Maternal intake of high n-6 polyunsaturated fatty acid diet during pregnancy causes transgenerational increase in mammary cancer risk in mice

Abstract

BackgroundMaternal and paternal high-fat (HF) diet intake before and/or during pregnancy increases mammary cancer risk in several preclinical models. We studied if maternal consumption of a HF diet that began at a time when the fetal primordial germ cells travel to the genital ridge and start differentiating into germ cells would result in a transgenerational inheritance of increased mammary cancer risk.MethodsPregnant C57BL/6NTac mouse dams were fed either a control AIN93G or isocaloric HF diet composed of corn oil high in n-6 polyunsaturated fatty acids between gestational days 10 and 20. Offspring in subsequent F1–F3 generations were fed only the control diet.ResultsMammary tumor incidence induced by 7,12-dimethylbenz[a]anthracene was significantly higher in F1 (p < 0.016) and F3 generation offspring of HF diet-fed dams (p < 0.040) than in the control offspring. Further, tumor latency was significantly shorter (p < 0.028) and burden higher (p < 0.027) in F1 generation HF offspring, and similar trends were seen in F3 generation HF offspring. RNA sequencing was done on normal mammary glands to identify signaling differences that may predispose to increased breast cancer risk by maternal HF intake. Analysis revealed 1587 and 4423 differentially expressed genes between HF and control offspring in F1 and F3 generations, respectively, of which 48 genes were similarly altered in both generations. Quantitative real-time polymerase chain reaction analysis validated 13 chosen up- and downregulated genes in F3 HF offspring, but only downregulated genes in F1 HF offspring. Ingenuity Pathway Analysis identified upregulation of Notch signaling as a key alteration in HF offspring. Further, knowledge-fused differential dependency network analysis identified ten node genes that in the HF offspring were uniquely connected to genes linked to increased cancer risk (ANKEF1, IGFBP6, SEMA5B), increased resistance to cancer treatments (SLC26A3), poor prognosis (ID4, JAM3, TBX2), and impaired anticancer immunity (EGR3, ZBP1).ConclusionsWe conclude that maternal HF diet intake during pregnancy induces a transgenerational increase in offspring mammary cancer risk in mice. The mechanisms of inheritance in the F3 generation may be different from the F1 generation because significantly more changes were seen in the transcriptome.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0866-x) contains supplementary material, which is available to authorized users.

Grape Juice Consumption with or without High Fat Diet during Pregnancy Reduced the Weight Gain and Improved Lipid Profile and Oxidative Stress Levels in Liver and Serum from Wistar Rats

“…In addition, excess weight gain during pregnancy may be associated with gestational diabetes, birth difficulties, and even health risks to the fetus during the perinatal period into adult life [5]. Recently studies showed that paternal and maternal obesity increase the chance of breast cancer in female offspring [6][7][8].…”

Dietary fat and obesity as modulators of breast cancer risk: Focus on DNA methylation

“…In rats, maternal intake of a high‐fat diet (43% of kcal from corn oil) during pregnancy caused a significant increase in the susceptibility of F1 offspring to DMBA‐induced mammary tumours, which was associated with increased expression of Dnmt1 in offspring mammary glands (de Assis et al, ). Studies utilizing the DMBA mammary tumour model in mice have also demonstrated a transgenerational (in F1–F3) enhancing effect of gestational exposure to a maternal high‐fat diet (38.9% of kcal from corn oil) on mammary tumourigenesis, although whether this is related to aberrant expression of Dnmt genes was not specifically addressed (Nguyen et al, ).…”

“…Experiments in mouse mammary tumour virus-neu mice demonstrated that both overweight-and obesity-inducing diets enhanced the development of spontaneous mammary tumours and increased mammary gland expression of Dnmt1 (Rossi et al, 2017). In contrast, calorie-restricted mice had stable mammary gland expression of of kcal from corn oil) on mammary tumourigenesis, although whether this is related to aberrant expression of Dnmt genes was not specifically addressed (Nguyen et al, 2017).…”

“…Positive associations between high‐fat diets (HFD) and BC incidence have been documented in observational and preclinical studies (Boyd et al, ; Cao, Hou, & Wang, ; Liu et al, ; Nguyen et al, ; Wu, Yu, Tseng, Stanczyk, & Pike, ). Moreover, obesity is considered a BC risk factor and may influence BC survival (Chen et al, ; Chen et al, ; Pierobon & Frankenfeld, ; Xia et al, ).…”

Influence of paternal consumption of a high-fat/high-sugar diet and/or orange juice during preconception on C57BL/6 female mice offspring breast cancer risk

“…More recently studies showed that dietary exposures during the intrauterine period may also alter later susceptibility to breast tumors development (DE ASSIS et al, 2012;NGUYEN et al, 2017). Exposure of Sprague-Dawley rats to a high-fat diet during pregnancy, for example, resulted in increased breast cancer risk in two generations of female offspring (daughters and grandchildren) (DE ASSIS et al, 2012).…”