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Reversal of increased mammary tumorigenesis by valproic acid and hydralazine in offspring of dams fed high fat diet during pregnancy.

ABSTRACT: Maternal or paternal high fat (HF) diet can modify the epigenome in germ cells and fetal somatic cells leading to an increased susceptibility among female offspring of multiple generations to develop breast cancer. We determined if combined treatment with broad spectrum DNA methyltransferase (DNMT) inhibitor hydralazine and histone deacetylase (HDAC) inhibitor valproic acid (VPA) will reverse this increased risk. C57BL/6 mouse dams were fed either a corn oil-based HF or control diet during pregnancy. Starting at age 7 weeks, female offspring were administered 3 doses of 7,12-dimethylbenz[a]anthracene (DMBA) to initiate mammary cancer. After last dose, offspring started receiving VPA/hydralazine administered via drinking water: no adverse health effects were detected. VPA/hydralazine reduced mammary tumor multiplicity and lengthened tumor latency in HF offspring when compared with non-treated HF offspring. The drug combination inhibited DNMT3a protein levels and increased expression of the tumor suppressor gene Cdkn2a/p16 in mammary tumors of HF offspring. In control mice not exposed to HF diet in utero, VPA/hydralazine increased mammary tumor incidence and burden, and elevated expression of the unfolded protein response and autophagy genes, including HIF-1?, NFkB, PERK, and SQSTM1/p62. Expression of these genes was already upregulated in HF offspring prior to VPA/hydralazine treatment. These findings suggest that breast cancer prevention strategies with HDAC/DNMT inhibitors need to be individually tailored.

SUBMITTER: Andrade FO

PROVIDER: S-EPMC6937280 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Project description:BackgroundMetabolic and endocrine environment during early life is crucial for metabolic imprinting. When dams were fed a high fat diet (HF diet), rat offspring developed hypothalamic leptin resistance with lean phenotype when weaned on a normal diet. Interestingly, when grown on the HF diet, they appeared to be protected against the effects of HF diet as compared to offspring of normally fed dams. The mechanisms involved in the protective effect of maternal HF diet are unclear.Methodology/principal findingsWe thus investigated the impact of maternal high fat diet on offspring subjected to normal or high palatable diet (P diet) on metabolic and endocrine parameters. We compared offspring born to dams fed P or HF diet. Offspring born to dams fed control or P diet, when fed P diet exhibited a higher body weight, altered hypothalamic leptin sensitivity and metabolic parameters suggesting that maternal P diet has no protective effect on offspring. Whereas, maternal HF diet reduces body weight gain and circulating triglycerides, and ameliorates corpulence index of offspring, even when subjected to P diet. Interestingly, this protective effect is differently expressed in male and female offspring. Male offspring exhibited higher energy expenditure as mirrored by increased hypothalamic UCP-2 and liver AdipoR1/R2 expression, and a profound change in the arcuate nucleus astrocytic organization. In female offspring, the most striking impact of maternal HF diet is the reduced hypothalamic expression of NPY and POMC.Conclusions/significanceHF diet given during gestation and lactation protects, at least partially, offspring from excessive weight gain through several mechanisms depending upon gender including changes in arcuate nucleus astrocytic organization and increased hypothalamic UCP-2 and liver AdipoR1/2 expression in males and reduced hypothalamic expression of NPY and POMC in females. Taken together our results reveal new mechanisms involved in the protective effect of maternal HF diet.

Project description:Objective: Procyanidins are polyphenolic bioactive compounds that exert beneficial effects against obesity and its related diseases. The aim of this study was to evaluate whether the supplementation with low doses of a grape seed procyanidin extract (GSPE) to dams during pre and postnatal periods has biological effects on their offspring at youth. Design: The metabolic imprinting effect of GSPE was evaluated in 30 days-old male offspring of four groups of rats that were fed either a standard diet (STD) or a high-fat diet (HFD) and supplemented with either GSPE at 25 mg per kg of body weight/day or vehicle during pregnancy and lactation. Results: A significant increase in the adiposity index and in the weight of all the white adipose tissue depots studied (retroperitoneal â??RWAT-, mesenteric â??MWAT-, epididymal â??EWAT- and inguinal â??IWAT-) was observed in offspring of dams fed with a HFD and treated with GSPE (HFT group), compared to the offspring of dams fed with the same diet and that do not received procyanidins (HF group). HFT animals also showed a higher number of cells in the EWAT, a sharply decrease of the circulating levels of monocyte chemoattractant protein-1 (MCP-1) as well as a moderate, but significant, decrease of plasma glycerol levels. The transcriptomic analysis performed in the EWAT showed 238 genes differentially expressed between HF and HFT animals, covering an entire range of processes related with the immune function and the inflammatory response (the metabolic pathway mainly reflected in the EWAT), adipose tissue remodeling and function, lipid and glucose homeostasis and metabolism of methyl groups. Conclusion: GSPE treatment to dams fed a HFD during pregnancy and lactation increases adiposity, decreases the circulating levels of MCP-1 and modulates the expression of key genes involved in the adipose tissue metabolism of their offspring. The microarray study was performed with the EWAT RNA samples of rats from the HF and the HFT groups (n=8 animals each).

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Reversal of increased mammary tumorigenesis by valproic acid and hydralazine in offspring of dams fed high fat diet during pregnancy.

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