jun Abe Tomoyuki Shirai 《Toxicology and applied pharmacology》2009,237(2):178-187
To verify whether anti-androgens cause transgenerational effects on spermatogenesis and DNA methylation in rats, gravid Crl:CD(SD) female rats (4 or 5/group, gestational day (GD) 0 = day sperm detected) were intraperitoneally treated with anti-androgenic compounds, such as vinclozolin (100 mg/kg/day), procymidone (100 mg/kg/day), or flutamide (10 mg/kg/day), from GD 8 to GD 15. Testes were collected from F1 male pups at postnatal day (PND) 6 for DNA methylation analysis of the region (210 bp including 7 CpG sites) within the lysophospholipase gene by bisulfite DNA sequencing method. F0 and F1 males underwent the sperm analysis (count, motility and morphology), followed by DNA methylation analysis of the sperm. Remaining F1 males were cohabited with untreated-females to obtain F2 male pups for subsequent DNA methylation analysis of the testes at PND 6. These analyses showed no effects on spermatogenesis and fertility in F1 males of any treatment group. DNA methylation status in testes (F1 and F2 pups at PND 6) or sperms (F1 males at 13 weeks old) of the treatment groups were comparable to the control at all observation points, although DNA methylation rates in testes were slightly lower than those in sperm. In F0 males, no abnormalities in the spermatogenesis, fertility and DNA methylation status of sperm were observed. No transgenerational abnormalities of spermatogenesis and DNA methylation status caused by anti-androgenic compounds were observed. 相似文献
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Mental illness remains the greatest chronic health burden globally with few in-roads having been made despite significant advances in genomic knowledge in recent decades. The field of psychiatry is constantly challenged to bring new approaches and tools to address and treat the needs of vulnerable individuals and subpopulations, and that has to be supported by a continuous growth in know ledge. The majority of neuropsychiatric symptoms reflect complex gene-environment interactions, with epigenetics bridging the gap between genetic susceptibility and environmental stressors that trigger disease onset and drive the advancement of symptoms. It has more recently been demonstrated in preclinical models that epigenetics underpins the transgenerational inheritance of stress-related behavioural phenotypes in both paternal and maternal lineages, providing further supporting evidence for heritability in humans. However, unbiased prospective studies of this nature are practically impossible to conduct in humans so preclinical models remain our best option for researching the molecular pathophysiologies underlying many neuropsychiatric conditions. While rodents will remain the dominant model system for preclinical studies (especially for addressing complex behavioural phenotypes), there is scope to expand current research of the molecular and epigenetic pathologies by using invertebrate models. Here, we will discuss the utility and advantages of two alternative model organisms–Caenorhabditis elegans and Drosophila melanogaster–and summarise the compelling insights of the epigenetic regulation of transgenerational inheritance that are potentially relevant to human psychiatry. 相似文献
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The history of Distilbène® (Diethylstilbestrol) told to grandchildren – the transgenerational effect
《Annales d'endocrinologie》2015,76(3):253-259
The Distilbène® story is a dramatic episode which belongs to the history of medicine. It provided several useful lessons such as the importance of evidence-based medicine and the hazard to develop treatments during pregnancy without careful animal verifications. However, this experience has also provided unexpected progress by suggesting new pathophysiological concepts: fetal programming of adult diseases and/or transgenerational transmission of environmental effects through epigenetic modifications. 相似文献
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2,4,6-trinitrotoluene (TNT) as an energetic compound widely used in military applications has aroused great concerns in recent years due to its large-scale contamination in soil and water; however, its toxicity is still largely unknown. In this study, we investigated the reproductive toxicity and the transgenerational effects of TNT on Caenorhabditis elegans (C. elegans). Our data showed that exposure to TNT at concentrations ranging from 10 to 100 ng/mL resulted in decreasing the lifespan, brood size, number of oocytes and eggs in uterus, while increasing the number of germ cell apoptosis in C. elegans. The apoptotic effects of TNT were blocked in mutants of cep-1 (w40), egl-1 (n487), and hus-1 (op241), indicating conserved genotoxic response genes was involved in mediating TNT-induced germ cell apoptosis. Parental exposure to TNT significantly increased the germ cell apoptosis from P0 to F2 generation, but the toxicity faded away in F3 and F4 generations. Furthermore, TNT was rapidly metabolized in P0, and the accumulation of 4-aminodinitrotoluene (4-ADNT), the main metabolite of TNT in C. elegans, showed a significant decrease from P0 to F1 and a slow decrease in the subsequent generations. Our results demonstrated that ingested TNT can cause severe transgenerational reproductive toxicity and be rapidly converted to 4-ADNT in the nematodes. These data provided basis for future studies on the effects of energetic compounds across generations. 相似文献
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Michihiro Kawano Xian-Yang Qin Midori Yoshida Tomokazu Fukuda Hiroko Nansai Yumi Hayashi Tamie Nakajima Hideko Sone 《Toxicology letters》2014
Di-(2-ethylhexyl)-phthalate (DEHP) is a phthalate ester that binds peroxisome proliferator-activated receptor α (PPARα) to induce proliferation of peroxisomes and regulate the expression of specific target genes. The question of whether the effect of DEHP on female reproductive processes is mediated via PPARα-dependent signaling is controversial. In this study, we investigated the effect of exposure to DEHP on ovarian expression of estrogen receptor α (Esr1) and aromatase (Cyp19a1) in three generations of Sv/129 wild-type (WT, +/+) and PPARα (−/−) knockout mice. Compared with untreated controls, ovarian expression of Esr1 decreased in response to DEHP treatment in the F0 (0.56-fold, P = 0.19), F1 (0.45-fold, P = 0.023), and F2 (0.35-fold, P = 0.014) generations of WT mice, but not PPARα-null mice. Our data indicate that transgenerational repression by DEHP of ovarian Esr1 gene expression is mediated by PPARα-dependent pathways. Further studies are required to elucidate the mechanisms underlying crosstalk between PPARα and Esr1 signaling in reproductive processes. 相似文献