HindawiOxidative Medicine and Cellular LongevityVolume 2021, Article ID 9073859, 18 pages ArticleOxidative Stress Profile of Mothers and Their Offspring afterMaternal Consumption of High-Fat Diet in Rodents: A SystematicReview and Meta-AnalysisR. Q. Moraes-Souza ,1,2 Giovana Vesentini ,1,3 Verônyca Gonçalves Paula ,1Yuri Karen Sinzato ,1 T. S. Soares ,1,2 Rafael Bottaro Gelaleti ,1Gustavo Tadeu Volpato ,2 and Débora Cristina Damasceno 11Laboratory of Experimental Research on Gynecology and Obstetrics, Gynecology, Postgraduate Course on Tocogynecology,Botucatu Medical School, São Paulo State University (Unesp), Botucatu, São Paulo State, Brazil2Laboratory of System Physiology and Reproductive Toxicology, Institute of Biological and Health Sciences, Federal University ofMato Grosso (UFMT), Barra do Garças, Mato Grosso State, Brazil3School of Rehabilitation, Faculty of Medicine, Université de Montréal and Research Center of the Institut Universitaire de Gériatriede Montréal, Montréal, Québec, CanadaCorrespondence should be addressed to Giovana Vesentini; [email protected] 13 April 2021; Revised 27 September 2021; Accepted 26 October 2021; Published 24 November 2021Academic Editor: Gabriele SaretzkiCopyright 2021 R. Q. Moraes-Souza et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.Maternal exposure to the high-fat diet (HFD) during gestation or lactation can be harmful to both a mother and offspring.The aim of this systematic review was to identify and evaluate the studies with animal models (rodents) that were exposed tothe high-fat diet during pregnancy and/or lactation period to investigate oxidative stress and lipid and liver enzyme profile ofmothers and their offspring. The electronic search was performed in the PUBMED (Public/Publisher MEDLINE), EMBASE(Ovid), and Web of Science databases. Data from 77 studies were included for qualitative analysis, and of these, 13 studieswere included for meta-analysis by using a random effects model. The pooled analysis revealed higher malondialdehyde levels inoffspring of high-fat diet groups. Furthermore, the pooled analysis showed increased reactive oxygen species and lower superoxidedismutase and catalase in offspring of mothers exposed to high-fat diet during pregnancy and/or lactation. Despite significantheterogeneity, the systematic review shows oxidative stress in offspring induced by maternal HFD.1. IntroductionDuring gestation, the developing fetus is totally dependenton the maternal environment for nutrition [1]. The intrauterine environment is a crucial determinant in the fetalprogramming of chronic diseases in adulthood. This conceptis called Fetal Origin of Adult Diseases (FOAD) [2]. However, after several studies, this term has been extended toDOHaD (Developmental Origins of Health and Disease)[3] and encompasses from the pregestational state (oocytes),gestation, and postnatal periods involving the entire periodof postnatal development and maturation from childhood toadolescence [4] although it is controversial. There is also otherevidence about these periods which the DOHaD includes thatspread worldwide through the “First 1000 Days” campaign,which supports the importance of the nutritional status ofinfants and nursing mothers during the fetal and neonatalperiods until two years after birth comprising between 280days before birth and approximately 730 infantile days afterbirth [5]. Although there is no single consensus, researchinvolving DOHaD thematic purposes to raise awareness aboutnutrition and health have been investigated [4].

2According to the World Health Organization (WHO),malnutrition refers to deficiencies, excesses, or imbalancesin a person’s intake of energy and/or nutrients [6], leadingto undernutrition or overnutrition [7]. The population isleaving traditional diets that are rich in fibers and grain fordiets that include increased levels of sugars, oil, and animalfats [8]. There are five times more obese than malnourishedadult people worldwide [6].The excess of high-fat diet (HFD) consumption is associated with the establishment of permanent state of inflammation [9] and an increased availability of some nutrients, suchas free fatty acids, and the glucose overloads the whole cascade of the electron transport chain and consequentlyincreases the production of reactive oxygen species [9, 10].The increased oxidative environment can be a vicious cyclebetween inflammatory processes [11]. These disorders inthe organism can contribute to the establishment of metabolic diseases [9, 11]. Furthermore, the excessive ROS causescumulative oxidative damage to macromolecules, includingDNA, proteins, and membrane lipid [12].Maternal consumption of HFD is an important factorthat causes harm to both mothers and their offspring [13,14]. In the last decades, epidemiological evidence has shownthat intrauterine life conditions influence growth, body composition, and the risk of developing chronic diseases [15].Animal studies also indicate that overnutrition duringpregnancy induces phenotypic changes that can enhancesusceptibility to diseases in adult offspring [16, 17], such ashyperglycemia [18], obesity [19–21], and metabolic syndrome [22]. The maternal HFD consumption also causesoxidative stress on offspring [23, 24]. However, the mechanisms are largely unknown. Lin et al. [25] suggested thatthe maternal redox state affects the placenta and consequently the fetal development changing transcription factorsand abnormal gene expression of antioxidant defenses of thefetuses. In addition, the adverse effects of oxidized molecules, such as lipids and proteins, at critical windows of thefetal development (prenatal or postnatal) “program” the susceptibility to the metabolic syndrome [23].Epidemiological studies in humans are limited in theirability to assess the influence of diet during pregnancy to offspring phenotype because it is difficult to distinct the effectsof intrauterine and post-natal maternal exposure and geneticfactors [24]. Therefore, research involving adequate experimental models is relevant, not only for ethical reasons butalso due to uncontrollable variables, such as lifestyle, socioeconomic, nutritional, and genetic factors. Hence, the objective of this systematic review was to identify and evaluate thestudies with animal models (rodents) that were exposed tothe HFD during pregnancy and/or lactation period to investigate oxidative stress of mothers and their offspring.2. Methods2.1. Literature Search. This systematic review was undertaken in accordance with the PRISMA [26] and registeredon PROSPERO-International Prospective Register of Systematic Reviews (Protocol number CRD42019120418). Theliterature search was performed on April 30, 2020, on titles,Oxidative Medicine and Cellular Longevityabstracts, and keywords in PUBMED (Public/PublisherMEDLINE), EMBASE (Ovid), and Web of Science databases. The following Medical Subject Headings (MeSH)and their synonyms were used in different combinationsand variations with the Boolean operators “OR” and“AND” to yield a sensitive and comprehensive, yet relevantcollection of possible articles “high-fat diet,” “oxidativestress,” “triglyceride,” “cholesterol,” “low-density lipoprotein,”“high density lipoprotein,” “Alanine transaminase,” “alanineaminotransferase,” and “rodent” (see Supplementary Table S1for complete search strategy). Our primary outcome was toevaluate oxidative stress levels of mothers and their offspring.The secondary outcomes were to investigate the lipid andliver enzyme profile of mothers and their offspring. Besidesthe electronic search, other sources were used, such as handsearching and screening of reference lists.Additional records were included from review articlesand author-based searches. The searches were restricted tooriginal studies that were published in the English languagein scientific journals submitted to the peer-review processwithout year restriction. Two reviewers (RQMS and VPG)independently screened the titles, abstracts, and full-textmanuscripts. Disagreements were resolved in consensus discussions with a third reviewer (DCD).2.2. Eligibility Criteria. Original animal studies were includedin the data set only if they fulfilled the following criteria:(1) Types of participants: these are rats and mice of anyage; nonrodents, spontaneously obese; and genetically modified animals; ex vivo and in vitro studiesinvolving human subjects were excluded.(2) Types of intervention: studies on dams are subjectedto an HFD around gestation (before and/or duringthe whole or any part of pregnancy) or lactation.HFD was considered chow-based HFD from any fattype (e.g., lard and vegetable oils). The % of fat andtime of diet exposure were not limited. Custommade diet (i.e., cafeteria), high-fiber diet, high-caloriediet, high-glucose diet, low-fat diet in short, and anyother diets than non-high-fat diet were excluded.(3) Comparisons: animals that were fed a standard dietwere included. The evaluation of articles presentingother forms of manipulation (i.e., surgery, drugs,stress, and exercise) was not considered.(4) Types of outcome measures: the included primaryoutcomes were oxidative stress of the dams and theiroffspring.(i) Oxidative stress status: malondialdehyde/thiobarbituricacid reactive substances (MDA/TBARS) (lipid oxidation), superoxide dismutase (SOD), catalase (CAT) andglutathione peroxidase (GPx) activities, 8-hydroxy-2′-deoxyguanosine (8-OHdG-DNA oxidation), quantification, and scavenging reactive oxygen species (ROS)

Oxidative Medicine and Cellular LongevitySecondary outcomes included the following:(i) Lipid profile: triglyceride (TG), total cholesterol(TC), high-density lipoprotein (HDL), and lowdensity lipoprotein (LDL) concentrations(ii) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities2.3. Data Extraction. Pairs of reviewers (RQMS and GV)independently extracted data into an excel spreadsheet.The following information was extracted from studies presenting eligibility criteria: publication characteristics (firstauthor, title, publication year, and journal), animal strain,intervention, and control diets (nutrient content, periodand time of administration, proportion of Kcal, and age ofthe start of intervention), specific methods used for assessment of oxidative stress, lipid and liver enzyme profile, andmaternal and offspring outcomes [sample size (n), mean,standard deviation (SD), and standard error (SE)]. Whendata were provided in graphical images, we extracted datausing WebPlotDigitizer 4.2 ( If relevant data were unclear, we contact authors to provide further information.2.4. Risk of Bias Assessment. Risk of bias for animal studieswas assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE’s tool), which wasevaluated in ten steps: three of selection (random group allocation, group similar at baseline, and blinded group allocation); two of them on performance (random housing andblinded intervention); two of detection (random and blindedoutcome assessment); one of attrition bias (reporting ofdrop-outs); one reporting (selective outcomes); and one toother potential bias [27]. Included studies were assessed independently by two reviewers (RQMS and GV), and any discrepancies were solved by discussion. The items were classified aslow, unclear, or high risk of bias (see SupplementaryFigure S2). The score of all the articles was defined as thepercentage of 0 to 100% and each category [27]. We assessedthe risk of bias of studies included in meta-analysis and didnot exclude studies based on high risk of bias.2.5. Statistical Analysis. Statistical analysis and forest plotswere conducted using Review Manager [28]. Studies wereconsidered for meta-analysis if interventions were considered to be similar in terms of period and length of exposure,more than two studies were available, all outcome data couldbe obtained, and assessment of outcomes were consideredcomparable. We presented separate pooled effects for damsand their offspring. If a study using the same methods forintervention and control groups reported outcome data separately for sex, the respective groups were pooled using therecommendations in the Cochrane Handbook [29]. Whenthe outcome was measured in different age cohorts, we thenconsidered more than one outcome from the same study. Incase of when the outcome was assessed in multiple tissues inthe same animal (e.g., blood, liver, and mesentery), only oneassessment was included in the meta-analysis to avoid dou-3ble counting the sample size. We conducted meta-analysison the levels of oxidative and antioxidative stress markersfor continuous variables, and the effect sizes were pooledand presented as standardized mean difference (SMD) sincethe outcomes were measured in different units across theincluded studies. Forest plot was generated by the softwareto illustrate the individual and pooled effect sizes along with95% confidence interval (CI) using random effects modelsdue to anticipated heterogeneity. The association of percentage of fat and death age and primary outcomes was assesseda using random effects metaregression model. All metaregression results were generated using R version 1.3.1093(The R Foundation, Vienna, Austria). Between-study heterogeneity was calculated using I 2 statistics, and we considered any degree of heterogeneity. We defined according toI 2 cut-offs of low for 40%, moderate for 30-60-%, substantial for 50-90%, and considerable for 75% [24]. p value lessthan 0.05 was considered to be statistically significant.Publication bias was not accessed in the included studiesbecause there were an insufficient number of studies for thisassessment (i.e., less than 10 studies included in the metaanalysis) [29].3. Results3.1. Search Results. Initial electronic searching using threedatabases yielded a number of 2372 of citations. In addition,33 articles were added from other sources. The removal of662 duplicates resulted in 1710 individual articles to besubjected to inclusion and exclusion criteria. Firstly, theinclusion and exclusion criteria were imposed on title andabstract (removal of 1515) and secondly on study designand methods (removal of 119). Finally, 77 citations wereselected for review and are shown in Figure 1 [13, 14, 20,21, 23, 25, 30–100]. Of these studies, 68 evaluated lipid andhepatic enzyme profile and 21 evaluated oxidative stress profilewith 12 overlaps (i.e., studies that presented both outcomes).3.2. Characteristics of Studies That Evaluated StressOxidative Profile. The first reports assessing the effects ofmaternal HFD on oxidative stress of dams and/or offspringwere published in 2009 [40]. All studies were published inthe last ten years. The characteristics of the selected maternalresults are shown in Table 1. Data could be retrieved from 4studies with six comparisons that provided sufficient data formeta-analysis [14, 25, 44, 47]. Only two rodent species havebeen used in the included studies: mice (C57Bl/6) [14 48]and rats (Sprague–Dawley and Wistar) [25, 44]. Fat contentin maternal HFD was 40% [30], 45% [14], and 49% [44] calories from fat (control group 10 and 11%), and the mainsource was the animal-derived fats (lard). The duration ofthe intervention was 19 (pregnancy only) [25], 42 (pregnancy and lactation) [44], 63 (premating period, pregnancy,and lactation) [14], and 113 (premating period, pregnancy,and lactation) [47] days. Feeding was reported as ad libitumin the included studies. All studies reported the MDA levelsas outcome, one investigated the maternal scavenging capacity on reactive oxygen species [25], and other two studies[44, 47] showed antioxidant enzymes as outcome. Different

Oxidative Medicine and Cellular LongevityIdentification4Records identified throughdatabase searching (n 2372)PUBMED: 505 EMBASE: 992web of science: 875Additional records identifiedthrough other sources(n 33)ScreeningRecords after duplicates removed(n 1710)Records screened(n 1711)EligibilityFull-text articles assessedfor eligibility (n 196)Records excluded(n 1515)Full-text articles excluded,with reasons (n 119) noadhering to interventioncriteria (47); conferenceabstracts (19); nocomparison established(6); other population (9)other outcomes reported(38)IncludedStudies included inqualitative synthesis⁎(n 77 21 oxidative stress,68 lipid profile and hepaticenzymes and 12 overlaps)Studies included inquantitative synthesis(meta-analysis) (n 13)Figure 1: Flow diagram of selection of articles based on PRISM guidelines ( were tested in the included studies, all studies usedblood samples [14, 25, 47], two used the liver [14, 25], oneused the mammary tissue [47], and one used placenta [25].Table 2 provides an overview of the study characteristicsand outcome measures of the offspring effects. We extracteddata from 18 studies that described 49 independent comparisons; however, not all necessary data for meta-analysiscould be extracted from papers [23, 25, 30–42, 45, 46]. Outof 18 selected studies, ten [23, 25, 33–38, 45, 46] used rats(four Sprague–Dawley and six Wistar) and eight studies[30–32, 34, 39–41, 43] used mice (C57BL/6). Data fromeleven studies were obtained from male offspring [30–33,37–40, 42, 43, 46], and six studies used groups of mixedsex [25, 34–36, 41, 45], whereas only one study representeddata obtained from females [23]. The death age of the offspring was between one day after birth [25] and 650 daysold [38, 40]. Among the included studies, there were no consistent patterns with respect to characteristics of HFD. Fatcontent in maternal HFD ranged from 29% [36] to 62%[41] calories from fat and the control group from 10 to20%. The lard was the main fat component used byanimal-derived fats in the twelve studies [23, 25, 30, 33,36–39, 41, 43, 45, 46]; other two studies [34, 35] used vegetaloils; and four studies did not report the fat component used[31, 32, 40, 43]. The duration of maternal HFD exposureranges from 19 [25] to 141 days [38, 45], while the offspringHFD exposure ranges from 1 [25, 35, 40] to 650 postnatalday [38, 45].The largest number of comparisons was reported on offspring’s levels of MDA (36/49), SOD activity (25/49), andGPx (24/49) while a limited number of studies reportedcomparisons of ROS (14/49), CAT activity (12/49), 8OHdG (4/49), and Thiols groups (2/49). The oxidative stresslevels were evaluated in sixteen (33%) liver samples; bloodsamples were assessed in fifteen assays (31%). Other sampleswere also used, three (6%) used sperm, three (6%) used tests,four (8%) used mesentery, two (4%) tested islet, two (4%)used femoral artery, two (4%) tested kidney, one used mesentery vessels (2%), and another one (2%) used cardiomyocytes (Table 2).3.3. Characteristics of Studies That Evaluated Lipid andHepatic Enzyme Profile. Supplementary Table S2 shows theperiod of maternal exposure to diet and the assessments of

Oxidative Medicine and Cellular Longevity5Table 1: Maternal oxidative stress repercussions.Outcomes of damsScavengingMDA ROS SOD CAT GPX capacity of reactiveoxygen speciesKcal of fat/main fat sourceMaternal HFDconsumption(days)40%/lard19 NM NM NM NM Blood40%/lard19 NM NM NM NM PlacentaRats Wistar71%/lard42 NMNMNMLiverRats Wistar71%/lard42 NM NM NM NMNMBlood45%/lard63 NM NM NM NMNMBlood45%/lard63 NM NM NM NMNMLiver113 NM NMBlood113 NM NMMammarytissueReferencesAnimalLin et al.,[25]aLin et al.,[25]bGonçalveset al., [44]aGonçalveset al., [44]bKim et al.,[14]aKim et al.,[14]bHarphoushet al., [47]aHarphoushet al., ) SampleevaluatedMDA: malondialdehyde; ROS: reactive oxygen species; SOD: superoxide dismutase; CAT: catalase; GPx: glutathione peroxidase; ROS: scavenging capacity ofreactive oxygen species; NM: not measured.maternal lipid and hepatic biomarkers. The HFD exposureranges from 19 to 141 days [25, 61]. The biochemicalparameters analyzed were TG, TC, HDL, LDL, and ALT.Of the 21 assessments on maternal TG level, 16 (76%)presented increased levels [14, 20, 25, 35, 43, 48, 51,52–60], four (19%) showed no change [21, 49, 53, 55], andone (5%) showed a decreased level [50]. The maternal TClevel was presented in ten evaluations, eight (80%) wereincreased [14, 20, 21, 40, 56, 60, 61], one (10%) showed nochange [55], and another (10%) was decreased [20]. Of thefour analyses of maternal HDL, two (50%) presented anincrease [56], and the other two (50%) presented nochange [14, 25]. Two studies (100%) evaluated maternalLDL assessments and showed higher levels of thisbiomarker [56]. The only paper with maternal analysis ofALT showed no change [14].The period of maternal diet exposure, characteristics ofoffspring (sexes and death age), and biochemical measurements of the offspring are presented in SupplementaryTable S3. The HFD exposure ranges from 21 to 154 days[23, 37, 61–64, 74, 88, 89]. In relation to gender, 31 articlesverified both genders [21, 35, 36, 41, 50, 54, 57, 58, 60–62,64–66, 68, 71, 72, 80–82, 84–92, 94, 96, 99]; 23 studiesanalyzed males [14, 18, 30–33, 37, 40, 42, 48, 51–53, 55,56, 63, 74, 75, 77, 78, 83, 91, 93, 100], 11 evaluated females[23, 59, 67, 70, 73, 76, 79, 87, 88, 95, 97], and only one didno report on the offspring sex [69]. The ranged age for theoffspring was between one day after birth [21, 30, 35, 40,50, 52, 53, 55, 62, 89] and 360 days old [71]. The observedbiochemical parameters were TG, TC, HDL, LDL, ALT,and AST. Of the 141 assessments about TG, 65 (46%)verified higher levels, 71 (50%) showed no change, and five(4%) presented lower levels. Of all 86 evaluations aboutTC, 21 (24%) showed increased levels, 58 (68%) verified nochange, and seven (8%) observed lower concentrations.There were 33 HDL assessments in the offspring. Of these,three (9%) were increased, 26 (79%) presented noabnormal HDL levels, and four (12%) had decreasedconcentrations. Furthermore, in 20 analyses of LDL of theoffspring, seven (35%) presented higher levels, 12 (60%) ofthem showed no change, and one (5%) observed lowerlevel. The AST enzymatic activity of the liver of theoffspring was increased in one article (12.5%), and in seven(87.5%), no change was observed. Of the 11 studies aboutALT measurements, four (36%) presented higher activity,and seven of them (64%) had no change. Given thesubstantial level of heterogeneity in the studies that assesslipid and hepatic enzyme profile, we did not present aquantitative analysis for this outcome.3.4. Effects of HFD on Stress Oxidative Status in Dams andOffspring. Four studies were included in the meta-analysison MDA levels in dams that received HFD compared withcontrols [14, 25, 44, 47]. The MDA levels of included studieswere measured from day 19.5 of pregnancy to the end of lactation. The effect size of MDA was not different in mothersexposed to HFD compared to control, SMD 2.15 (95% CI:-0.21 to 4.52, p 0:07; I 2 89%) (Figure 2). Two studieswere included in the meta-analysis on SOD (SMD: -2.62;95% CI: -9.15 to 3.90, p 0:43; I 2 94%) and CAT (SMD:-0.73; 95% CI: -1.56 to 0.09, p 0:08; I 2 92%) were not different in mothers exposed to HFD compared to control(Supplementary Figure S1).Data on MDA levels of the offspring were available fromfive studies [23, 37, 42, 43, 45] between 21 and 650 days oflife. Two studies were included two times in meta-analysisas the MDA levels were analyzed in two separate age cohorts(90 and 180 days) [23, 37]. Another study was included

aMiranda et al., [36]aMiranda et al., [36]bOliveira et al., [46]Rodriguez-Gonzalezet al., [38]aRodriguez-Gonzalezet al., [38]bRodriguez-Gonzalezet al., [38]cRodriguez-Gonzalezet al., [38]dRodriguez-Gonzalezet al., [38]eRodriguez-Gonzalezet al., [38]fRodriguez-Gonzalezet al., [38]aGray et al., [33]Mdaki et al., [35]Zhang et al., [42]bZhang et al., [42]aEmiliano et al., [23]Emiliano et al., [23]bEmiliano et al., [23]cEmiliano et al., [23]dResende et al., [37]aResende et al., [37]bResende et al., [37]cResende et al., [37]dLin et al., %/lard46%/lard46%/lard46%/lard46%/lard46%/lardRats (Wistar)Rats (Wistar)Rats (Wistar)Rats (Wistar)Rats (Wistar)Rats (Wistar)Rats (Wistar)141141141141141141141989898524940%/oil vegetable animal fat45%/lard4242212121212121212119Maternal HFDconsumption %/lardKcal of fat/mainfat sourceRats (Sprague–Dawley)Rats (Wistar)Rats (Wistar)Rats (Wistar)Rats (Wistar)Rats (Wistar)Rats (Wistar)Rats (Wistar)Rats (Wistar)Rats (Sprague–Dawley)Rats (Sprague–Dawley)Rats (Sprague–Dawley)Rats (Sprague–Dawley)Rats (Wistar)Rats (Wistar)Rats 090180901801Death age(days)Outcomes of offspringNMNM NMNMNMNMNMNMNMNMNMNM NMNMNMNMNMNMNMNMNMNMNMNMNMNM NMNM NM NM NMNMNMNMNMNM NM NM NM NMNM NM NM NMNMNMNMNMNMNM NM NMNM NM NM NMNMNMNMNMNMNMNMNMNMNMNMNMNMNMNM NM NM NMNM NM NM NMNM NM NM NMNMNMNMNMNMNMNMNMNMMDA 8-OHdG ROS SOD CAT GPX ThiolsTable 2: Oxidative stress repercussions from senteryLiverSampleevaluated6Oxidative Medicine and Cellular Longevity

%/lard45%/unidentified45%/unidentified31%/oil vegetable animal fat31%/oil vegetable animal d57.50%/unidentifiedRats (Wistar)Rats (Wistar)Rats (Wistar)Rats (Wistar)Rats (Wistar)Rats (Wistar)Rats (Wistar)Mice (C57BL/6)Mice (C57BL/6)Mice (C57BL/6)Mice (C57BL/6)Ito et al., [34]aIto et al., (C57BL/6)(C57BL/6)(C57BL/6)46%/lardRats ts (Wistar)Yokomizo et al., [41]Yokomizo et al., [41]bTorrens et al., [39]aTorrens et al., [39]bTozuka et al., [40]aTozuka et al., [40]bTozuka et al., [40]cTozuka et al., [40]d46%/lardRats (Wistar)a46%/lardKcal of fat/mainfat sourceRats (Wistar)AnimalRodriguez-Gonzalezet al., [38]bRodriguez-Gonzalezet al., [38]cRodriguez-Gonzalezet al., [38]dRodriguez-Gonzalezet al., [38]eRodriguez-Gonzalezet al., [38]fRodriguez-Gonzalezet al., [38]gRodriguez-Gonzalezet al., [38]hRodriguez-Gonzalezet al., [38]iRodriguez-Gonzalezet al., [38]jRodriguez-Gonzalezet al., [38]kRodriguez-Gonzalezet al., [38]lcaCao et al., 1141141141141141141141Maternal HFDconsumption e 2: 50110650450110650450Death age(days)NMNM NMNMNMNMNMNMNMNMNMNMNMNMNMNMNMNMNM NMNMNMNMNMNM NM NMNMNMNM NM NM NM NMNM NMNMNMNMNMNM NM NM NMNM NM NM NMNMNMNMNMNMNMNMNMNMNMNMNMNMNMNMNMNMNMNMNMNMNMNMNM NM NM NM NM NM NM NMNM NM NM NMNM NM NM NMNM NM NM NMNM NM NM NM A 8-OHdG ROS SOD CAT GPX ThiolsOutcomes of offspringIsletIsletFemoral arteryFemoral dSampleevaluatedOxidative Medicine and Cellular Longevity7

Mice (C57BL/6)Mice (C57BL/6)Mice 9%/lardKcal of fat/mainfat source848498Maternal HFDconsumption (days)MMMSexoffspring22422410Death age(days)NMNMNM NMNM NM NM NMNM NM NM NMNM NMNMNMMDA 8-OHdG ROS SOD CAT GPX ThiolsOutcomes of offspringMDA: malondialdehyde; 8-OHdG: 8-hydroxy-2 ′ -deoxyguanosine; ROS: reactive oxygen species; SOD: superoxide dismutase; CAT: catalase; GPx: glutathione peroxidase; NM: not measured.Glastras et al., [32]Glastras et al., [31]Bringhenti et al., [30]ReferencesTable 2: ve Medicine and Cellular Longevity

Oxidative Medicine and Cellular Longevity9HFDControlStd. mean differenceStudy or subgroup Mean SD Total Mean SD Total Weight IV, Random, 95%Cl3.31 2.310 4.67 2.18 12 27.9% –0.59 [–1.45, 0.28]Gonçalves, 20182.43 [0.79, 4.07]6.09 1.526 3.11 0.5Harphoush, 20196 25.5%28.55 4.065 18.07 3.382.64 [0.91, 4.36]Kim, 20167 25.1%4.83 [2.21, 7.45]27.94 3.076 14.79 1.79Lin, 20116 21.4%Std. mean differenceIV, Random, 95%Cl2731 100.0% 2.15 [–0.21, 4.52]Total (95%Cl)Heterogeneity: Tau2 5.03; Chi2 27.23, df 3 (P 0.00001); I2 89%–10Test for overall effect: Z 1.78 (P 0.07)–505Control HFD10Figure 2: Meta-analysis of HFD maternal consumption on MDA levels compared with controls. HFD: high-fat diet; 95% CI: 95%confidence interval; IV: inverse variance.Study or subgroupStd. mean differenceHFDControlMean SD Total Mean SD Total Wight IV, Random, 95%ClCao, 2018Emiliano, 2011-180 daysEmiliano, 2011-90 daysResende, 2013-180 daysResende, 2013-90 daysRodríguez-González, 2019-110 daysRodríguez-González, 2019-450 daysRodríguez-González, 2019-650 daysZhang, 201112.712.431.2 0.0480.3503.3 0.2440.65 0.024451.53 110.29537.2 71.51552.1493.516.7983.28 1.2160.8060.2 0.04861.3 0.24460.3 0.24414 323.92 46.611 449.07 56.6712 525.15 97.71914.9 6.32Total (95%Cl)78Heterogeneity: Tau2 2.12; Chi2 49.86, df 8 (P 0.00001); I2 84%Test for overall effect: Z 4.11 (P 4%14.7%14.5%4.64 [2.55, 6.74]10.88 [5.45, 16.31]4.08 [1.79, 6.37]7.57 [3.70, 11.43]1.86 [0.41, 3.32]1.46 [0.62, 2.31]1.32 [0.40, 2.24]0.27 [–0.53, 1.08]0.22 [–0.68, 1.13]80 100.0%2.39 [1.25, 3.53]Std. mean differenceIV, Random, 95%Cl–10–50510Control HFD(a)Study or subgroupStd. mean differenceHFDControlMean SD Total Mean SD Total Weight IV,

low, unclear, or high risk of bias (see Supplementary Figure S2). The score of all the articles was defined as the percentage of 0 to 100% and each category [27]. We assessed the risk of bias of studies included in meta-analysis and did not exclude studies based on high risk of bias. 2.5. St