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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 (https://apps.automeris.io/wpd/). 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 (http://www.prisma-statement.org).samples 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