Abstract
Maternal exposure to dietary factors during pregnancy influences the risk of many adult-onset diseases in the later life of offspring. Here, we investigated the effects of maternal n-3 polyunsaturated fatty acid (PUFA) diet on breast cancer risk of female offspring. Pregnant C57BL/6J mice were fed a normal diet (control group), or a high-fat diet rich in safflower oil (SO), fish oil (FO) or flaxseed oil (FSO) (n = 10) throughout gestation and lactation. Their female offspring were fed an AIN-93G diet from weaning. Tumor incidences in offspring induced by 7,12-dimethylbenz[α]anthracene (DMBA) were higher in high-fat groups than in the control group, and were lower in FO and FSO groups than in the SO group. The plasma concentrations of 17β-estradiol (E2), in both pregnant dams and offspring, were significantly lower in FO and FSO groups compared with the SO group. The FO and FSO offspring showed delayed puberty onset, and their mammary glands contained decreased numbers of epithelial terminal end buds (TEBs, targets for malignant transformation) compared with SO offspring. Reduced cell proliferation and increased apoptosis in FO and FSO offspring were observed compared with SO offspring. In line with these changes, maternal exposure to FO promoted the expression of long noncoding RNA (lncRNA) in p53 and apoptosis signaling pathways and inhibited that in NF-κB and Jak-STAT signaling pathways, while FSO promoted the expression of lncRNA in p53 signaling pathways and inhibited that in NF-κB, Jak-STAT and MAPK signaling pathways. In conclusion, maternal exposure to a high-fat diet rich in n-3 PUFAs, both marine- and plant-based, has a protective effect on mammary tumor risk of female offspring in later life.
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Most studies that have investigated the effects of n-3 fatty acids on breast cancer have used eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) as the test fatty acids. In the present study, the hypothesis that maternal exposure to high-fat diets supplemented with n-3 PUFAs (EPA, DHA, ALA) during gestation and lactation may weaken the high-fat diet induced increased risk of female mice offspring developing mammary tumors was assessed and compared the effect of different types of n-3 fatty acids. In addition, plausible mechanisms for modulating the multistage carcinogenesis process by n-3 PUFAs were investigated to explain the link between maternal diets and breast cancer risk in offspring.
The present study demonstrated that maternal exposure to high-fat diets was associated with increased breast cancer risk of female offspring, and n-3 PUFAs, both marine- and plant based types, could attenuate multiple aspects of the effect. The ALA diet during pregnancy and lactation was as effective as the fish oil n-3 PUFA diet in decreasing the breast cancer risk of offspring. ALA decreased the incidence of DMBA-induced mammary tumorigenesis by 26% and 16% in FO and FSO offspring, respectively, compared with SO offspring. The findings support the hypothesis that maternal consumption of n-3 PUFAs alleviated the high-fat diet-induced increased risk of female offspring developing mammary cancer, and ALA had a comparably protective effect with EPA and DHA. The protective effects of n-3 PUFAs were associated with up-regulated lncRNA in the p53 signaling pathway, and down-regulated lncRNA in NF-κB and Jak-STAT signaling pathways. These data raise the possibility that prevention of breast cancer could be started from the fetus period by modifying the dietary fatty acid intake of pregnant women.