Lasting Effects on Body Weight and Mammary Gland Gene Expression in Female Mice upon Early Life Exposure to n3 but Not n6 HighFat Diets.

Exposure to an imbalance of nutrients prior to conception and during critical developmental periods can have lasting consequences on physiological processes resulting in chronic diseases later in life. Developmental programming has been shown to involve structural and functional changes in important tissues. The aim of the present study was to investigate whether early life diet has a programming effect on the mammary gland. Wild-type mice were exposed from 2 weeks prior to conception to 6 weeks of age to a regular low-fat diet, or to high-fat diets based on either corn oil or flaxseed oil. At 6 weeks of age, all mice were shifted to the regular low fat diet until termination at 10 weeks of age. Early life exposure to a high fat diet, either high in n6 (corn oil) or in n3 (flaxseed oil) polyunsaturated fatty acids, did not affect birth weight, but resulted in an increased body weight at 10 weeks of age. Transcriptome analyses of the fourth abdominal mammary gland revealed differentially expressed genes between the different treatment groups. Exposure to high-fat diet based on flaxseed oil, but not on corn oil, resulted in regulation of pathways involved in energy metabolism, immune response and inflammation. Our findings suggest that diet during early life indeed has a lasting effect on the mammary gland and significantly influences postnatal body weight gain, metabolic status, and signaling networks in the mammary gland of female offspring. (Authors abstract)

Developmental programming involves structural and functional changes in important tissues leading to altered cell number, imbalance in distribution of different cell types within the organ,
and altered blood supply or receptor numbers. Tissues and organs that have been identified as targets for programming include heart, kidney, liver, pancreas, and adipose tissue. Differentiation of the mammary gland has also been demonstrated to be sensitive to changes in diet during early life. Studies in rodents have, in general, be supportive of a tumor promoting effect of consumption of a diet rich in n6 polyunsaturated fatty acids (PUFAs) during early life, whereas consumption of a diet with a lower n6/n3 PUFA ratio is potentially associated with a decreased incidence of cancer.  The goal of the present study was to determine the extent to which diet in early life has a lasting effect on mammary gland development and to identify the underlying cellular-response pathways based on genome-wide analysis of the transcriptome.
The effect of different types of dietary fat, using high fat diets high in n6 or in n3 PUFAs, and studied gene expression profiles in relation to postnatal growth curves in mice was studied. Mice were exposed to different experimental diets through the mother, starting 2 weeks pre conception and continuing prenatally through in utero and lactational periods, then from weaning (3 weeks) until the age of 6 weeks, before switching them to standard mouse chow.
Final assessments were done in sexually mature nulliparous females at 10 weeks of age.

Using a murine model for early life dietary fat exposure on female pups, the present study found changes in the mammary gland transcriptome that accompanies excessive postnatal weight gain following perinatal exposure to fatty diets high in n6 or in n3 PUFAs. he FO test diet specifically, having a low n6 to n3 ratio, affected the serum fatty acid profile of mouse pups.  This effect persisted for at least 4 weeks after switching to a normal diet, since serum levels of several n3 PUFAs remained elevated, and serum arachidonic acid was reduced, compared to mice exposed to the control or CO diets. These results indicate that perinatal and early life exposure to the FO diet modulated the serum fatty acid profile by altering circulating long chain PUFAs, which appears to be a more lasting effect.

Postnatal body weight gain of the female offspring was increased after perinatal exposure to a high fat diet as compared to regular low fat diet exposure. This increase in body weight persisted until termination of the animals at 10 weeks of age (i.e. 4 weeks after cessation of treatment) when the high-fat diet was based on FO, but not when based on CO. Although additional studies are needed to elucidate whether this is a temporary or permanent effect, this finding is unexpected, because n-6 PUFAs have long been labeled ‘bad’ due to adverse effects on cardiovascular and other health outcomes while n3 PUFAs are generally regarded as ‘protective’ fatty acids.  Further studies are needed to localize the susceptible stage(s). Assuming the current findings in mice reflect the human response, then the present study suggests the nature and degree of dietary fat consumption during fetal and/or lactational development may contribute to the susceptibility to breast cancer risk later in life. (Editors comments)