(The FASEB Journal. 2005;19:1586-1591.)
© 2005 FASEB
Role of compensatory mammary growth in epigenetic control of gene expression
Chung S. Park1
Animal and Range Sciences Department, North Dakota State University, Fargo, North Dakota, USA
1 Correspondence: Animal and Range Sciences Department, Hultz Hall, North Dakota State University, Fargo, ND 58105, USA. E-mail: c.park{at}ndsu.edu
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ABSTRACT
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To better understand the role of nutrition in regulating mammary gland development and lactation, we designed a novel stair-step compensatory nutrition regimen that is a unique combination of dietary energy restriction and realimentation (refeeding) phases; the basic concept of this regimen is to exploit the biological nature of the compensatory growth phenomenon in concert with one or more hormone-sensitive allometric phases of mammary development (i.e., peripuberty through gestation). Nutritionally induced compensatory growth during different developmental stages before first parturition positively affects mammary development and life-long lactation performance. This permanent enhancement of mammary gland growth and lactation potential strongly suggests a possible mechanistic link between nutritionally induced compensatory growth, epigenetic control of mammary gene expression, and metabolic imprinting. We hypothesize that compensatory-directed metabolic imprinting once set during late pregnancy prior to the first parturition persistently maintains and exerts its adaptive response on mammogenesis and galactopoiesis (i.e., maintenance and/or enhancement of milk secretion). The ability to influence heritable genes regulating milk synthesis may be used to improve the quality and quantity of milk (e.g., infant health, the secretion of certain immunoglobulins or growth factors) as well as the longevity of lactation.—Park, C. S. Role of compensatory mammary growth in epigenetic control of gene expression.
Key Words: compensatory growth • mammary development • lactation potential • metabolic imprinting • epigenetics
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INTRODUCTION
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LACTATION POTENTIAL is largely influenced by the degree of mammary development (1)
. Nutritional events during hormone-sensitive growth phases, especially late gestation prior to first parturition, can significantly affect mammary development and subsequent lactation potential (2
3
4)
. The goal of this paper is to summarize key findings from our 15 years of work on nutritionally directed compensatory mammary growth, differentiation, and subsequent lactation potential. Epigenetic control of gene expression and metabolic imprinting will be addressed briefly as a potential explanation for the long-lasting effects of nutritionally induced compensatory mammary growth.
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NUTRITIONALLY DIRECTED COMPENSATORY MAMMARY DEVELOPMENT AND LACTATION POTENTIAL
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Stair-step compensatory nutrition model
We have developed a nutrition regimen that is a combination of alternating dietary energy restriction and realimentation phases. The basic concept of this model is to exploit the biological nature of both dietary energy restriction and the compensatory growth phenomenon in concert with one or more hormone-dependent allometric phases of mammary development (i.e., prepuberty, puberty, and late gestation). Energy restriction (i.e., providing all known essential nutrients but reducing caloric intake) has a profound influence on the biology and health of animals including the retardation of aging and the reduction of cancer incidence and other late-life diseases (5)
. Through modulation of endocrine and enzymatic status, energy restriction shifts the physiological focus to energy-conserving activities, mainly maintenance and repair functions, and decreases certain energy-wasteful metabolic pathways (e.g., substrate cycles) that are not essential for growth (6)
. Realimentation (refeeding) after energy restriction induces compensatory growth, which is characterized by an accelerated anabolism, a reduced maintenance requirement, an activated endocrine status, and an altered tissue composition (7
, 8)
. Compensatory growth enhances the efficiency of general body development and induces hyperplasia and hypertrophy of tissues and organs, including the mammary gland (9)
. Hence, when using the stair-step compensatory nutrition model, mammary development is minimized during the energy restriction phase and maximized during the realimentation or compensatory growth phase.
We have examined various stair-step compensatory nutrition regimens (one-, two-, or three-step models) for dairy and beef heifers, gilts, and female rats. Our flag ship regimen was a three-step program for dairy heifers; a step is one energy restriction phase followed by one realimentation phase. Specifically, step 1 (prepuberty) entailed energy restriction for 3 months followed by realimentation for 2 months. Step 2 (puberty) was energy restricted for 4 months followed by realimentation for 3 months. Finally, step 3 (gestation) consisted of 4 months of energy restriction and concluded with 2 months realimentation (10)
. While multistep programs (i.e., two or more compensatory growth phases) are effective, there have been increasing demands by a number of scientists in nutrition and biology for a simplified regimen. Furthermore, realizing that most mammary development takes place during gestation, our recent thrust has been on one-step regimens designed to induce compensatory mammary gland development during the last trimester of gestation after energy restriction during midgestation (4
, 11
, 12)
. Our latest gestational model described herein is for rats (4)
. Control rats were offered ad libitum access to the control diet (AIN 93G with 16% protein and 17 MJ/kg gross energy) [13] throughout the trial. The compensatory nutrition regimen began with dietary energy restriction (40%) during the first 10 days of gestation, followed by dietary energy realimentation (free access to the control diet) for the remainder of the trial, thus providing a theoretically overall 20% reduction in energy intake compared with that of the control group. The energy-restricted diet was formulated to provide an intake of protein, vitamins, and minerals similar to that of the control group except for energy; i.e., during the energy restriction phase, rats were fed the energy-restricted diet (27% protein and 17 MJ/kg gross energy) at 60% of the mean intake consumed ad libitum by the control group.
In general, animals reared on compensatory nutrition regimens show improvements in growth efficiency and mammary development and subsequent lactation performance. The mammary gland from compensatory animals shows increased cell proliferation with concurrent elevations of the expression of genes involved in cell proliferation and differentiation (2
, 4
, 14)
. As a result of improved mammogenesis, animals have higher lactation potential and longevity of lactation; more significantly, this effect carries through to subsequent lactations (2
, 10
, 15)
. The data presented hereafter are a composite from studies using various animal species and regimens with one-, two-, or three-step phases.
Mammary cell proliferation and differentiation
The number of mammary secretory cells is a major factor in determining lactation performance. Proper nutritional status especially during late gestation is critical to maximal mammary cell proliferation as most epithelial cell proliferation occurs during the last trimester of gestation (16)
. Cell proliferation is consistently greater in mammary tissues from rats in compensatory growth groups during midgestation, late gestation, and early lactation compared with those from control groups (Table 1
). Even more noteworthy, cell proliferation is greater in mammary tissues from the compensatory group during both the first and second lactation cycles compared with those from the control group (2)
, suggesting that compensatory mammary hyperplasia induced during critical periods of mammary development through the first pregnancy leads to a permanent increase in cell number.
Ornithine decarboxylase is a key regulating enzyme in the biosynthesis of polyamines in mammalian cells and plays an important role in the control of a variety of biological processes including cellular metabolism, differentiation, membrane function, and proliferation. Ornithine decarboxylase activity increases markedly during the initial stage of cell proliferation and differentiation, and elevated activities of ornithine decarboxylase are normally present in rapidly growing tissues (17
, 18)
. Ornithine decarboxylase mRNA is higher in mammary tissues collected from compensatory rats during midpregnancy (14)
as well as early lactation of the first lactation cycle (2
, 4)
; more important, this increase persists through the second lactation cycle (2
, 4)
. The increase in ornithine decarboxylase may be correlated to the metabolic shift necessary for the increased cell proliferation and for the increased milk protein synthesis during the early phase of lactogenesis.
Distinct steps of cellular differentiation take place during gestation and lactation. The caseins are major milk proteins and are secreted only by differentiated mammary tissues. The extent to which casein is synthesized in the mammary gland depends on the accumulation of corresponding mRNA. The changes in ß-casein mRNA levels in mammary tissues are summarized in Table 2
. The expression of the ß-casein gene is higher (40–74%) in mammary tissues during late gestation from heifers reared on a compensatory nutrition regimen than in those from conventionally raised heifers. In early lactating mammary tissues from rats on compensatory nutrition, there is also a pronounced increase in ß-casein message, amounting to 132% and 48% for first and second lactation cycles, respectively (3)
. The 
- and 
-casein and whey acidic protein mRNA are also higher in lactating mammary tissues from rats reared on a compensatory nutrition regimen (21)
. The increase in major milk protein genes is an indication of increased differentiation and functional activity in mammary tissues.
Lactation is characterized by widespread changes in the metabolism of tissues to ensure a sufficient supply of substrates to the mammary gland for milk production. The membrane-bound enzyme -glutamyltranspeptidase is involved in the regulation of the entry of amino acids into the cell (22)
. Mammary tissues obtained during both early and late lactation from compensatory nutrition rats have higher levels of -glutamyltranspeptidase mRNA compared with those from the control group over two lactation cycles (2)
. This elevation in the expression of -glutamyltranspeptidase may be related to the increased secretion of total protein (20)
and casein (10)
in milk from animals reared on compensatory nutrition regimens. As with cell proliferation, differentiation, as evidenced by increased messages of ß-casein and -glutamyltranspeptidase, remains enhanced over several lactation cycles, which may indicate that compensatory mammary hyperplasia is associated with stable permanent changes in gene expression.
Lactation potential
One of the most notable effects of our compensatory nutrition regimen is the enhancement of lactation performance (Table 3
). Studies encompassing one to four lactation cycles show that dairy heifers reared on compensatory growth regimens produce an average of 10% more milk than conventionally reared control heifers (10
, 15
, 24)
.
Major factors that influence peak milk yields are the number of secretory alveolar cells and the secretory activity of the cells (27)
. Persistency and longevity of lactation are chiefly regulated by rate of cell proliferation during late pregnancy to early lactation and programmed cell death (apoptosis) during late lactation (28)
. Mammary tissue collected during late lactation from stair-step rat exhibits less cell death during the first and second lactation cycles (2)
. Further, caspase-3 enzyme (an enzyme correlated with apoptosis because of its location in the protease cascade pathway) activities in late lactating mammary tissues from compensatory group rats are lower than in those from control rats for the first and second lactation cycles (4)
, indicating that mammary cell death may be occurring at a slower rate in the compensatory group.
Finally, insulin-like growth factor-I (IGF-I), which regulates mammary gland development through both promotion of cell cycle progression and inhibition of apoptosis (29)
, is lower in mammary tissues from the compensatory group than in those from the control group during early lactation and higher during late lactation (3)
. The expression of IGF-I during early lactation may be a possible negative factor for milk production in rats, and the compensatory-mediated increase in IGF-I mRNA during late lactation may have a suppressing effect on apoptosis of mammary cells.
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NUTRITION AND EPIGENETIC CONTROL OF GENE EXPRESSION
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The term metabolic imprinting describes the process whereby cells have a biological memory for nutritional influence that can be passed on to daughter cells through mitotic cell division (30)
. Epigenetics refers to stable alterations in gene expression that arise during development and cell proliferation and are subsequently retained through mitosis (31)
. While such epigenetic changes in the genome are heritable but do not involve mutations of the DNA itself, DNA methylation is accepted as one of the most important underlying biological mechanisms regulating the metabolic imprinting process (32)
. DNA methylation is a postreplication process by which cytosine nucleotides in CpG sequences are methylated to 5-methylcytosine, forming gene-specific methylation patterns (33)
. DNA methylation might be responsible for the stable maintenance of a particular gene expression pattern through mitotic cell division (34)
. Nutrition research has recently emphasized the role of diet in DNA methylation and effects on stable epigenetic changes. Restricted feeding during early phases of development causes metabolic imprinting that leads to increased susceptibility to cardiovascular disease in later life (35)
, increased insulin sensitivity as an adaptive response (36)
, or decreased longevity (37)
. The hormonal milieu present during pregnancy results in lasting changes in the pattern of gene expression in the mammary gland, leading to permanent changes in cell fate that determine the subsequent proliferative response of the gland (38)
. These hormonally induced persistent changes in gene expression may be mediated by epigenetic alterations in DNA methylation status of promoter sequences (39)
. Choi et al. (19)
. observed that the 5'-methyldeoxycytidine level was lower in mammary tissue collected during the compensatory growth phase from late gestation heifers compared with that from control heifers. This decrease in DNA methylation may be correlated to the increased expression of milk protein genes.
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WORKING HYPOTHESIS: COMPENSATORY GROWTH-DIRECTED METABOLIC IMPRINTING
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The permanent effect of this nutrition regimen on mammary development and lactation strongly suggests a possible mechanistic link between nutritionally induced compensatory mammary growth, epigenetic control of gene expression, and metabolic imprinting (Fig. 1
). Through alterations in endocrine status, energy restriction during midgestation redirects energy flow to energy-conserving activities. Subsequent realimentation (refeeding) during late gestation induces compensatory growth that is characterized by activation of hormonal and gene signals resulting in accelerated growth and metabolism. The synergistic interaction of nutritionally induced compensatory growth with developmentally related allometric growth initiates an up-regulation of genes affecting cell proliferation and differentiation. This compensatory developmental cascade triggers, most likely via a specific hormonal environment, alterations in DNA methylation patterns resulting in epigenetic changes in mammary gene expression. Increased mammary cell proliferation causes permanent hyperplastic and hypertrophic growth of the parenchymal tissues of the mammary gland; this may launch the metabolic imprinting process. Therefore, compensatory directed metabolic imprinting once set during the last trimester of the first pregnancy persistently maintains and exerts its adaptive response on mammogenesis and life-long galactopoiesis (i.e., maintenance and/or enhancement of milk secretion).
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Figure 1. Proposed mechanism of how nutritionally induced compensatory mammary development leads to metabolic imprinting.
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Of all the potential effects of early nutrition experiences upon metabolic imprinting mechanisms, a permanent alteration in cell number is the simplest and easiest to put forward. Cell proliferation is dependent on nutrient availability, the general nutritional status, and certain hormonal signals (30)
. During compensatory allometric development (e.g., late gestation), the mammary gland may increase in size by an increase either in cell number (hyperplasia) or in cell size (hypertrophy). The number of mammary cells determines the metabolic activity of mammary gland. Hence, a permanent increase in cell number will persistently affect mammary gland metabolism.
Most tissues involved in imprinting undergo continuous cellular turnover. Hence, cells exposed to nutritional stimuli during a specific critical window of growth must pass the effects of the exposure onto their progeny. Waterland and Garza (30)
proposed that putative metabolic imprinting must meet certain criteria. First, the susceptibility to the imprinting phenomenon must be limited to a critical window of development. The last trimester of pregnancy is the most hormone-sensitive stage during which the majority of allometric mammary development takes place. We have shown that compensatory growth once induced during late gestation has pronounced effects on gene expression, mammogenesis, and lactation. Second, the specific effect should be persistent, lasting the lifetime of the animal. Our studies clearly reveal that the increase in mammary cell proliferation is evident over two lactations. Third, the imprinting should exhibit an adaptive response with a specific measurable result. Indeed, compensatory mammary growth induced during critical stages of development through the first pregnancy enhances lactation performance over multiple lactation cycles.
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CONCLUSIONS AND IMPLICATIONS
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We have established that the stair-step compensatory nutrition regimen has lasting effects on mammary development, differentiation, and lactation. Thus, the principal challenge will be to document the extent to which nutritionally directed compensatory mammary hyperplasia induced once during the first gestation affects methylation status, thereby producing stable epigenetic changes in genes, the result being a metabolic imprinting process. If heritable genes regulating milk synthesis are identified, the possibility exists to manipulate genes to further improve lactation as well as the longevity of lactation. In the biomedical field, the ability to influence heritable genes regulating milk synthesis may be used to improve quality and quantity of milk (e.g., infant health, the secretion of certain immunoglobulins or growth factors); in the animal industry, an increase in lactation efficiency could increase profits without increasing cow number, which has economic as well as environmental impact (e.g., land use).
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ACKNOWLEDGMENTS
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I thank F. Aslroosta, M. Baik, P. Best, D. Carlson, Y. Choi, J. Crenshaw, R. Danielson, M. Encinias, J. Ford, Jr., H. Kim, S. Kim, M. Laubach, R. Maddock, G. Marx, Y. Moon, W. Poland, J. Schroeder, and C. Westby for their direct scientific contribution to these studies. I am grateful to W. Keller for her assistance with these studies including laboratory analysis, data collection, and manuscript preparation. Special thanks are given to J. Berg for secretarial assistance. Research on which this review is based was supported by USDA-National Research Initiative, NIH-National Cancer Institute, American Institute for Cancer Research, North Dakota State Board of Agricultural Research, North Dakota Livestock Endowment Foundation, and Hoffmann LaRoche Company.
Received for publication May 31, 2005.
Accepted for publication June 3, 2005.
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REFERENCES
|
|---|
- Dijkstra, J., France, J., Dhanoa, M. S., Maas, J. A., Hanigan, M. D., Rook, A. J., Beever, D. E. (1997) A model to describe growth patterns of the mammary gland during pregnancy and lactation. J. Dairy Sci. 80,2340-2354[Abstract]
- Moon, Y. S., Park, C. S. (1999) Nutritionally-directed compensatory growth enhances mammary development and lactation potential in rats. J. Nutr. 129,1156-1160[Abstract/Free Full Text]
- Moon, Y. S., Park, C. S. (2002) Effects of controlled compensatory growth on mammary gland development and lactation in rats. Asian-australas. J. Anim. Sci. 15,1364-1370
- Kim, H. H., Park, C. S. (2004) A compensatory nutrition regimen during gestation stimulates mammary development and lactation potential in rats. J. Nutr. 134,756-761[Abstract/Free Full Text]
- Hursting, S. D., Lavigne, J. A., Berrigan, D., Perkins, S. N., Barrett, J. C. (2003) Calorie restriction, aging and cancer prevention: mechanisms of action and applicability to humans. Annu. Rev. Med. 54,131-152[CrossRef][Medline]
- Newsholme, E. A. (1980) A possible metabolic basis for the control of body weight. N. Engl. J. Med. 302,400-405[Medline]
- Wilson, P. N., Osbourn, D. F. (1960) Compensatory growth after undernutrition in mammals and birds. Biol. Rev. Camb. Philos. Soc. 35,324-363[Medline]
- Ashworth, A., Millward, D. J. (1986) Catch-up growth in children. Nutr. Rev. 44,157-163[Medline]
- Park, C. S. (2002) Heifer rearing for optimum lifetime production. Garnsworthy, P. C. Wiseman, J. eds. Recent Developments in Ruminant Nutrition 4. ,581-596 Nottingham University Press Nottingham, UK.
- Ford, J. A., Jr, Park, C. S. (2001) Nutritionally directed compensatory growth enhances heifer development and lactation potential. J. Dairy Sci. 84,1669-1678[Abstract]
- Encinias, A. M., Encinias, H. B., Klein, D., Lardy, G. P., Bauer, M. L., Park, C. S. (2001) Effects of a modified stair-step compensatory growth model for gestating beef heifers. J. Anim. Sci. 79(Suppl. 1),296(abstr.)
- Laubach, M. S., Carlson, D. B., Keller, W. L., Park, C. S. (2003) Compensatory growth during late gestation and its effects on metabolic status and health of transition heifers. J. Dairy Sci. 86(Suppl. 1),166(abstr.)
- Reeves, P. G., Nielsen, F. H., Fahey, G. C., Jr (1993) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J. Nutr. 123,1939-1951
- Kim, S. H., Moon, Y. S., Keller, W. L., Park, C. S. (1998) Compensatory nutrition-directed mammary cell proliferation and lactation in rats. Br. J. Nutr. 79,177-183[CrossRef][Medline]
- Park, C. S., Baik, M. G., Keller, W. L., Berg, I. E., Erickson, G. M. (1989) Role of compensatory growth in lactation: a stair-step nutrient regimen modulates differentiation and lactation of bovine mammary gland. Growth Dev. Aging 53,159-166[Medline]
- Thordarson, G., Talamantes, F. (1987) Role of the placenta in mammary gland development and function. Neville, M. C. Daniel, C. W. eds. The Mammary Gland Development, Regulation, and Function ,459-498 Plenum Press New York, NY.
- Russell, D. H., McVicker, T. A. (1972) Polyamine biogenesis in the rat mammary gland during pregnancy and lactation. Biochem. J. 130,71-76[Medline]
- Lin, C. H., Correia, L., Tolia, K., Gesell, M. S., Tolia, V., Lee, P. C., Luk, G. D. (1998) Early weaning induces jejunal ornithine decarboxylase and cell proliferation in neonatal rats. J. Nutr. 128,1636-1642[Abstract/Free Full Text]
- Choi, Y. J., Jang, K., Yim, D. S., Baik, M. G., Myung, K. H., Kim, Y. S., Lee, H. J., Kim, J. S., Han, I. K. (1998) Effects of compensatory growth on the expression of milk protein gene and biochemical changes of the mammary gland in Holstein cows. J. Nutr. Biochem. 9,380-387[CrossRef]
- Park, C. S., Danielson, R. B., Kreft, B. S., Kim, S. H., Moon, Y. S., Keller, W. L. (1998) Nutritionally directed compensatory growth and effects on lactation potential of developing heifers. J. Dairy Sci. 81,243-249[Abstract]
- Park, C. S., Choi, Y. J., Keller, W. L., Harrold, R. L. (1988) Effects of compensatory growth on milk protein gene expression and mammary differentiation. FASEB J. 2,2619-2624[Abstract]
- Meister, A. (1973) On the enzymology of amino acid transport. Science 180,33-39[Free Full Text]
- Choi, Y. J., Han, I. K., Woo, J. H., Lee, H. J., Jang, K., Myung, K. H., Kim, Y. S. (1997) Compensatory growth in dairy heifers: the effect of a compensatory growth pattern on growth rate and lactation performance. J. Dairy Sci. 80,519-524[Abstract]
- Park, C. S., Erickson, G. M., Choi, Y. J., Marx, G. D. (1987) Effect of compensatory growth on regulation of growth and lactation: response of dairy heifers to a stair-step growth pattern. J. Anim. Sci. 64,1751-1758
- Peri, I., Gertler, A., Bruckental, I., Barash, H. (1993) The effect of manipulation in energy allowance during the rearing period of heifers on hormone concentrations and milk production in first lactation cows. J. Dairy Sci. 76,742-751[Abstract/Free Full Text]
- Crenshaw, J. D., Park, C. S., Swantek, P. M., Keller, W. L., Zimprich, R. C. (1989) Lactation response of gilts to a phased feeding regimen designed to induce compensatory growth. J. Anim. Sci. 67(Suppl. 2),107-108(abstr.)
- Forsyth, I. A. (1996) The insulin-like growth factor and epidermal growth factor families in mammary cell growth in ruminants: action and interaction with hormones. J. Dairy Sci. 79,1085-1096[Abstract]
- Walker, N. I., Bennett, R. E., Kerr, J. F. R. (1989) Cell death by apoptosis during involution of the lactating breast in mice and rats. Am. J. Anat. 185,19-32[CrossRef][Medline]
- Kleinberg, D. L., Feldman, M., Ruan, W. (2000) IGF-I: an essential factor in terminal end bud formation and ductal morphogenesis. J. Mammary Gland Biol. Neoplasia 5,7-17[CrossRef][Medline]
- Waterland, R. A., Garza, C. (1999) Potential mechanisms of metabolic imprinting that lead to chronic disease. Am. J. Clin. Nutr. 69,179-197[Abstract/Free Full Text]
- Riggs, A. D., Martienssen, R. A., Russo, V. E. A. (1996) Introduction. Russo, V. E. A. Martienssen, R. A. Riggs, A. D. eds. Epigenetic Mechanisms of Gene Regulation ,1-4 Cold Spring Harbor Laboratory Press Plainview, NY.
- Jaenisch, R., Bird, A. (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33(Suppl.),245-254
- Razin, A., Shemer, R. (1999) Epigenetic control of gene expression. Results Probl. Cell Differ. 25,189-204[Medline]
- Holliday, R., Pugh, J. E. (1975) DNA modification mechanisms and gene activity during development. Science 187,226-232[Free Full Text]
- Lucas, A., Baker, B. A., Desai, M., Hales, C. N. (1996) Nutrition in pregnant or lactating rats programs lipid metabolism in the offspring. Br. J. Nutr. 76,605-612[CrossRef][Medline]
- de Souza Caldeira Filho, J., Sanchez Moura, A. (2000) Undernutrition during early lactation period induces metabolic imprinting leading to glucose homeostasis alteration in aged rats. Res. Commun. Mol. Pathol. Pharmacol. 108,213-226[Medline]
- Hales, C. N., Ozanne, S. E. (2003) For debate: fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure. Diabetologia 46,1013-1019[CrossRef][Medline]
- Sivaraman, L., Stephens, L. C., Markaverich, B. M., Clark, J. A., Krnacik, S., Conneely, O. M., O’Malley, B. W., Medina, D. (1998) Hormone-induced refractoriness to mammary carcinogenesis in Wistar-Furth rats. Carcinogenesis 19,1573-1581[Abstract/Free Full Text]
- Ginger, M. R., Gonzalez-Rimbau, M. F., Gay, J. P., Rosen, J. M. (2001) Persistent changes in gene expression induced by estrogen and progesterone in the rat mammary gland. Mol. Endocrinol. 15,1993-2009[Abstract/Free Full Text]
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INTRODUCTION
