Maternal Low-Protein Diet Deregulates DNA Repair and DNA Replication Pathways in Female Offspring Mammary Gland Leading to Increased Chemically Induced Rat Carcinogenesis in Adulthood

ZAPATERINI, JOYCE R.; FONSECA, ANTONIO R. B.; BIDINOTTO, LUCAS T.; COLOMBELLI, KETLIN T.; ROSSI, ANDRÉ L. D.; KASS, LAURA; JUSTULIN, LUIS A.; BARBISAN, LUIS F.

Frontiers in Cell and Developmental Biology

Frontiers

Año: 2022 vol. 9

Studies have shown that maternal malnutrition, especially a low-proteindiet (LPD), plays a key role in the developmental mechanisms underlying mammarycancer programming in female offspring. However, the molecular pathwaysassociated with this higher susceptibility are still poorly understood. Thus,this study investigated the adverse effects of gestational and lactational lowprotein intake on gene expression of key pathways involved in mammary tumorinitiation after a single dose of N-methyl-N-nitrosourea (MNU) in female offspring rats. PregnantSprague?Dawley rats werefed a normal-protein diet (NPD) (17% protein) or LPD (6% protein) fromgestational day 1 to postnatal day (PND) 21. After weaning (PND 21), femaleoffspring (n=5, each diet) were euthanized for histological analysis orreceived NPD (n=56 each diet). At PND 28 or 35, female offspring received asingle dose of MNU (25 mg/kg body weight) (n=28 each diet/timepoint). After 24h, some females (n=10 each diet/timepoint) were euthanized for histological,immunohistochemical, and molecular analyses at PDN 29 or 36. The remaining animals(n=18 each diet/timepoint) were euthanized when tumors reached ≥2 cm or at PND 250.Besides the mammary gland development delay observed in LPD 21 and 28 groups,the gene expression profile demonstratedthat maternal LPD deregulated 21 genes related to DNA repair and DNAreplication pathways in the mammary gland of LPD 35 group after MNU. We furtherconfirmed an increased γ-H2AX (DNA damagebiomarker) and in ER-α immunoreactivity inmammary epithelial cells in the LPD group at PND 36. Furthermore, these earlypostnatal events were followed by significantly higher mammary carcinogenesis susceptibility inoffspring at adulthood. Thus, the results indicate that maternal LPD influenced the programming of chemicallyinduced mammary carcinogenesis in female offspring through increase in DNAdamage and deregulation of DNA repair and DNA replication pathways. Also, Cidea upregulation genein the LPD 35 group may suggest that maternal LPD could deregulate genespossibly leading to increased risk of mammary cancer development and/or poorprognosis. These findings increase thebody of evidence of early-transcriptional mammary gland changes influenced by maternal LPD, resulting indifferential response to breast tumor initiation and susceptibility and mayraise discussions about lifelong prevention of breast cancer risk.