Amelioration of oxidative kidney damage in offspring by maternal trans-fatty acid exposure in mice by secoisolariciresinol diglucoside. / äºšéº»æœ¨é šç´ å¯¹æ¯é¼ åå¼è„‚è‚ªé ¸æš´éœ²è‡´å­ä»£è‚¾æ°§åŒ–æŸä¼¤çš„ä¿æŠ¤ä½œç”¨.

OBJECTIVES: Trans-fatty acids (TFAs), primarily derived from the food industry's production processes, have become a globally recognized public health issue due to the detrimental impact they have on human well-being. Secoisolariciresinol diglucoside (SDG) is a polyphenolic compound derived from flax lignans, possessing antioxidative properties. This study aims to investigate the protective effect of SDG on kidney oxidative damage in offspring of mice caused by maternal exposure to TFA during pregnancy and lactation. METHODS: A total of 30 c57BL/6 female rats were randomly divided into 5 groups: a control group, a TFA-exposed group, a low-(TFA+LSDG) group, a medium-(TFA+MSDG) group, and a high-(TFA+HSDG) group (n=6 in each group). With the exception of the control group, the maternal mice in the remaining 4 groups received a daily oral gavage of TFA at a dosage of 60 mg/(kg·BW) throughout the experimental period. The mothers in the control group were administered physiological saline via oral gavage once daily. Meanwhile, the 3 SDG intervention groups were provided with ad libitum access to SDG feed containing 10 mg/kg (low), 20 mg/kg (medium), and 30 mg/kg (high) of SDG. The female mice were conceived overnight. If the vaginal plug appeared in the next morning, the female mice were conceived and included in the experimental stage until the end of the 21th day lactation period. The body weight and kidney mass of offspring were recorded, and the kidney coefficient was calculated. The kidney was detected by HE staining to observe the histopathological changes, and the level of reactive oxidative species (ROS) was detected by fluorescence probe-dihydroethidium (DHE) staining; the expression levels of total superoxide dismutase (T-SOD) and malondialdehyde (MDA) in renal homogenate were detected, and the expression of nuclear factor E2-related fator2 (Nrf2) and hemeoxygenase-1 (HO-1) protein was analyzed by immunohistochemistry (IHC) staining. The mRNA expressions of Nrf2 and HO-1 were detected by real-time PCR, and the protein expression of Cu/Zn-superoxide dismutase (Cu/Zn-SOD), Mn-superoxide dismutase (Mn-SOD), glutathione peroxidase-1 (GPx-1), Nrf2 and HO-1 were detected by Western blotting. RESULTS: Compared with the control group, the kidney coefficient in the TFA-exposed group was increased, the morphology and structure of kidney tissue was abnormal; the activity of T-SOD enzyme was decreased, and the content of MDA was increased, the level of ROS was increased; the expressions of Cu/Zn-SOD, Mn-SOD, GPx1 protein were decreased, and the mRNA and protein expressions of Nrf2 and HO-1 were decreased, there were all significant difference (all P<0.05). Compared with the TFA-exposed group, the ROS levels were reduced, and the T-SOD enzyme activity as well as the protein expression of Cu/Zn-SOD, GPx-1, Mn-SOD, Nrf2 and HO-1 were up-regulated in the low, middle and high dose SDG intervention groups; the kidney coefficient and MDA content were decreased in the middle and high dose SDG groups; the Nrf2 mRNA expression in the high dose SDG group was up-regulated, there were all significant difference (all P<0.05). CONCLUSIONS: Maternal exposure to TFA during pregnancy and lactation can lead to oxidative damage in the kidney of offspring, and the SDG intervention may alleviate TFA-induced oxidative damage by up-regulating the expression of Nrf2 and HO-1 signal pathway.

Cellular toxicity of dietary trans fatty acids and its correlation with ceramide and diglyceride accumulation.

High fatty acid (FA) levels are deleterious to pancreatic ß-cells, largely due to the accumulation of biosynthetic lipid intermediates, such as ceramides and diglycerides, which induce ER stress and apoptosis. Toxicity of palmitate (16:0) and oleate (18:1 cis-Δ9) has been widely investigated, while very little data is available on the cell damages caused by elaidate (18:1 trans-Δ9) and vaccenate (18:1 trans-Δ11), although the potential health effects of these dietary trans fatty acids (TFAs) received great publicity. We compared the effects of these four FAs on cell viability, apoptosis, ER stress, JNK phosphorylation and autophagy as well as on ceramide and diglyceride contents in RINm5F insulinoma cells. Similarly to oleate and unlike palmitate, TFAs reduced cell viability only at higher concentration, and they had mild effects on ER stress, apoptosis and autophagy. Palmitate increased ceramide and diglyceride levels far more than any of the unsaturated fatty acids; however, incorporation of TFAs in ceramides and diglycerides was strikingly more pronounced than that of oleate. This indicates a correlation between the accumulation of lipid intermediates and the severity of cell damage. Our findings reveal important metabolic characteristics of TFAs that might underlie a long term toxicity and hence deserve further investigation.

Maternal trans fat intake during pregnancy or lactation impairs memory and alters BDNF and TrkB levels in the hippocampus of adult offspring exposed to chronic mild stress.

This study aimed to assess the influence of maternal dietary fat intake during pregnancy or lactation on memory of adult offspring after chronic mild stress (CMS) exposure. Female Wistar rats were supplemented daily with soybean oil/fish oil (SO/FO) or hydrogenated vegetable fat (HVF) by oral gavage (3.0g/kg body weight) during pregnancy or lactation. On post-natal day (PND) 60, half of the animals were exposed to CMS following behavioral assessments. While the adult offspring born under influence of SO/FO and HVF supplementations during pregnancy showed higher levels of n-3 and n-6 fatty acids (FA) series DHA and ARA metabolites, respectively, in the hippocampus, adult offspring born from supplemented dams during lactation showed higher levels of their precursors: ALA and LA. However, only HVF supplementation allowed TFA incorporation of adult offspring, and levels were higher in lactation period. Adult offspring born from dams supplemented with trans fat in both pregnancy and lactation showed short and long-term memory impairments before and after CMS. Furthermore, our study also showed higher memory impairment in offspring born from HVF-supplemented dams during lactation in comparison to pregnancy. BDNF expression was increased by stress exposure in offspring from both SO/FO- and HVF-supplemented dams during pregnancy. In addition, offspring from HVF-supplemented dams showed decreased TrkB expression in both supplemented periods, regardless of stress exposure. In conclusion, these findings show for the first time that the type of dietary FA as well as the period of brain development is able to change FA incorporation in brain neural membranes.

Lifelong consumption of trans fatty acids promotes striatal impairments on Na(+)/K(+) ATPase activity and BDNF mRNA expression in an animal model of mania.

PURPOSE: To evaluate the toxicity of chronic consumption of processed foods that are rich in trans fat on the lipid composition of brain membranes, as well as its functional repercussions. METHODS: A second generation of male rats born from mothers and grandmothers supplemented with soybean oil (SOC, an isocaloric control group) or hydrogenated vegetable fat (HVF, rich in TFA) (3g/kg; p.o.) were kept under oral treatment until 90 days of age, when they were exposed to an AMPH-induced model of mania. RESULTS: The HVF group presented 0.38% of TFA incorporation in the striatum, affecting Na(+)/K(+) ATPase activity, which was decreased per se and following AMPH-exposure. The HVF group also showed increased protein carbonyl (PC) and brain-derived neurotrophic factor (BDNF) mRNA levels after AMPH administration, while these oxidative and molecular changes were not observed in the other experimental groups. Additionally, a negative correlation between striatal Na(+)/K(+) ATPase activity and PC levels (r(2)=0.49) was observed. CONCLUSION: The prolonged consumption of trans fat allows TFA incorporation and increases striatal oxidative status, thus impairing the functionality of Na(+)/K(+)-ATPase and affecting molecular targets as BDNF mRNA. We hypothesized that the chronic intake of processed foods (rich in TFA) facilitates the development of neuropsychiatric diseases, particularly bipolar disorder.

Chronic consumption of trans fat can facilitate the development of hyperactive behavior in rats.

In recent decades, the increased consumption of processed foods, which are rich in hydrogenated vegetable fat (HVF), has led to a decreased consumption of fish and oilseed, rich in omega-3 fatty acids. This eating habit provides an increased intake of trans fatty acids (TFA), which may be related to neuropsychiatric conditions, including inattention and hyperactivity. In this study, we evaluated the potential connection between prolonged trans fat consumption and development of hyperactivity-like symptoms in rats using different behavioral paradigms. Trans fat intake for 10 months (Experiment 1), as well as during pregnancy and lactation across two sequential generations of rats, (Experiment 4) induced active coping in the forced swimming task (FST). In addition, HVF supplementation was associated with increased locomotion before and after amphetamine (AMPH) administration (Experiment 2). Similarly, HVF supplementation during pregnancy and lactation were associated with increased locomotion in both young and adult rats (Experiment 3). Furthermore, trans fat intake across two sequential generations increased locomotor and exploratory activities following stressors (Experiment 4). From these results, we suggest that chronic consumption of trans fat is able to enhance impulsiveness and reactivity to novelty, facilitating hyperactive behaviors.

Toxicological aspects of trans fat consumption over two sequential generations of rats: Oxidative damage and preference for amphetamine.

Chronic consumption of processed food causes structural changes in membrane phospholipids, affecting brain neurotransmission. Here we evaluated noxious influences of dietary fats over two generations of rats on amphetamine (AMPH)-conditioned place preference (CPP). Female rats received soybean oil (SO, rich in n-6 fatty acids (FA)), fish oil (FO, rich in n-3 FA) and hydrogenated vegetable fat (HVF, rich in trans fatty acids (TFA)) for two successive generations. Male pups from the 2nd generation were maintained on the same supplementation until 41 days of age, when they were conditioned with AMPH in CPP. While the FO group showed higher incorporation of n-3 polyunsaturated-FA (PUFA) in cortex/hippocampus, the HVF group showed TFA incorporation in these same brain areas. The SO and HVF groups showed AMPH-preference and anxiety-like symptoms during abstinence. Higher levels of protein carbonyl (PC) and lower levels of non-protein thiols (NPSH) were observed in cortex/hippocampus of the HVF group, indicating antioxidant defense system impairment. In contrast, the FO group showed no drug-preference and lower PC levels in cortex. Cortical PC was positively correlated with n-6/n-3 PUFA ratio, locomotion and anxiety-like behavior, and hippocampal PC was positively correlated with AMPH-preference, reinforcing connections between oxidative damage and AMPH-induced preference/abstinence behaviors. As brain incorporation of trans and n-6 PUFA modifies its physiological functions, it may facilitate drug addiction.

Cross-generational trans fat intake modifies BDNF mRNA in the hippocampus: Impact on memory loss in a mania animal model.

Recently, we have described the influence of dietary fatty acids (FA) on mania-like behavior of first generation animals. Here, two sequential generations of female rats were supplemented with soybean oil (SO, rich in n-6 FA, control group), fish oil (FO, rich in n-3 FA) and hydrogenated vegetable fat (HVF, rich in trans FA) from pregnancy and during lactation. In adulthood, half of each group was exposed to an amphetamine (AMPH)-induced mania animal model for behavioral, biochemical and molecular assessments. FO supplementation was associated with lower reactive species (RS) generation and protein carbonyl (PC) levels and increased dopamine transporter (DAT) levels, while HVF increased RS and PC levels, thus decreasing catalase (CAT) activity and DAT levels in hippocampus after AMPH treatment. AMPH impaired short- (1 h) and long- (24 h) term memory in the HVF group. AMPH exposure was able to reduce hippocampal BDNF- mRNA expression, which was increased in FO. While HVF was related to higher trans FA (TFA) incorporation in hippocampus, FO was associated with increased percentage of n-3 polyunsaturated FA (PUFA) together with lower n-6/n-3 PUFA ratio. Interestingly, our data showed a positive correlation between brain-derived neurotrophic factor (BDNF) mRNA and short- and long-term memory (r(2) = 0.53; P = 0.000/r(2) = 0.32; P = 0.011, respectively), as well as a negative correlation between PC and DAT levels (r(2) = 0.23; P = 0.015). Our findings confirm that provision of n-3 or TFA during development over two generations is able to change the neuronal membrane lipid composition, protecting or impairing the hippocampus, respectively, thus affecting neurothrophic factor expression such as BDNF mRNA. In this context, chronic consumption of trans fats over two generations can facilitate the development of mania-like behavior, so leading to memory impairment and emotionality, which are related to neuropsychiatric conditions.

Cross-generational trans fat intake facilitates mania-like behavior: oxidative and molecular markers in brain cortex.

Since that fast food consumption have raised concerns about people's health, we evaluated the influence of trans fat consumption on behavioral, biochemical and molecular changes in the brain-cortex of second generation rats exposed to a model of mania. Two successive generations of female rats were supplemented with soybean oil (SO, rich in n-6 FA, control group), fish oil (FO, rich in n-3 FA) and hydrogenated vegetable fat (HVF, rich in trans FA) from pregnancy, lactation to adulthood, when male rats from 2nd generation received amphetamine (AMPH-4 mg/kg-i.p., once a day, for 14 days) treatment. AMPH increased locomotor index in all animals, which was higher in the HVF group. While the FO group showed increased n-3 polyunsaturated fatty acid (PUFA) incorporation and reduced n-6/n-3 PUFA ratio, HVF allowed trans fatty acid (TFA) incorporation and increased n-6/n-3 PUFA ratio in the brain-cortex. In fact, the FO group showed minor AMPH-induced hyperactivity, decreased reactive species (RS) generation per se, causing no changes in protein carbonyl (PC) levels and dopamine transporter (DAT). FO supplementation showed molecular changes, since proBDNF was increased per se and reduced by AMPH, decreasing the brain-derived neurotrophic factor (BDNF) level following drug treatment. Conversely, HVF was related to increased hyperactivity, higher PC level per se and higher AMPH-induced PC level, reflecting on DAT, whose levels were decreased per se as well as in AMPH-treated groups. In addition, while HVF increased BDNF-mRNA per se, AMPH reduced this value, acting on BDNF, whose level was lower in the same AMPH-treated experimental group. ProBDNF level was influenced by HVF supplementation, but it was not sufficient to modify BDNF level. These findings reinforce that prolonged consumption of trans fat allows TFA incorporation in the cortex, facilitating hyperactive behavior, oxidative damages and molecular changes. Our study is a warning about cross-generational consumption of processed food, since high trans fat may facilitate the development of neuropsychiatric conditions, including bipolar disorder (BD).

Intake of trans fatty acids causes nonalcoholic steatohepatitis and reduces adipose tissue fat content.

We investigated the effects of dietary trans fatty acids, PUFA, and SFA on body and liver fat content, liver histology, and mRNA of enzymes involved in fatty acid metabolism. LDL receptor knockout weaning male mice were fed for 16 wk with diets containing 40% energy as either trans fatty acids (TRANS), PUFA, or SFA. Afterwards, subcutaneous and epididymal fat were weighed and histological markers of nonalcoholic fatty liver disease (NAFLD) were assessed according to the Histological Scoring System for NAFLD. PPARalpha, PPARgamma, microsomal triglyceride transfer protein (MTP), carnitine palmitoyl transferase 1 (CPT-1), and sterol regulatory element binding protein-1c (SREBP-1c) mRNA were measured by quantitative RT-PCR. Food intake was similar in the 3 groups, although mice fed the TRANS diet gained less weight than those receiving the PUFA diet. Compared with the PUFA- and SFA-fed mice, TRANS-fed mice had greater plasma total cholesterol (TC) and triglyceride (TG) concentrations, less epididymal and subcutaneous fat, larger livers with nonalcoholic steatohepatitis (NASH)-like lesions, and greater liver TC and TG concentrations. Macrosteatosis in TRANS-fed mice was associated with a higher homeostasis model assessment of insulin resistance (HOMA(IR)) index and upregulated mRNA related to hepatic fatty acid synthesis (SREBP-1c and PPARgamma) and to downregulated MTP mRNA. Diet consumption did not alter hepatic mRNA related to fatty acid oxidation (PPARalpha and CPT-1). In conclusion, compared with PUFA- and SFA-fed mice, TRANS-fed mice had less adiposity, impaired glucose tolerance characterized by greater HOMA(IR) index, and NASH-like lesions due to greater hepatic lipogenesis. These results demonstrate the role of trans fatty acid intake on the development of key features of metabolic syndrome.

Trans-fatty acids in the diet stimulate atherosclerosis.

Epidemiological evidence has associated dietary trans-fatty acids (TFAs) with coronary heart disease. It is assumed that TFAs stimulate atherosclerosis, but this has not been proven. The purpose of this study was to determine the effects of consuming 2 concentrations of TFAs obtained from commercially hydrogenated vegetable shortening on atherosclerotic development in the presence or absence of elevated dietary cholesterol. Low-density lipoprotein receptor-deficient mice were fed 1 of 7 experimental diets for 14 weeks: low regular fat (LR), low trans-fat (LT), regular high fat, high trans-fat (HT), or a diet containing 2% cholesterol with low regular fat (C + LR), low trans-fat (C + LT), or high trans-fat (C + HT). The extent of lesion development was quantified by en face examination of the dissected aortae. Dietary cholesterol supplementation significantly elevated serum cholesterol levels. Surprisingly, this rise was partially attenuated by the addition of TFAs (C + LT and C + HT) in the diet. Serum triglyceride levels were elevated with the higher-fat diets and with the combination of trans-fat and cholesterol. Animals consuming TFAs in the absence of dietary cholesterol developed a significantly greater extent of aortic atherosclerotic lesions as compared with control animals (LT > LR and HT > regular high fat). Atherosclerotic lesions were more extensive after cholesterol feeding, but the addition of TFAs to this atherogenic diet did not advance atherosclerotic development further. In summary, TFAs are atherogenic on their own; but they do not stimulate further effects beyond the strongly atherogenic effects of dietary cholesterol.

Trans fatty acids: effects on cardiometabolic health and implications for policy.

In both developed and developing countries, trans fatty acids (TFA) are largely consumed from partially hydrogenated vegetable oils. This article focuses on TFA as a modifiable dietary risk factor for cardiovascular disease, reviewing the evidence for lipid and non-lipid effects; the relations of trans fat intake with clinical endpoints; and current policy and legislative issues. In both observational cohort studies and randomized clinical trials, TFA adversely affect lipid profiles (including raising LDL and triglyceride levels, and reducing HDL levels), systemic inflammation, and endothelial function. More limited but growing evidence suggests that TFA also exacerbate visceral adiposity and insulin resistance. These potent effects of TFA on a multitude of cardiovascular risk factors are consistent with the strong associations seen in prospective cohort studies between TFA consumption and risk of myocardial infarction and coronary heart disease (CHD) death. The documented harmful effects of TFA along with the feasibility of substituting partially hydrogenated vegetable oils with healthy alternatives indicate little reason for continued presence of industrially produced TFA in food preparation and manufacturing or in home cooking fats/oils. A comprehensive strategy to eliminate the use of industrial TFA in both developed and developing countries, including education, food labeling, and policy and legislative initiatives, would likely prevent tens of thousands of CHD events worldwide each year.