UNIVERSIDADE ESTADUAL PAULISTA 

“JÚLIO DE MESQUITA FILHO” 

FACULDADE DE MEDICINA 
 
 
 
 
 
 
 
 
 

Rafaianne Queiroz de Moraes Souza 
 
 
 
 
 
 
 
 

Repercussões bioquímicas e reprodutivas de 

mães e descendentes após o consumo materno 

de dieta hiperlipídica em roedores: Revisão 

Sistemática 
 
 
 
 
 

Tese apresentada à Faculdade 
de Medicina, Universidade 
Estadual Paulista “Júlio de 
Mesquita Filho”, Campus de 
Botucatu, para obtenção do título 
de Doutora em Ginecologia, 
Obstetrícia e Mastologia. 

  
  
  
 
 

Orientadora: Profa. Dra. Débora Cristina Damasceno 

Coorientador: Prof. Dr. Gustavo Tadeu Volpato 

 

 

Botucatu 

2019 



 
 

 

Botucatu 

2019 
 

 
 

 
  

Rafaianne Queiroz de Moraes Souza 
 
 
 

 
 
 
 

 

Repercussões bioquímicas e reprodutivas de mães 
e descendentes após o consumo materno de dieta 

hiperlipídica em roedores: Revisão Sistemática 

  
 
 
 
 

Tese apresentada à Faculdade 
de Medicina, Universidade 
Estadual Paulista “Júlio de 
Mesquita Filho”, Campus de 
Botucatu, para obtenção do título 
de Doutor(a) em Ginecologia, 
Obstetrícia e Mastologia (Área de 
Concentração: Ciências da 
Saúde). 

  
  
  
  
 
 

Orientadora: Profa. Dra. Débora Cristina Damasceno 

Coorientador: Prof. Dr. Gustavo Tadeu Volpato 

 

 
 

 
Botucatu 

2019 
 



 
 

 

 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 



 
 

 
 
 
 
 

 
 
 
 
 

“Sou feita de retalhos. 

Pedacinhos coloridos de cada vida que passa pela minha e que 

vou costurando na alma. 

Nem sempre bonitos, nem sempre felizes, mas me acrescentam 

e me fazem ser quem eu sou. 

Em cada encontro, em cada contato, vou ficando maior... 

Em cada retalho, uma vida, uma lição, um carinho, uma 

saudade... 

Que me tornam mais pessoa, mais humana, mais completa. 

 

E penso que é assim mesmo que a vida se faz: de pedaços de 

outras gentes que vão se tornando parte da gente também. 

E a melhor parte é que nunca estaremos prontos, finalizados... 

Haverá sempre um retalho novo para adicionar à alma. 

 

Portanto, obrigada a cada um de vocês, que fazem parte da 

minha vida e que me permitem engrandecer minha história 

com os retalhos deixados em mim. Que eu também possa deixar 

pedacinhos de mim pelos caminhos e que eles possam ser parte 

das suas histórias. 

 

E que assim, de retalho em retalho, possamos nos tornar, um 

dia, um imenso bordado de nós”. 

 
Cris Pizzimenti 

 
 

 
 



 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

Dedicatórias 
 

 



 
 

 

A Deus por toda graça e misericórdia infinita, pelo amor e cuidado 

de cada segundo. 

 

“Porque dEle e por Ele, e para Ele, são todas as coisas; glória, 

pois, a Ele eternamente” (Romanos 11:36) 

 

À minha família, por todo apoio, carinho e ensinamentos, tudo que 

sou devo a vocês. Especialmente ao meu filho, Miguel Queiroz M. Souza, 

que chegou a este mundo me ensinando que sempre é preciso lutar! 

 

“A família é o amor de Deus nos oferecendo um pouquinho do céu 

aqui na Terra.” (Autor desconhecido) 

  



 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

 

Agradecimentos  



 
 

Ao meu esposo, Bruno Andrade de Souza, que escolheu sonhar este sonho 

comigo, sempre esteve ao meu lado. Por todo incentivo, amparo e carinho, muito 

obrigada! 

Ao meu filho amado, Miguel Q. M Souza, pelo amor, carinho e hoje ser a 

maior alegria da minha vida. 

À minha mãe, Maria Joana Queiroz, por ser meu maior exemplo e me 

ensinar que devemos lutar por nossos sonhos. 

À minha sogra, Maria das Graças Andrade de Souza, por ser solicita e 

viajar 800 Km para cuidar do meu filho sempre que necessário, permitindo que eu 

pudesse estudar tranquilamente, nunca poderei retribuir tudo o que a senhora fez 

por nós!  

Ao meu Coorientador, Prof. Dr. Gustavo Tadeu Volpato, por ser mais que 

um professor em minha vida, um “pai científico”, um amigo querido. Sempre serei 

grata pelos anos de convivência e me lembrarei que só cheguei até aqui pela 

primeira oportunidade que recebi.  

À minha orientadora, Profa. Dra. Débora C. Damasceno, obrigada por se 

preocupar não só pelo meu aprendizado, mas também por questões pessoais. Nunca 

esquecerei das perguntas: Vocês estão com frio? Fome? Onde irão dormir? Serei 

eternamente grata, por ter este sentimento maternal e por sempre desejar o melhor 

para nós. Todos os ensinamentos me tornaram uma profissional e ser humano 

melhor. 

À minha amiga e parceira de longa data, Thaigra de Sousa Soares, por estar 

ao meu lado nesta jornada, obrigada por tudo. 

À Vêronyca de Paula Gonçalves, por ter mudado seus planos e decido a 

nos ajudar, não encontro palavras suficientes para expressar minha gratidão. 

À Giovana Vesentini, por todo tempo, ensinamento e paciência. Este 

trabalho se tornou possível por meio das suas contribuições. 

À profa. Dra. Yuri Karen Sinzato, por compartilhar conhecimentos, pela 

amizade e por ser um exemplo para mim. 

À minha família FISIOTOX (professores Gustavo Tadeu Volpato, 



 
 

Kleber Eduardo de Campos e Madileine F. Américo e todos os alunos), não 

poderei citar todos os nomes, porque durante quase 10 anos muitos passaram por lá 

e marcaram a minha vida, obrigada não só pelas discussões e reuniões científicas, 

mas pelos cafés e conversas do dia-a-dia.  

Aos meus colegas e amigos do LAPGO, aos que já saíram e os que ainda 

permanecem, obrigada por me acolherem e permitir que eu fizesse parte também 

desta família. 

Aos meus amigos Eduardo Kloppel, Carolina A. Miranda, Verônyca P. 

Gonçalves, Rosa Jacinto Volpato, Nágilla Orleane, por me abrigar, pela amizade 

e carinho para comigo. 

À Mariana Pirani e Larissa Lopes, por compartilhar conhecimentos, pela 

amizade e cada palavra de incentivo. 

Aos animais Pizza, Dristy, Lex, Madona e Brotinho, que me acolheram 

em seus lares e sempre me recepcionaram com carinho. 

À Carolina Saullo, por compartilhar conhecimento sobre constituição 

dietética. 

Aos assistentes de suporte acadêmico (ASA) da Unidade de Pesquisa 

Experimental (UNIPEX) da Faculdade de Medicina de Botucatu, especialmente aos 

Srs. Danilo Chaguri, Carlos Roberto Gonçalves de Lima, José Márcio Cândido 

e Jurandir Antônio, pela manutenção dos biotérios, limpeza e cuidados com os 

animais. Apesar deste trabalho não ser uma pesquisa original, participo de outros 

projetos. Então, agradeço por todo auxilio. Muito obrigada!  

À Faculdade de Medicina de Botucatu – Unesp, em especial ao Laboratório 

de Pesquisa Experimental de Ginecologia e Obstetrícia (LAPGO), por todos os 

recursos dispensados a mim. 

Aos funcionários da Seção de Pós-graduação da Faculdade de Medicina 

de Botucatu, em particular à secretária do Programa de Pós-graduação em 

Ginecologia, Obstetrícia e Mastologia, Sra. Solange Sako Cagliari, obrigada por 

ser sempre solicita e pelos auxílios prestados.  

Ao Escritório de Apoio à Pesquisa (EAP) da Faculdade de Medicina de 



 
 

Botucatu, Unesp, pelo serviço prestado. Em especial ao Prof. Dr. José Eduardo 

Corrente, pelos cálculos e análises estatísticas para os projetos que correram em 

paralelo a esta revisão sistemática. 

À equipe da biblioteca da Unesp de Botucatu pela confecção da ficha 

catalográfica e outros auxílios realizados. 

À Coordenação de Aperfeiçoamento de Pessoal de Nível Superior 

(CAPES), pela concessão da bolsa, permitindo total dedicação a execução desse 

estudo. 

A todos aqueles que contribuíram direta ou indiretamente para a realização 

deste trabalho. Obrigada por todos os gestos singelos ou grandiosos. É necessário 

ser grato, porque ninguém caminha sozinho! 

   

 

 

 

 

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Sumário 
 

 



 
 

Capítulo 1 ................................................................................................ 13 

1. Considerações iniciais ................................................................... 14 

2. Atividades desenvolvidas durante o doutorado ............................. 15 

2.1 Artigos publicados ................................................................... 15 

2.2 Apresentação de pôsteres em congressos .................... ......... 22 

2.3 Participações em bancas ......................................................... 22 

2.4 Coorientações concluídas de alunos ....................................... 23 

2.5 Atividades de ensino ................................................................ 23 
 

Capítulo 2 ................................................................................................ 24 

Abstract .......................................................................................... 26 

I. Introduction .................................................................................... 27 

II. Methods ......................................................................................... 28 

(1) Literature search ........................................................................ 28 
(2) Inclusion and exclusion criteria .................................................. 29 
(3) Data extration............................................................................. 30 
(4) Qualitative assessment .............................................................. 31 

III. Results ........................................................................................... 31 

(1) Description of the data set ......................................................... 31 
(2) Study characteristics .................................................................. 32 
(3) Analysis of bias .......................................................................... 35 

IV. Discussion ..................................................................................... 36 

V. Conclusion ..................................................................................... 46 

VI. References .................................................................................... 47 

VII. Appendix S1. Supplementary methods .......................................... 74 

Anexo1........................................................................................... 76 
Anexo2........................................................................................... 77 
Anexo3........................................................................................... 78 

 

Capítulo 3 ................................................................................................ 79 

Submissão da parte 1 do trabalho - PROSPERO ................................ 80 

PROSPERO registration mensagem ................................................... 89 

 

 
 
 

 
 
 
 
 



 
 
 

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Capítulo 1 



 
 
 

14 
 
 
 

 

 

 

1. CONSIDERAÇÕES INICIAIS 

 

Este estudo faz parte de um projeto mais amplo intitulado 

“Avaliação de descendentes expostas ao diabetes moderado 

intrauterino, submetidas à dieta hiperlipídica no período pós-natal e 

tratadas com mistura de cálcio e vitamina D durante a prenhez” 

(Protocolo CEUA 1218/2017). Obteve financiamento da FAPESP 

(Processo número 2016/25207-5, vigência de 01/07/2018 a 

30/06/2020).  

No primeiro projeto elaborado como sendo o doutorado de 

Rafaianne Queiroz Moares Souza, a metodologia contemplava os 

estudos sobre o útero materno e parâmetros fetais referente os 

animais do projeto completo descrito acima. Para obtenção de filhas 

de diabéticas (FDmod) com idade adulta, são necessários pelo menos 

180 dias (meio ano). Ao longo deste experimento, foi observado que 

as ratas FDmod apresentaram dificuldades para acasalamento, o que 

retardou o tratamento desses animais, bem como o experimento como 

um todo. Após o segundo ano de tentativas frustradas para obtenção 

de ratas prenhes, advindas de ambiente intrauterina hiperglicêmico e 

alimentadas com dieta hiperlipídica, a aluna obteve uma pequena 

amostragem de animais prenhes. Estes animais foram tratados, mas 

durante o experimento, todos os animais prenhes e não-prenhes 

foram a óbito em virtude de uma contaminação bacteriana, confirmada 

por exames específicos realizados no Laboratório Clínico do Hospital 

Veterinário da FMVZ – Unesp. Desta forma, a aluna precisou reiniciar 

todo o experimento para obtenção de todos os grupos experimentais. 

No entanto, como a aluna ainda está coletando os dados novamente 



 
 
 

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para apresentação desta tese foi realizada uma revisão sistemática a 

respeito deste assunto. Os resultados sobre prenhez e tratamento 

com vitamina D e/ou cálcio continuam em andamento e estarão sob a 

responsabilidade desta aluna e de outras estudantes envolvidas no 

projeto completo para que sejam tabulados, analisados, discutidos e, 

posteriormente, publicados em revista de âmbito internacional. 

 

 
2. ATIVIDADES EXECUTADAS DURANTE O DOUTORADO 

 

A aluna iniciou o Doutorado em março de 2015, durante todo 

esse período participou das atividades desenvolvidas no Laboratório 

de Fisiologia de Sistemas e Toxicologia Reprodutiva (FISIOTOX) da 

Universidade Federal do Mato Grosso (UFMT) e no Laboratório de 

Pesquisa Experimental em Ginecologia e Obstetrícia (LAPGO), 

pertencente ao Programa de Pós-graduação em Ginecologia, 

Obstetrícia e Mastologia da Faculdade de Medicina de Botucatu, 

Universidade Estadual Paulista (UNESP). 

 

2.1 Artigos Publicados 
 

2.1.1. Soares TS, Andreolla AP, Miranda CA, Klöppel E, Rodrigues 

LS, Moraes-Souza RQ, Damasceno DC, Volpato GT, Campos 

KE. Effect of the induction of transgenerational obesity on 

maternal-fetal parameters. Syst Biol Reprod Med. 2018; 

64(1):51-59.  



 
 
 

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2.1.2. Afiune LAF, Leal-Silva T, Sinzato YK, Moraes-Souza RQ, 

Soares TS, Campos KE, Fujiwara RT, Herrera E, Damasceno 

DC, Volpato GT. Beneficial effects of Hibiscus rosa-sinensis L. 

flower aqueous extract in pregnant rats with diabetes. PLoS 

One. 2017; 12(6):e0179785.  

 

 



 
 
 

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2.1.3. Moraes-Souza RQ, Reinaque AP, Soares TS, Silva AL, 

Giunchetti RC, Takano MA, Akamatsu MA, Kubrusly FS, Lúcio-

Macarini F, Raw I, Iourtov D, Ho PL, Bueno LL, Fujiwara RT, 

Volpato GT. Safety evaluation of a vaccine: Effect in maternal 

reproductive outcome and fetal anomaly frequency in rats using 

a leishmanial vaccine as a model. PLoS One. 2017; 

12(3):e0172525 (Publicação referente à Dissertação de 

Mestrado). 

 



 
 
 

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2.1.4. Pinheiro MS, Rodrigues LS, S L Neto, Moraes-Souza RQ, 

Soares TS, Américo MF, Campos KE, Damasceno DC, Volpato 

GT. Effect of Bauhinia holophylla treatment in streptozotocin-

induced diabetic rats. An Acad Bras Cienc. 2017; 89(1):263-

272.  

 



 
 
 

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2.1.5. Moraes-Souza RQ, Soares TS, Carmo NO, Damasceno DC, 

Campos KE, Volpato GT. Adverse effects of Croton urucurana 

B. exposure during rat pregnancy. J Ethnopharmacol. 

2017;199:328-333 (Publicação referente à Monografia). 

 



 
 
 

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2.1.6. Damasceno DC, Leal-Silva T, Soares TS, Moraes-Souza RQ, 

Volpato GT. Medicinal plants for diabetes treatment during 

pregnancy. Curr Med Chem. 2017; 24(4):404-410. 

 

 

 

 



 
 
 

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2.2 Apresentação de pôsteres em congressos nacionais e 

internacionais 

 

2.2.1. MORAES-SOUZA, R. Q.; CRUZ, L. L.; SOARES, T.S.; PAULA, 

V. G.; SINZATO, Y. K.; DAMASCENO, D. C.; VOLPATO, G. T 

“Effects of Curatella americana treatment on complications of 

diabetic pregnancy”. In: 6th International Symposium on 

Metabolic Programming and Microbiome and 3rd Meeting of 

Ibero-American DOHaD chapter, 2018, Cancun. Book of 

abstracts, 2018. v. 1. p. B60008. 

 

2.2.2. MORAES-SOUZA, R.Q.; REINAQUE, A. P. B.; SOARES, T.S.; 

BUENO, L. L.; FUJIWARA, R. T.; VOLPATO, G. T. 

“Repercussões maternas de ratas vacinadas com proteína 

peroxidoxina recombinante de Leishmania braziliensis durante 

a prenhez”. In: I Workshop do Programa de Imunologia e 

Parasitologia Básicas e Aplicadas, 2015, Barra do Garças. Livro 

de Resumos, 2015. v. 1. p. 11-11. 

 

2.2.3. MORAES-SOUZA, R.Q.; NETO, L.S.; ALVES, D. G.; SOARES, 

T.S.; CAMPOS, K. E.; AMERICO, M.F.; DAMASCENO, D. C.; 

VOLPATO, G. T. “Effect of Hancornia speciosa aqueous extract 

treatment on biochemical parameters in diabetic pregnant rats”. 

In: XX Congresso da Sociedade Brasileira de Diabetes, 2015, 

Porto Alegre. Diabetology & Metabolic Syndrome, 2015. v. 7. p. 

A76. 

 

Além das apresentações e participações em congresso, a 

aluna foi coautora de outros 36 resumos publicados em anais. 

 
2.3 Participações em bancas de trabalhos de conclusão de curso 

 

2.3.1. Participação em banca de Thalita Bohnen Carneiro. Efeitos 

materno-placentário-fetais em diferentes intensidades 

glicêmicas no início da prenhez dentro do modelo experimental 



 
 
 

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de diabete moderado, 2016 (Enfermagem) Universidade 

Federal de Mato Grosso. 

 

2.3.2. Participação em banca de Bruno Stephano Ferreira da Silva. 

Repercussões fetais do tratamento com Curatella americana 

em ratas prenhes com diabete de intensidade moderada, 2018 

(Enfermagem) Universidade Federal de Mato Grosso. 

 

2.4 Coorientações concluídas de alunos 

 
2.4.1. Vanessa Caruline Araujo da Silva.Repercussões maternas e 

fetais de ratas tratadas com Micofenolato de Sódio antes da 

prenhez. 2016. Orientador: prof. Dr. Gustavo Tadeu Volapto. 

Nível: iniciação científica.  

 

2.4.2. Cristielly Maria Barros Barbosa. Efeitos adversos do tratamento 

com Ciclosporina antes e durante a prenhez. 2016. Orientador: 

prof. Dr. Gustavo Tadeu Volapto. Nível: Iniciação Científica. 

 

2.4.3. Mário Cezar Fiuza Carlos. Repercussões maternas e fetais de 

ratas tratadas com Tacrolimo antes da prenhez. 2015. 

Orientador: prof. Dr. Gustavo Tadeu Volapto. Nível: Iniciação 

Científica. 

 

2.5 Atividades de ensino 

 

Atuação como professora convidada para ministrar o tema 

“Placentação e Anexos embrionários”. Disciplina de Histologia e 

Embriologia, cursos de Graduação Enfermagem e Biomedicina. Carga 

horária: 4 horas. Período: 2016, 2018 e 2019.  
  



 
 
 

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Capítulo 2 



 
 
 

25 
 
 
 

REPERCUSSÕES BIOQUÍMICAS E REPRODUTIVAS DE MÃES E 
DESCENDENTES APÓS O CONSUMO MATERNO DE DIETA 
HIPERLIPÍDICA EM ROEDORES: REVISÃO SISTEMÁTICA 

 

BIOCHEMICAL AND REPRODUCTIVE REPERCUSSIONS OF 

MOTHERS AND THEIR OFFSPRING AFTER MATERNAL 

CONSUMPTION OF HIGH-FAT DIET IN RODENTS: A 

SYSTEMATIC REVIEW 

 

Rafaianne Queiroz Moraes Souza 1,2, Giovana Vesentini 1*, Verônyca 

Gonçalves Paula 1, Yuri Karen Sinzato 1, Thaigra de Sousa Soares 

1,2, Rafael Bottaro Gelaleti 1, Gustavo Tadeu Volpato 2, Débora 

Cristina Damasceno 1 

 

1 Laboratory of Experimental Research on Gynecology and Obstetrics, 

Gynecology, Obstetrics and Mastology Postgraduate Course, Botucatu 

Medical School, São Paulo State University (Unesp), Botucatu, São Paulo 

State, Brazil 
2 Laboratory of System Physiology and Reproductive Toxicology, Institute of 

Biological and Health Sciences, Federal University of Mato Grosso (UFMT), 

Barra do Garças, Mato Grosso State, Brazil. 

 

*Correspondence to:  Giovana Vesentini  

Departamento de Ginecologia e Obstetrícia  

Faculdade de Medicina de Botucatu, UNESP  

Distrito de Rubião Júnior, s/n  

Telefone: 55 14 38801631  

CEP: 18.618-970 Botucatu, Estado de São Paulo, 

Brasil  

Email: gi.vesentini@hotmail.com 

 

Este artigo foi redigido de acordo com as normas de publicação da revista 

Biological Reviews (Fator de Impacto = 11,7), para a qual será submetido.  



 
 
 

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ABSTRACT 

 

Maternal exposure to the high-fat diet (HFD) during gestation or 

lactation can be harmful to both mother and offspring. The objective of 

this systematic review was to synthesize the available data on the 

effects of maternal HFD on the reproductive parameter and 

biochemical profile in rodents. The electronic search was performed in 

the PUBMED (Public/Publisher MEDLINE), EMBASE (Ovid) and Web 

of Science databases. Data from 76 studies showed that change in 

biochemical and reproductive parameters is dependent on the 

experimental design. Furthermore, the heterogeneity found in the 

studies makes it impossible to comparisons. In addition, studies often 

omit or neglect important information, such as a description of the diet 

or methodological details. These factors make it difficult to affirm the 

true effect of maternal HFD consumption for both mother and offspring. 

 

 

Keywords: high-fat diet, pregnancy, triglycerides, cholesterol, oxidative 

stress, descendants. 

 

  



 
 
 

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I. INTRODUCTION 

 

During gestation, the developing fetus is totally dependent on the 

maternal environment for nutrition (Barker, 1998). The intrauterine 

environment is a crucial determinant in the fetal programming of 

chronic diseases in adulthood. This concept is called Fetal Origin of 

Adult Diseases - FOAD (Barker, 2007). However, after several studies, 

this term has been extended to DOHaD (Developmental Origins of 

Health and Disease) (Gillman et al., 2007), which refers to a larger 

critical period of development, ranging from the original fetal period of 

Barker's proposal to the pre-gestational, embryofetal and postnatal 

periods. The range of life periods that the DOHaD hypothesis covers 

is still controversial. There is evidence that the critical period of 

development occurs from the phase encompassing meiosis and 

gametogenesis to the entire period of postnatal development and 

maturation from childhood to adolescence (Suzuki et al., 2018). There 

is also other evidence about periods the DOHaD covers, disseminated 

worldwide through the “First 1000 Days” campaign, that affirms the 

importance of the nutritional status of infants and nursing mothers in 

the fetal and neonatal period until two years after birth comprising 

between 280 days before birth and approximately 730 infantile days 

after birth (Organization 1,000 Days). Although there is no single 

consensus, research-involving DOHaD thematic purposes to raise 

awareness about nutrition and health have been investigated (Suzuki 

et al., 2018). 

According to the World Health Organization (WHO), malnutrition 

refers to deficiencies, excesses or imbalances in a person’s intake of 

energy and/or nutrients (WHO, 2016), leading to undernutrition or 

overnutrition (Academy of Nutrition and Dietetics, 2018). The 



 
 
 

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population is abandoning traditional diets that are rich in fibers and 

grain for diets that include increased levels of sugars, oils, and animal 

fats (WHO, 2002). There are five times more obese than malnourished 

adult people worldwide (WHO, 2016). Maternal consumption of high-

fat diet (HFD) is an important factor that causes harm to both mother 

and her offspring (Yu et al., 2013a; Kim et al., 2016). In the last 

decades, epidemiological evidence has shown that intrauterine life 

conditions influence growth, body composition and the risk of 

developing chronic diseases (Langley‐Evans, 2015). Animal studies 

also indicates that overnutrition during pregnancy induces phenotypic 

changes can enhance susceptibility to diseases in adult offspring 

(Parlee et al., 2013; Williams et al., 2014), such as hyperglycemia (Li 

et al.,2015), obesity (White et al.,  2009; Franco et al., 2012;  Desai et 

al., 2014) and metabolic syndrome (Desai et al., 2014). 

Epidemiological studies in humans are limited in their ability to 

assess the diet influence during pregnancy to offspring phenotype, as 

it is difficult to separate the effects of intrauterine and post-natal 

maternal exposure and genetic factors (Friedman, 2018). Therefore, 

research involving adequate experimental models is relevant, not only 

for ethical reasons but also due to uncontrollable variables, such as 

lifestyle, socioeconomic, nutritional and genetic factors. Hence, the 

objective of this systematic review was to identify and evaluate the 

studies with animal models (rodents) that were exposed to the HFD 

content in the pregnancy and/or lactation period to investigate 

biochemical and reproductive repercussions of mothers and offspring.  

 

II. METHODS 

(1) Literature search 

This systematic review was undertaken in accordance with the 



 
 
 

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PRISMA (Liberati et al., 2009) and registered on PROSPERO - 

International Prospective Register of Systematic Reviews (Protocol 

number CRD42019120418). The literature search was performed from 

inception to December 13th, 2018, on titles, abstracts, and keywords, 

in PUBMED (Public/Publisher MEDLINE), EMBASE (Ovid) and Web 

of Science databases. The following Medical Subject Headings 

(MeSH) and their synonyms were used in different combinations and 

variations with the Boolean operators "OR" and "AND" to yield a 

sensitive and comprehensive, yet relevant collection of possible 

articles “high-fat diet”, “oxidative stress", "triglyceride", "cholesterol", 

"low-density lipoprotein", "high density lipoprotein", "Alanine 

transaminase", "alanine aminotransferase" and "rodent" (See 

Appendix Supplementary S1 for complete search strategy). Besides 

the electronic search, other sources were used, such as hand 

searching and screening of reference lists. 

Additional records were included from review articles and author-

based searches. The searches were restricted to original studies that 

were published in the English language in scientific journals that were 

submitted to the peer-review process, without year restriction. After 

screening of titles and abstracts, three reviewers (RQMS, VPG, and 

DCD) independently examined full-text articles. Disagreements were 

resolved in consensus discussions. 

 

(2) Inclusion and exclusion criteria 

Studies were included in the data set only if they fulfilled the 

following criteria: (i) All rodent models. Non-rodents, spontaneously 

obese, genetically modified animals; ex vivo and in vitro studies 

involving human subjects were excluded; (ii) Studies on rodents being 

dams were subjected to an HFD around gestation (before and/or 



 
 
 

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during the whole or any part of pregnancy), or lactation. HFD was 

considered as chow-based HFD from any fat type (e. g., lard and 

vegetable oils). Custom-made diet (i.e. cafeteria), high-fiber diet, high-

calorie diet, high-glucose diet, low-fat diet in short, and any other diet 

than non-high-fat diet were excluded. (iii) For comparison, animals that 

were fed a standard diet were included. The evaluation of articles that 

used to nutritional manipulation (i. e., surgery, drugs, stress, and 

exercise) was not considered. (iv) The primary outcomes were 

included lipid profile, oxidative stress of the dams and offspring and 

maternal reproductive outcomes. 

• Lipid profile: Triglyceride (TG), Total Cholesterol (TC), High-

density lipoprotein (HDL), Low-density lipoprotein (LDL) 

concentrations, 

• Alanine aminotransferase (ALT) and Aspartate 

aminotransferase (AST) activities.  

• Oxidative stress status: Malondialdehyde / Thiobarbituric 

acid reactive substances (MDA/TBARS) (lipid oxidation), 

Superoxide dismutase (SOD), Catalase (CAT) and 

Glutathione peroxidase (GPx) activities, 8-hydroxy-2' -

deoxyguanosine (8-OHdG - DNA oxidation), quantification 

and scavenging reactive oxygen species (ROS). 

• Reproductive outcomes: Litter size, maternal and offspring 

weight. 

 

(3)  Data extraction 

For studies presenting eligibility criteria, relevant data were 

extracted such as publication year, animal strain, study design, and 

intervention, maternal and offspring outcomes were all collected. 

 



 
 
 

31 
 
 
 

(4) Qualitative assessment 

Risk of bias for animal studies was assessed using the 

Systematic Review Centre for Laboratory Animal Experimentation 

(SYRCLE’s tool), which was evaluated in ten steps: three of selection 

(random group allocation, group similar at baseline and blinded group 

allocation), two of them on performance (random housing and blinded 

intervention), two of detection (random and blinded outcome 

assessment), one of attrition bias (reporting of drop-outs), one 

reporting (selective outcomes), one to other potential bias (Hooijmans 

et al., 2014). Included studies were assessed independently by two 

reviewers (RQMS and GV) and any discrepancies were solved by 

discussion. The items were classified as low, unclear or high risk of 

bias. The score of all the articles was defined as the percentage of 0 

to 100% and each category (Hooijmans et al., 2014). We did not 

exclude studies based on high risk of bias. 

 

 

III. RESULTS 

(1) Description of the data set 

Initial electronic searching across three databases yielded a 

number of 2007 citations. In addition, 32 articles were added from other 

sources. The removal of 676 duplicates resulted in 1363 individual 

articles to be subjected to inclusion and exclusion criteria. Firstly, the 

inclusion and exclusion criteria were imposed on title and abstract 

(removal of 1229), and secondly on study design and methods 

(removal of 58). Finally, 76 citations were selected for review (Figure 

1). 

 

 



 
 
 

32 
 
 
 

(2) Study characteristics 

Figure 2A shows the year of publication of the studies. Only eight 

(11%) articles had more than ten years of publication, and 33 (43%) 

have been published from 2009 to 2014, 35 (46%) were published in 

the last five years.  

Among of the rodent strains, 26 (34%) were C57Bl/6 (mice), two 

(3%) Swiss (mice), four (5%) were Institute of Cancer Research- ICR 

(mice), 26 (34%) Sprague-Dawley (rats) and 18 (24%) Wistar (rats) 

(Figure 2B). 

Figure 2C shows the characteristics of the maternal diets, which 

were shown as chow fat content ranged from 16 to 64.5% calories. 

Twelve studies, (approximately 15%) use of less than 39%Kcal. 46 

studies, (approximately 59%) use of 40 – 49% Kcal and 20 (26%) 

employ more than 50% Kcal. Furthermore, from the 76 articles 

included in this review, 49 used the as source the animal-derived fats 

(mainly lard) and eight used vegetal oils, two articles used mixed (one 

used lard and corn oil and other used vegetable shortening, milk fat, 

soybean oil ) and 17 did not identify the source of fat (Figure 2D). 

After analyzing the included papers, 12 studies assessed litter 

size, of these 10 papers (83.34%) presented no change, one study 

(8.33%) showed greater litter size and one study (8.33%) with 

decreased litter size (Figure 3A). Furthermore, 12 studies (52%) 

presented higher maternal body weight and other 11 studies (48%) 

showed no abnormal weight (Figure 3B). There were 33 assessment 

the offspring's weight, 22(67%) presented no offspring weight 

changes, six (18%) evaluations had greater offspring weight and five 

(15%) showed lower weights (Figure 3C). 

Table 1 shows the period of maternal exposure to diet and the 

biochemical biomarker assessments of mothers. The HFD exposure 



 
 
 

33 
 
 
 

ranges from 19 to 141 days. The biochemical parameters were TG, 

TC, HDL, LDL, ALT, and measurements of oxidative stress status. In 

the 21 studies that investigate the maternal TG level, 16 (76%) 

presented higher levels, four (19%) no change and one (5%) of them 

showed a decrease. The maternal TC had ten evaluations, eight (80%) 

of which increased, one (10%) did not change and another (10%) 

decreased. There were four maternal HDL evaluations [two (50%) 

increased and others two (50%) did not change]. The two articles 

(100%) about maternal LDL assessments showed higher levels of this 

biomarker. The only maternal analysis of ALT did not change. 

Regarding the oxidative stress status in this systematic review, the 

results of the studies were included according to the quantification of 

pro-oxidants (MDA, 8-OHdG, and ROS) and antioxidant enzymes 

(SOD, CAT, and GPx). In four (100%) maternal evaluations, the MDA 

levels increased, there was only one maternal analysis of ROS and 

was increased. The maternal SOD antioxidant enzyme was evaluated 

in only one study and this was increased. Maternal GPx was also 

observed higher in only one study. The maternal scavenging capacity 

on reactive oxygen species was verified to be decreased in two 

assessments. 

Table 2 shows the period of maternal exposure to diet, 

characteristics of offspring (sexes and death age) and biochemical 

measurements of the biomarker of the offspring. The HFD exposure 

ranges from 19 to 154 days. In relation to sex, thirty-one articles 

verified both sexes; thirty studies analyzed males, fourteen evaluated 

females and another reported no explanation. The age that the 

offspring killed ranged between one day after birth up to 650 days old. 

The observed biochemical parameters were TG, TC, HDL, LDL, ALT, 

AST and oxidative stress status. Of the 139 articles about TG, 65 



 
 
 

34 
 
 
 

(47%) verified higher levels, others 69 (50%) showed no change and 

five (3%) presented lower levels. Of all 84 articles about TC, 22 (26%) 

showed an increased level, 54 (64%) verified no change and eight 

(10%) observed lower concentrations. There were 30 HDL 

assessments in the offspring, of these four (13%) were increased, 21 

(70%) presented no abnormal HDL levels and five (17%) showed 

decreased concentrations. Furthermore, in 20 papers with LDL 

analysis in offspring, seven (35%) verified higher levels, 12 (60%) of 

them showed no change and one (5%) observed low level. The activity 

of the liver AST enzyme in the offspring was increased in one article 

(12.5%) and in other seven (87.5%) there was no change. In 11 studies 

about ALT measurements, in four (36%) was showed higher activity, 

in six of them (55%) no change and in one paper (9%) a decrease was 

verified. 

In relation to oxidative stress status in offspring, there were 21 

studies on MDA analysis, of these 14 (67%) confirmed high 

concentrations and seven (33%) showed no change. There were three 

ROS evaluations, two of them (66.67%) verified high values and one 

(33.33%) no change. The studies showed determinations of oxidative 

DNA damage, such as 8-OHdG, which three papers (75%) observed 

high levels and one (25%) no change. There were 18 articles about 

fetal SOD activity, three (16.67%) of which were increased, one 

(5.56%) presented no change and 14 (77.77%) articles showed low 

SOD activity. There were 11 investigations measured CAT activity, one 

(10%) paper presented no change and ten (91%) of them observed a 

decreased activity. The offspring GPx activity was evaluated in 17 

papers, 3 (18%) of which had high activity, 4 (23%) no change and 10 

(59%) showed a decrease. In the two studies using thiol 

measurements, one (50%) showed no change and another (50%) 



 
 
 

35 
 
 
 

verified a decreased level. (Table 2). 

The most commonly used sample was blood with approximately 

65% (34 analyses used the serum and 31 contained plasma samples). 

Other samples were also used, 21 (20%) used liver, three (3%) 

sampled mesentery, two (2%) used kidneys, one (1%) reported milk, 

one (1%) placenta, one (1%) used sperm, one (1%) testis, one (1%) 

studied femoral artery, two (2%) used muscles, one (1%) sampled 

cardiomyocytes, and another (1%) reported islet (Figure 4). 

 

(3) Analysis of bias 

The assessment of the SYRCLE risk of bias tool to assess the 

quality of animal studies indicated a high or unknown risk of bias for 

the studies in the majority of categories (Figure 5). Although the 

majority of included studies reported the baseline characteristics (64 

studies - 84% were low risk), and 12 studies omitted this information 

(16% were high risk), there was unclear information about the methods 

used to generate allocation sequence in 32 studies (42% were unclear 

risk and 44 studies no description. 58% were at high risk. No 

description about concealment of the allocation sequence (76 studies 

- 100%). Information about performance bias, such as animals 

randomly housed (21 studies - 28% were high risk), care and blinded 

investigation of intervention/exposure of each animal was deficient (75 

studies - 99% of them were high risk). Furthermore, detection bias was 

assessed as high risk due to no description of random selection for 

outcome assessment (74 studies - 97%) and blinded assessor about 

outcomes was 100%. While more than 53% (40 studies) of the 

included studies reported high attrition bias, the remaining two 

categories were classified as low risk of bias, which were reporting bias 

(75 studies - 99%) and other potential bias (76 studies - 100%). 



 
 
 

36 
 
 
 

 

IV. DISCUSSION 

 

The objective of this study is to perform a systematic review on 

animal models submitted to a maternal high-fat feeding compared to 

standard diet to identify the experimental design and the most suitable 

biomarkers of the dams and offspring that were influenced by 

inadequate diet. After analyzing several full-text (paper), it was 

demonstrated that there was a lack of uniformity in the methodologies 

and diet composition. This led to the difficulty of comparing the studies, 

especially with regard to biomarkers for the definition of risks and injury 

for both mother and offspring after the maternal consumption of an 

HFD. 

Systematic reviews are commonly used for human studies (Tajali 

et al., 2010; Santos et al., 2017). However, reviews using an animal 

model predominantly rodents have been highlighted (Ainge et al., 

2011; Lagisz et al., 2015; Besson et al., 2016; Ribaroff et al., 2017). 

Rodents (mice and rats) are ideal models to induce metabolic 

alterations (Ramalho et al., 2017) and suitable for investigating the 

mechanisms related to DOHaD (Chavatte-Palmer et al., 2016). 

Considering these and other advantages, rodents were employed in 

this review. 

To establish a complete search, there was no year limitation of 

the included studies. In this context, the majority of the articles are 

related to the last five years and this might be explained because the 

investigations on developmental plasticity and fetal programming have 

been started in these last years (Barker et al., 1993; Gillman et al., 

2007). In this review, only articles that used diets with a higher fat 

content than the control group were evaluated. The major source was 



 
 
 

37 
 
 
 

lard, which mainly consists of non-essential fatty acids (Tellechea et 

al., 2017). Some studies have used plant-originated fat, which contains 

essential fatty acids (polyunsaturated) (Sasidharan et al., 2013, 

Jurgoński et al., 2014). According to Tellechea et al. (2017), maternal 

exposure to the diet rich in lard is directly related to metabolic 

syndrome-related phenotypes in offspring rats. Besides that, essential 

fatty acids contain fundamental nutrients to fetal and postnatal 

development and normal cell function (Mennitti et al., 2015). However, 

an excess may harm and have adverse consequences for offspring 

(Mennitti et al., 2015). The different sources, concentrations and 

exposure periods of HFD can be responsible for the heterogeneity of 

results on reproductive and biochemical parameters (Lagisz et al., 

2015). Several authors presented the energy from fat (% Kcal) and 

others in centesimal composition. To facilitate such comparisons, the 

values were standardized in % Kcal in this review. Considering that 

carbohydrate provides four calories/gram, protein provides four 

calories/gram and fat provides nine calories/gram, these values were 

used in our review (United States Department of Agriculture - USDA, 

2019).  

The HFD model in animals has shown to be effective in producing 

maternal obesity by increasing body weight (Tellechea et al., 2017). 

Some studies present greater maternal body weight (Khan et al.,  

2005; Férézou-Viala et al., 2007; Jungheim et al., 2010; Yamaguchi et 

al., 2010; Krasnow et al., 2011; Masuyama & Hiramatsu, 2012; 

Cheong et al., 2014; Masuyama & Hiramatsu, 2014; Masuyama et al., 

2015; Kim et al., 2016; Lecoutre et al., 2016; Mdaki et al., 2016). 

However, this parameter presents no change depending on the 

experimental design (Koukkou et al., 1998; Ghosh et al., 2001; 

Zambrano et al., 2010; Cerf et al., 2011; Lin et al., 2011; Yang et al., 



 
 
 

38 
 
 
 

2012; Yu et al., 2013b, Desai et al., 2014; Brenseke et al., 2015; 

Umekawa et al., 2015; Albert et al., 2017). 

While one study showed that the HFD maternal consumption 

during pregnancy can interfere with reproductive parameters such as 

lower litter size (Cheong et al., 2014), other study verified greater litter 

size (Krasnow et al., 2011). The result found about decreased litter 

size might be due to increased FoXO3a levels and, consequently, a 

reduction in the number of primordial follicles in the ovaries and oocyte 

apoptosis (Liu et al., 2009; Cheong et al., 2014). Such differences 

might be justified by the short period of diet exposure (28 days), 

despite the high-fat concentration (60% Kcal) (Krasnow et al., 2011). 

After analysis of the full-text, we observed that most of the 

experimental models related to the included studies caused no change 

in litter size (Guo & Jen., 1995; Férézou-Viala et al., 2007; Nasu et al., 

2007; Cerf et al., 2011; Lin et al., 2011; Masuyama & Hiramatsu, 2012; 

Ornellas et al., 2013; Brenseke et al., 2015; Masuyama et al., 2015 

Mdaki et al., 2016; Albert et al., 2017).  

Maternal overnutrition is a risk factor for fetal growth, which might 

be increased or decreased (Christians et al., 2019). This complex 

process depends on the fetal genotype and epigenetics, such as 

intrauterine insults and a variety of growth factors and proteins. The 

fetal growth depends not only on the maternal organism but also on 

fetuses and placenta, as well as the availability of oxygen and nutrients 

to the fetus (Bequer et al., 2018). Although, most rodent studies report 

that offspring exposed to HFD during pregnancy and/or lactation 

present no abnormal body weight (Koukkou et al.,  1998; Ghosh et al., 

2001; Khan et al., 2005; Zambrano et al., 2010; Franco et al., 2012; 

Yang et al., 2012; Hou et al., 2015; Umekawa et al., 2015; Zhou et al., 

2015; Lecoutre et al., 2016; Albert et al., 2017; Sheen et al., 2018), 



 
 
 

39 
 
 
 

some studies show that maternal HFD consumption results in lighter 

offspring (Melo et al., 2014; Zheng et al., 2014; Reynold et al., 2015; 

Mdaki et al., 2016; Huang et al., 2017; Kunle-Alabi et al., 2018). Other 

studies demonstrated heavier fetuses (Masuyama & Hiramatsu, 2012; 

2014; Masuyama et al., 2015). The phenotypes of offspring body 

weight are unclear and it seems to be due to differences in the HFD 

consumption period, fat source, and animal strain (Sullivan et al., 

2010). 

The consumption of a high-fat diet with animal or plant-derived 

fats leads to increased TG (triglyceride) levels (Buettner et al., 2007), 

as observed in most studies included in this review, in which the 

majority of TG measurements has been increased in the mother (Lin 

et al., 2011; Franco et al., 2012; Masuyama & Hiramatsu, 2012; 

Ornellas et al., 2013; Masuyama & Hiramatsu, 2014; MacPherson et 

al., 2015; Masuyama et al., 2015; Kim et al., 2016; Mdaki et al., 2016; 

Albert et al., 2017; Rahman et al., 2017). Although these findings are 

similar in several studies, the results using diet vary in different 

laboratories due to animal strain and diet variety (Buettner et al., 2007). 

It is important to emphasize that even though maternal TG does not 

change; the maternal consumption HFD may cause metabolic 

alterations in offspring (Desai et al., 2014). 

The TG determinations analyzed in offspring showed an increase 

(approximately 47% of included studies), (Guo & Jen., 1995; Ghosh et 

al., 2001; khan et al., 2003; Chechi et al., 2009; Tokuza et al., 2009; 

Yamaguchi et al., 2010; Zambrano et al., 2010; Dong et al., 2011; 

Emiliano et al., 2011; Ashino et al., 2012; Chen et al., 2012; Li et al., 

2012; Masuyama & Hiramatsu, 2012; Yang et al., 2012; Ornellas et al., 

2013; Resende et al., 2013; Chen et al., 2014b; Desai et al., 2014; 

Masuyama & Hiramatsu, 2014; Melo et al., 2014; Yokomizo et al., 



 
 
 

40 
 
 
 

2014; Bringhenti et al., 2015; MacPherson et al., 2015; Masuyama et 

al., 2015; Reynold et al., 2015; Seet et al., 2015;  Umekawa et al., 

2015; Vega et al., 2015;  Zhou et al., 2015; Bringhenti et al., 2016; Ito 

et al., 2016; Mazzucco et al., 2016; Tsuduki et al., 2016; Zambrano et 

al., 2016; Albert et al., 2017;  Huang et al., 2017; Moussa et al., 2017; 

Nguyen et al., 2017; Lomas-Soria et al., 2018; Miranda et al., 2018) as 

expected since the HFD-induced nutrient overload is necessary for the 

development of metabolic alterations (Hariri & Thibault, 2010; James 

et al., 2012). Consequently, there are increased serum TG levels 

(Gheibi et al., 2017). A possible mechanism involved is the AcsI3 gene 

(acyl-CoA synthetase long-chain family member 3), which is lower 

after HFD exposure (Huang et al., 2017). Moreover, suppression of 

this gene is related to the reduced lipid synthesis and TG storage due 

to the lower cellular uptake of fatty acids (Bu et al., 2009; 

Poppelreuther et al., 2012). However, other authors observed no 

change in serum TG levels (approximately 50% of included studies) 

(Guo & Jen., 1995; Kokkou et al., 1998; khan et al., 2003; khan et al., 

2004; khan et al., 2005; Férézou-Viala et al., 2007; Chechi et al., 2009; 

Tokuza et al., 2009; Yamaguchi et al., 2010;  Cerf et al., 2011; Zhang 

et al., 2011; Ashino et al.,  2012; Chen et al., 2012; Yang et al., 2012;  

Rajja et al.,  2013; Ornellas et al., 2013; Chen et al., 2014a; Chen et 

al., 2014b; Desai et al.,  2014; Yokomizo et al., 2014; Zheng et al., 

2014; Brenseke et al., 2015; Gray et al., 2015b; Hou et al., 2015;  

Umekawa et al., 2015; Vega et al., 2015; Ito et al., 2016; Kim et al., 

2016; Lecoutre et al., 2016; Mazzucco et al., 2016; Mdaki et al., 2016; 

Tsuduki et al., 2016; Zambrano et al., 2016; Moussa et al., 2017; 

Glastras et al., 2017; Moussa et al., 2017; Sheen et al., 2018; Tanaka 

et al., 2018; Zhao et al., 2018; Kunle-Alabi et al., 2018; Miranda et al., 

2018; Zhao et al., 2018). Approximately 3% of included studies 



 
 
 

41 
 
 
 

observed decreased TG concentrations (Seet et al., 2015; Tsuduki et 

al., 2016; Mousavi et al., 2017). The most analyses that showed no 

change or all decrease in TG concentration were performed in the 

blood samples. This fact may have contributed to the results presented 

in this review. A higher TG transfer to the liver due to the HFD 

consumption may have occurred and contributed to the development 

of non-alcoholic fatty liver diseases, leading to changes in the TG 

synthesis and transport.  (Bugianesi et al., 2005; Fabbrini et al., 2010). 

The HFD exposure is associated with dyslipidemia, which 

involves higher total cholesterol and LDL levels, as well as a reduction 

in HDL-cholesterol levels (Adiels et al., 2008; Klop et al., 2013). The 

results found in this review show that few articles evaluated these 

biomarkers in the mother and were divergent in offspring analyses. 

This suggests that such biomarkers are not efficient to reveal the injury 

induced by high-fat consumption, which depends on the experimental 

model employed. 

The excess of common nutrients in HFD may exceed the adipose 

tissue capacity to process excessive energy and this excessive fat 

might be deposited in the liver (Despres & Lemieux, 2006). Overload 

in the liver results in increased ALT and AST activities (Sultan, 2008; 

Fraulob et al., 2010). Despite the diet influence on the liver, few studies 

evaluated ALT and AST levels. The studies included in this review 

showed unchanged maternal ALT levels, but there were higher ALT 

and AST activities in the offspring (Tsuduki et al., 2016; Kunle-Alabi et 

al., 2018; Tanaka et al., 2018). 

The redox status, nutritional and environmental factors play an 

important role in the susceptibility to oxidative stress and other 

metabolic alterations (Luo et al., 2006). Oxidative stress occurs due to 

increased production of reactive oxygen species (ROS) and/or failure 



 
 
 

42 
 
 
 

of the antioxidant system (Bringhenti et al., 2015). This imbalance was 

observed in the full papers evaluated in this review both for mother (Lin 

et al., 2011; Vega et al., 2015; Kim et al., 2016) and offspring (Tokuza 

et al., 2009; Emiliano et al., 2011; Lin et al., 2011; Zhang et al., 2011; 

Torrens et al., 2012; Resende et al., 2013; Yokomizo et al., 2014; 

Bringhenti et al., 2015; Rodriguez-Gonzalez et al., 2015; Glastras et 

al., 2016; Ito et al., 2016; Kim et al., 2016; Mdaki et al., 2016; Glastras 

et al., 2017; Miranda et al., 2018; Tanaka et al., 2018 ), most of which 

show changes in pro or antioxidant biomarkers. Malondialdehyde 

(MDA) and 8-hydroxy-2 '-deoxyguanosine (8-OHdG) were the pro-

oxidants or lipid peroxidation products included in this review. MDA is 

a final product of lipid peroxidation measured by the quantification of 

thiobarbituric acid reactive substances (TBARS) (Lee et al., 2012). 8-

OHdG is one of the major products of DNA oxidation and may be 

modified (Hasan, et al., 2017). These biomarkers represent a 

detrimental environment for both mothers and their offspring (Eriksson 

et al., 2003; Hjort et al., 2018; Reece et al., 2004). The association of 

HFD and increased pro-oxidants can be explained by endothelial 

dysfunction (Mdaki et al., 2016) and increased inflammatory process 

(Zhang et al., 2011, Glastras et al., 2017). 

The enzymatic antioxidant system composed of superoxide 

dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), 

the three main endogenous antioxidants, is triggered according to the 

organism requirement to protect itself against the oxidative insult 

caused by maternal HFD exposure (Emiliano et al., 2011). The lower 

antioxidant profile observed in several studies (Emiliano et al., 2011; 

Lin et al., 2011; Resende et al., 2013; Rodriguez-Gonzalez et al., 2015; 

Bringhenti et al., 2015; Miranda et al., 2018) may be due to the 

enzymatic rapid consumption and depletion (Noeman et al., 2011). 



 
 
 

43 
 
 
 

The higher antioxidant defenses verified in two of the studies are 

related to the compensation against the increase of oxidants 

(Rodriguez-Gonzalez et al., 2015; Vega et al., 2015). Both the increase 

and reduction of antioxidants represent an attempt to stabilize ROS 

(Birben et al., 2012). 

It is important to note that several papers tested blood samples 

for biochemical analysis (plasma or serum) (Guo & Jen., 1995; Kokkou 

et al., 1998; Ghosh et al., 2001; Khan et al., 2003; Khan et al., 2004; 

Khan et al., 2005; Férézou-Viala et al., 2007; Nasu et al., 2007; Chechi 

et al., 2009; Elahi et al., 2009; Tokuza et al., 2009; Jungheim et al., 

2010; Yamaguchi et al., 2010; Zambrano et al., 2010; Cerf et al., 2011; 

Dong et al., 2011; Emiliano et al., 2011; Lin et al., 2011; Zhang et al., 

2011; Ashino et al., 2012; Chen et al., 2012; Li et al., 2012; Masuyama 

& Hiramatsu, 2012; Yang et al., 2012; Yu et al., 2013a; b; Ornellas et 

al., 2013; Rajja et al., 2013; Resende et al., 2013; Yu et al., 2013a , 

Chen et al., 2014a; Chen et al., 2014b; Desai et al., 2014; Hou et al., 

2015; Masuyama & Hiramatsu, 2014; Zheng et al., 2014; Brenseke et 

al., 2015; Gray et al., 2015b; Masuyama et al., 2015; Reynold et al., 

2015; Seet et al., 2015; Umekawa et al., 2015; Vega et al., 2015; 

Bringhenti et al., 2016; Ito et al., 2016; Kim et al., 2016; Lecoutre et al., 

2016; Mazzucco et al., 2016; Mdaki et al., 2016; Tsuduki et al., 2016; 

Zambrano et al., 2010; Albert et al., 2017; Elahi & Matata, 2017; 

Glastras et al., 2017; Huang et al., 2017; Mousavi et al., 2017; Moussa 

et al., 2017; Nguyen et al., 2017; Rahman et al., 2017; Kunle-Alabi et 

al., 2018; Lomas-Soria et al., 2018; Miranda et al., 2018; Sheen et al., 

2018; Tanaka et al., 2018; Zhao et al., 2018). Blood is an effective 

material for the evaluation of biochemical profile because it informs the 

health state at the collection time (Liu et al., 2010). The second type of 

sample most used was the liver (Lin et al., 2011; Zhang et al., 2011; 



 
 
 

44 
 
 
 

Ashino et al., 2012; Chen et al., 2012; Ornellas et al., 2013; Yokomizo 

et al., 2014; Chen et al., 2014a;b; Melo et al., 2014; Bringhenti et al., 

2015; Zhou et al., 2015; Vega et al., 2015; Ito et al., 2016; Kim et al., 

2016; Tsuduki et al., 2016; Huang et al., 2017; Lomas-Soria et al., 

2018; Miranda et al., 2018; Tanaka et al., 2018; Zhao et al., 2018). The 

hepatic tissue undergoes maturation stages during late gestation and 

early postnatal life. Hence, the liver is highly susceptible to inadequate 

nutrition maternal (Bruce et al., 2016). There were also few 

determinations in other samples, such as mesentery (Emiliano et al., 

2011; Gray et al., 2015a; Resende et al., 2013), kidney (Glastras et al., 

2016; 2017), muscle (MacPherson et al., 2015), placenta (Lin et al., 

2011), milk (Franco et al., 2012), islet (Yokomizo et al., 2014), sperm 

and testis (Rodriguez-Gonzalez et al., 2015), cardiomyocytes (Mdaki 

et al., 2016), and femoral artery (Torrens et al., 20112). The non-

uniformity of the samples is related to the objectives of each research. 

The difference in sample type also caused variation in the results, as 

for example in TG measurements that even with the same 

methodology was found increased in liver or muscle and without 

alterations in blood samples (Ashino et al., 2012; Yang et al.,  2012; 

Ornellas et al., 2013; Chen et al., 2014b). 

An inadequate feeding during the prenatal period likely increases 

the risk of chronic diseases, such as diabetes and metabolic changes 

during adult offspring (Ganu et al., 2012; Ross & Desai, 2013). The 

overnutrition during pregnancy is a risk factor for the mother and their 

offspring, corroborating the DOHaD theory (Gillman et al., 2007).  

The selected articles were evaluated with an appropriate bias risk 

assessment instrument applied to experimental models (Hooijmans et 

al., 2014). A good design describes the process of randomization, such 

as bias origin and their influence in the results (Festing, 2014). Most 



 
 
 

45 
 
 
 

articles only cite randomization of animals; however, they do not 

correctly describe the process. The blindness of researchers and data 

analysis are also an argument for bias, which was neglected in the 

studies. This probably occurs because of the difficulty for blinding 

during management with animals and with diet. From the 

implementation of more appropriate methodologies could reduce the 

bias, contributing to improving the reliability and interpretation of 

results (Ribaroff et al., 2017).  

In this review, there are methodological limitations of the included 

studies that culminated in the lack of consensus of results. Firstly, the 

description of diet composition, both in the control and HFD groups, 

sometimes is ignored by the authors or not clearly reported. However, 

by neglecting this information, the investigators hinder the 

interpretations and make the impractical reproducibility of these 

studies (Kilkenny et al., 2010). Secondly, the articles selected present 

a variability of the standard diet (control group) characteristics, which 

causes difficulty for comparison among the experimental groups and 

control groups from different studies, showing that there is no 

consensus in the researches involving high-fat diet. The American 

Institute of Nutrition (AIN) published the formula use to standard chow 

for experimental rodents, AIN-93G, which shows all the necessary 

nutrients to be used during the early growth phase and during 

reproduction (Reeves, 1997). Thirdly, the fact that we have not 

restricted the strains, fat concentration, and source, offspring sex, 

period and number of days of maternal consumption of the HFD, age 

at which pups were analyzed are factors that contribute to the 

heterogeneity of the found results. Despite limitations, this review 

presents strengths, such as an extensive view of the literature. We 

used different databases with a large number of terms and keywords 



 
 
 

46 
 
 
 

to increase the number of searches. In addition, we showed the 

consequences for both mothers and their offspring. 

 

V. CONCLUSION 

 

In conclusion, this systematic review shows that maternal HFD 

consumption can change the material parameters and cause damages 

to their descendants depending on the experimental design. The 

heterogeneity found in the studies makes the comparisons impossible. 

In addition, studies often omit or neglect important information, such 

as a description of the diet or methodological details. These factors 

make it difficult to affirm the true effect of maternal HFD consumption 

for both mother and offspring. 

 

  



 
 
 

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59 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Figure 1. Flow diagram of selection of articles based on PRISM 
guidelines (http://www.prisma-statement.org). 

 
  

Records identified through 
database searching  

(n = 2007) 

S
c
re

e
n
in

g
 

In
c
lu

d
e
d

 
E

lig
ib

ili
ty

 
Id

e
n
ti
fi
c
a
ti
o
n
 

Additional records identified through 
other sources  

(n = 32) 

Records after duplicates removed  
(n = 1363) 

Records screened  
(n = 1363) 

Records excluded  
(n = 1229) 

Full-text articles assessed 
for eligibility  

(n = 134) 

Full-text articles excluded, 
with reasons  

(n =58) 
No adhering to intervention 

criteria (31); 
Conference abstracts (19); 
No comparison established 

(6); 
Other population (1) 

Other outcomes reported (1) 

 
 
 
 
 
 
 
 
 
 

Studies included in 
qualitative synthesis  

(n = 76) 

http://www.prisma-statement.org/


 
 
 

60 
 
 
 

 
Figure 2. Characteristics of the studies. A: Publication dates; B: Strain 
of rodents; C: Energy value in% kilocalories; D: Main Source of fat. 

 
 
 

  



 
 
 

61 
 
 
 

 
Figure 3. Reproductive repercussions. A: Litter size; B: Maternal 

body weight; C: Offspring body weight. 

 



 
 
 

62 
 
 
 

 

Table1. Biochemical repercussions of dams. 

References Animal 
Kcal of 

fat  

Maternal HFD 
consumption 

(days) 

Outcomes of dams 

TG TC HDL LDL ALT MDA ROS SOD GPX 
Scavenging capacity of 
reactive oxygen species 

Lin et al., 2011a Rats 40% 19 ↑ NM ↔ NM NM ↑ NM NM NM ↓ 

Lin et al., 2011b Rats 40% 19 NM NM NM NM NM ↑ NM NM NM ↓ 

Rahman et al., 2017 Rats 57,50% 35 ↑ NM NM NM NM NM NM NM NM NM 

Nasu et al., 2007 Rats 56.7 % 42 ↔ NM NM NM NM NM NM NM NM NM 

Guo & Jen., 1995a Rats 64% 49 ↓ NM NM NM NM NM NM NM NM NM 

Mdaki et al., 2016a Rats 40%/ 49 ↑ NM NM NM NM NM NM NM NM NM 

Albert et al., 2017 Rats 45% 52 ↑ NM NM NM NM NM NM NM NM NM 

Yamaguchi et al., 2010a Rats 33% 84 ↑ NM NM NM NM NM NM NM NM NM 

Franco et al., 2012a Rats 29% 98 ↑ ↓ NM NM NM NM NM NM NM NM 

Franco et al., 2012b Rats 29% 98 ↑ ↑ NM NM NM NM NM NM NM NM 

Desai et al., 2014a Rats 60% 98 ↔ ↑ NM NM NM NM NM NM NM NM 

Seet et al., 2015a Rats 60% 98 ↔ NM NM NM NM NM NM NM NM NM 

MacPherson et al., 2015 Rats 41% 110 ↑ NM NM NM NM NM NM NM NM NM 

Kim et al., 2016 a Mice 45% 63 ↑ ↑ ↔ NM ↔ ↑ NM NM NM NM 

Kim et al., 2016b Mice 45% 63 ↑ NM NM NM NM NM NM NM NM NM 

Umekawa et al., 2015a Mice 45% 63 ↔ ↔ NM NM NM NM NM NM NM NM 

Yu et al., 2013a Mice 32% 63 NM ↑ ↑ ↑ NM NM NM NM NM NM 

Yu et al., 2013b Mice 32% 63 NM ↑ ↑ ↑ NM NM NM NM NM NM 

Masuyama & Hiramatsu, 
2012a 

Mice 
62% 70 ↑ NM NM NM NM NM NM NM NM NM 



 
 
 

63 
 
 
 

Masuyama & Hiramatsu, 
2014a 

Mice 
62% 70 ↑ NM NM NM NM NM NM NM NM NM 

Masuyama et al., 2015a Mice 62% 70 ↑  NM NM NM NM NM NM NM NM 

Tokuza et al., 2009a Mice 57.50% 79 ↑ ↑ NM NM NM NM NM NM NM NM 

Ornellas et al., 2013a Mice 49% 105 ↑ ↑ NM NM NM NM NM NM NM NM 

Vega et al., 2015a Mice 46% 141 NM NM NM NM NM ↑ ↑ ↑ ↑ NM 

Vega et al., 2015b Mice 46% 141 ↑ ↑ NM NM NM NM NM NM NM NM 

Abbreviations: TG – Triglycerides; TC – Total cholesterol; HDL – High density lipoprotein cholesterol; LDL – Low density lipoprotein cholesterol; ALT – Alanine transaminase; 
AST – Aspartate transaminase; MDA – Malondialdehyde; ROS – Reactive oxygen species; SOD – Superoxide dismutase; CAT – Catalase; GPx – Glutathione peroxidase; 
ROS - Scavenging capacity of reactive oxygen species; NM - not measured. 

  



 
 
 

64 
 
 
 

Table2. Biochemical repercussions of offspring. 

References Animal 
Kcal of 

fat  

Maternal 
HFD 

consumption 
(days) 

 
Sex 

offspring 

  
Death 
age 

(days) 

Outcomes of offspring  

 TG TC HDL LDL ALT AST MDA 
8-

OHdG 
ROS SOD CAT GPX Thiols 

Lin et al., 2011c rats 40% 19 M/F 1 NM NM NM NM NM NM NM NM NM NM NM NM NM 

Cerf et al., 2011a rats 20% 21 M/F 1 ↔ NM NM NM NM NM NM NM NM NM NM NM NM 

Cerf et al., 2011b rats 30% 21 M/F 1 ↔ NM NM NM NM NM NM NM NM NM NM NM NM 

Cerf et al., 2011c rats 40% 21 M/F 1 ↔ NM NM NM NM NM NM NM NM NM NM NM NM 

Dong et al., 2011 rats 35% 21 M 98 ↑ NM ↓ ↑ NM NM NM NM NM NM NM NM NM 

Emiliano et al., 2011a rats 47% 21 F 90 ↑ ↔ NM NM NM NM NM NM NM NM NM NM NM 

Emiliano et al., 2011b rats 47% 21 F 180 ↑ ↔ NM NM NM NM NM NM NM NM NM NM NM 

Emiliano et al., 2011c rats 47% 21 F 90 NM NM NM NM NM NM NM NM NM NM NM NM NM 

Emiliano et al., 2011d rats 47% 21 F 180 NM NM NM NM NM NM NM NM NM NM NM NM NM 

Kunle-Alabi et al., 
2018a 

rats 30% 21 M 120 ↔ ↓ ↑ ↓ ↑ ↔ NM NM NM NM NM NM NM 

Kunle-Alabi et al., 
2018b 

rats 30% 21 F 120 ↔ ↓ ↔ ↔ ↑ ↔ NM NM NM NM NM NM NM 

Resende et al., 
2013a 

rats 47.40% 21 M 90 ↑ ↔ NM NM NM NM ↑ NM NM NM NM NM NM 

Resende et al., 
2013b 

rats 47.40% 21 M 90 NM NM NM NM NM NM NM NM NM NM NM NM NM 

Resende et al., 
2013c 

rats 47.40% 21 M 180 ↑ ↔ NM NM NM NM ↑ NM NM NM NM NM NM 

Resende et al., 
2013d 

rats 47.40% 21 M 180 NM NM NM NM NM NM NM NM NM NM NM NM NM 

khan et al., 2005a rats 48% 31 M 180 ↔ ↔ ↔ NM NM NM NM NM NM ↓ ↓ ↓ NM 

khan et al., 2005b rats 48% 31 F 180 ↔ ↔ ↔  NM NM NM NM NM ↓ ↓ ↓ NM 

Rahman et al., 2017 rats 57.50% 35 M 28 NM ↔ ↔ ↔ NM NM NM NM NM ↓ ↓ ↓ NM 



 
 
 

65 
 
 
 

Moussa et al., 2017a rats 44% 42 M 70 ↔ ↔ ↔ ↔ NM NM NM NM NM ↓ ↓ ↔ NM 

Moussa et al., 2017b rats 44% 42 F 70 ↔ ↔ ↔ ↔ NM NM NM NM NM NM NM NM NM 

Moussa et al., 2017c rats 44% 42 M 140 ↑ ↔ ↔ ↔ NM NM NM NM NM NM NM NM NM 

Moussa et al., 2017d rats 44% 42 F 140 ↔ ↔ ↔ ↔ NM NM NM NM NM NM NM NM NM 

Moussa et al., 2017e rats 44% 42 M 210 ↑ ↔ ↔ ↔ NM NM NM NM ↔ NM NM NM NM 

Moussa et al., 2017f rats 44% 42 F 210 ↔ ↑ ↓ ↔ NM NM NM NM NM NM NM NM NM 

Yang et al., 2012a rats 45% 42 F 84 ↑  NM NM NM NM NM NM NM NM NM NM NM 

Yang et al., 2012b rats 45% 42 F 84 ↔ ↔ NM NM NM NM NM NM NM NM NM NM NM 

Zhang et al., 2011a rats 45% 42 M 84 ↑ NM NM NM NM NM ↔ NM NM NM NM NM NM 

Zhang et al., 2011b rats 45% 42 M 84 ↔ NM NM NM NM NM ↑ NM NM NM NM NM NM 

Zhou et al., 2015 rats 45% 42 M/F 84 ↑ NM NM NM NM NM NM NM NM NM NM NM NM 

Kokkou et al., 1998 rats 54% 47 ? 15 ↔ ↓ NM NM NM NM NM NM NM NM NM NM NM 

Guo & Jen., 1995a rats 64% 49 M/F 1 ↔ NM NM NM NM NM NM NM NM NM NM NM NM 

Guo & Jen., 1995b rats 64% 49 M/F 22 ↑ NM NM NM NM NM NM NM NM NM NM NM NM 

Mdaki et al., 2016a rats 40%/ 49 M/F 1 ↔ NM NM NM NM NM NM NM NM NM NM NM NM 

Mdaki et al., 2016b rats 40% 49 M/F 1 NM NM NM NM NM NM ↑ NM NM NM NM NM NM 

Albert et al., 2017 rats 45% 52 M 110 ↑ ↔ ↔ ↔ ↔ ↔ NM NM NM NM NM NM NM 

Ashino et al., 2012a rats 45% 52 M 28 ↑ NM NM NM NM NM NM NM NM NM NM NM NM 

Ashino et al., 2012b rats 45% 52 M 82 ↑ NM NM NM NM NM NM NM NM NM NM NM NM 

Ghosh et al., 2001 rats 43% 52 F 160 ↑ ↔ ↓ NM NM NM NM NM NM NM NM NM NM 

Gray et al., 2015a rats 45% 52 M 140 NM NM NM NM NM NM NM NM NM NM NM NM NM 

khan et al., 2003a rats 48% 52 M 80 ↔ ↔ ↔ NM NM NM NM NM NM NM NM NM NM 

khan et al., 2003b rats 48% 52 M 180 ↔ ↔ ↔ NM NM NM NM NM NM NM NM NM NM 

khan et al., 2003c rats 48% 52 M 360 ↔ ↓ ↓ NM NM NM NM NM NM NM NM NM NM 



 
 
 

66 
 
 
 

khan et al., 2003d rats 48% 52 F 80 ↔ ↔ ↔ NM NM NM NM NM NM NM NM NM NM 

khan et al., 2003e rats 48% 52 F 180 ↔ ↔ ↔ NM NM NM NM NM NM NM NM NM NM 

khan et al., 2003f rats 48% 52 F 360 ↑ ↑ ↓ NM NM NM NM NM NM NM NM NM NM 

khan et al., 2004a rats 48% 52 M 180 ↔ ↔ ↔ NM NM NM NM NM NM NM NM NM NM 

khan et al., 2004b rats 48% 52 F 180 ↔ ↔ ↔ NM NM NM NM NM NM NM NM NM NM 

khan et al., 2005c rats 48% 52 M 180 ↔ ↔ ↔ NM NM NM NM NM NM NM NM NM NM 

khan et al., 2005d rats 48% 52 F 180 ↔ ↔ ↔ NM NM NM NM NM NM ↓ NM NM NM 

Reynold et al., 2015a rats 45% 52 F 24  ↑  ↑ NM NM NM NM NM NM NM NM NM 

Reynold et al., 2015b rats 45% 52 F 150 ↑ ↑ ↔ ↑ NM NM NM NM NM NM NM NM NM 

Hou et al., 2015a rats 31% 56 M 1 ↔ ↔   NM NM NM NM NM NM NM NM NM 

Hou et al., 2015b rats 31% 56 M 56 ↔ ↔   NM NM NM NM NM NM NM NM NM 

Gray et al., 2015b rats 45% 63 M 150 ↔  ↑ ↔ NM NM NM NM NM NM NM NM NM 

Chen et al., 2012a rats 43% 76 M 91 ↑  NM NM NM NM NM NM NM NM NM NM NM 

Chen et al., 2012b rats 43% 76 M 91 ↔  NM NM NM NM NM NM NM NM NM NM NM 

Rajja et al., 2013 rats 43% 76 F 98 ↔  NM NM NM NM NM NM NM NM NM NM NM 

Sheen et al., 2018 rats 58% 77 M 120 ↔ ↔ NM NM ↔ ↔ NM NM NM NM NM NM NM 

Chen et a