Ajpendo 00495 2015

Am J Physiol Endocrinol Metab 311: E405–E422, 2016.
First published June 28, 2016; doi:10.1152/ajpendo.00495.2015. Review
Biological underpinnings of breastfeeding challenges: the role of genetics,

diet, and environment on lactation physiology
Sooyeon Lee1 and Shannon L. Kelleher1,2,3,4
1
Departments of Cellular and Molecular Physiology, 2Pharmacology, and 3Surgery, Pennsylvania State Hershey College of
Medicine, Hershey, Pennsylvania; and 4Department of Nutritional Sciences, The Pennsylvania State University, University
Park, Pennsylvania
Submitted 20 November 2015; accepted in final form 22 June 2016
Lee S, Kelleher SL. Biological underpinnings of breastfeeding challenges: the

role of genetics, diet, and environment on lactation physiology. Am J Physiol
Endocrinol Metab 311: E405–E422, 2016. First published June 28, 2016;
doi:10.1152/ajpendo.00495.2015.—Lactation is a dynamic process that has
evolved to produce a complex biological fluid that provides nutritive and nonnu-
tritive factors to the nursing offspring. It has long been assumed that once lactation
is successfully initiated, the primary factor regulating milk production is infant
demand. Thus, most interventions have focused on improving breastfeeding edu-
cation and early lactation support. However, in addition to infant demand, increas-
ing evidence from studies conducted in experimental animal models, production
animals, and breastfeeding women suggests that a diverse array of maternal factors
may also affect milk production and composition. In this review, we provide an
overview of our current understanding of the role of maternal genetics and
modifiable factors, such as diet and environmental exposures, on reproductive
endocrinology, lactation physiology, and the ability to successfully produce milk.
To identify factors that may affect lactation in women, we highlight some infor-
mation gleaned from studies in experimental animal models and production
animals. Finally, we highlight the gaps in current knowledge and provide com-
mentary on future research opportunities aimed at improving lactation outcomes in
breastfeeding women to improve the health of mothers and their infants.
lactation; mammary gland; genetics; diet; environment
BREAST MILK IS A COMPLEX BIOLOGICAL FLUID that provides for that contribute to lactation insufficiency. In addition, numerous
optimal infant growth and development, but only if lactation social, psychological, and behavioral factors associated with
functions properly to produce an adequate volume of milk that early breastfeeding cessation have been described, and the
contains optimal amounts of nutritive and nonnutritive factors. reader is referred to excellent reviews on these topics (81, 90,
Successful lactation requires extensive breast tissue expansion 192, 280). What is much less appreciated and poorly under-
and differentiation during pregnancy, followed by the ability to stood is the role that maternal genetics and modifiable factors
produce sufficient amounts of milk after birth. Although ⬃75% such as energy balance, diet, and environmental exposures may
of new mothers intend to breastfeed, not all women are able to have on reproductive endocrinology, lactation physiology, and
breastfeed their infants exclusively for the first 6 mo of life, as the ability to successfully breastfeed. The major unsolved
recommended by the American Academy of Pediatrics and the questions regarding these maternal factors have been outlined
World Health Organization. In fact, it has been estimated that in a recent review (209). In this review, we provide a broad
the prevalence of women who overtly fail to produce enough overview on our current understanding of the molecular etiol-
milk may be as high as ⬃10 –15% (15, 64, 206) and can ogy behind these factors that play a critical role in lactation
quickly lead to hypernatremia (28, 231, 293, 311), nutritional physiology and the ability to optimally nourish the nursing
deficiencies (16, 139, 287), or failure to thrive (141, 164, 207). infant. Because studies in breastfeeding women are profoundly
Moreover, the prevalence of lactation “insufficiency” may be lacking, some aspects and comparisons will be drawn from
much higher, as ⬃40 –50% of women in the US (1, 162) and experimental animal models and studies in production animals
60 –90% of women internationally (76, 99, 113, 135, 266) cite where relevant; however, it is important to note that lactation
“not producing enough milk” or “baby not satisfied with breast physiology between humans and other mammals can vary, and
milk” as the primary reasons for weaning prior to 6 mo. The where appropriate these differences will be discussed in con-
etiology of lactation insufficiency is clearly multifactorial and text.
complex. Breast hypoplasia or other abnormal breast condi-
tions and previous breast surgeries (206) are certainly factors Mammary Gland Biology and the Production of Milk
The mammary gland is a highly complex exocrine gland that
Address for reprint requests and other correspondence: S. L. Kelleher, 500 functions to produce, secrete, and deliver milk to the infant.
University Dr., Hershey, PA (e-mail: [email protected]). Mammary glands are unique in that most development occurs
http://www.ajpendo.org 0193-1849/16 Copyright © 2016 the American Physiological Society E405
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Review
E406 ROLE OF GENETICS, DIET, AND ENVIRONMENT ON LACTATION
postnatal. From birth to puberty, the rudimentary branches micronutrients (6). In addition, breast milk contains human
elongate through the mammary fat pad and form terminal end milk oligosaccharides (reviewed in Ref. 269) and numerous
buds in preparation for functional activation during pregnancy growth factors, hormones, chemokines, and cytokines (re-
and lactation. Successful lactation requires coordination of viewed in Ref. 259) as well as DNA, RNA, microRNAs, white
mechanisms responsible for nutrient transport, milk produc- blood cells, and live bacteria (reviewed in Ref. 153) and stem
tion, and secretion from the mammary gland and is driven by cells (reviewed in Ref. 111). Breast milk composition changes
molecular, biochemical, and cellular events that are regulated over the course of lactation. In women, secretory activation
largely by reproductive hormones, which has been described occurs after parturition (30 – 40 h after birth), and the first fluid
thoroughly by Anderson et al. (7). During early pregnancy, produced is colostrum (225). Only a small volume (⬃30 ml/24 h)
primary hormones, including estrogen, progesterone, prolactin, of colostrum is available for the first few days, but contains
and placental lactogen, induce the physiological transition of high concentrations of immunological components such as
the mammary gland from a nonsecreting branched tissue into a secretory IgA, lactoferrin, and leukocytes as well as develop-
highly active secreting organ comprised of a vast network of mental factors such as epidermal growth factor (49, 147, 225).
ducts and alveoli that are grouped into seven to 10 lobes in The concentration of lactose, the most osmotically active
humans (243). Following this morphological change, the alve- component in breast milk, is low in colostrum, thus explaining
olar cells increase the expression of lactogenic genes, which the low volume of colostrum that is secreted and also indicat-
differentiates them into secretory mammary epithelial cells ing that the primary function of colostrum is immunological
(MECs) or lactocytes, and this process is termed secretory rather than nutritional (17). Compared with mature milk, co-
differentiation (225). In response to progesterone and estrogen lostrum contains higher levels of sodium, chloride, and mag-
withdrawal, concomitant with prolactin release following par- nesium and lower levels of potassium and calcium (17, 147,
turition, the differentiated epithelium gains a remarkable ca- 225). As the mammary gland transitions from pregnancy to
pacity to finely coordinate the synthesis and transport of lactation, tight junctions between MECs close, and conse-
various milk constituents for the onset of milk secretion, quently the sodium/potassium ratio declines and the lactose
termed secretory activation (225), which usually occurs after concentration increases (147). This reflects secretory activation
full-term birth in humans (210). During this time, tight junc- and the synthesis of transitional milk, which marks the period
tions between lactocytes close and limit the passage of ions of copious milk production and the secretion of nutritive and
(e.g., sodium and chloride) and small molecules, which is nonnutritive factors to support nutritional and developmental
important for the establishment of lactation and motivating needs of the growing infant. After the first month, breast milk
milk secretion (147, 272). Milk ejection is regulated by oxy- is considered fully mature and contains ⬃0.9 –1.2 g protein/dl,
tocin, which acts on myoepithelial cells to generate contractile 3.2–3.6 g fat/dl, and 6.7–7.8 g lactose/dl (17). Although there
force required for milk ejection during lactation (103). In is a dramatic shift in composition during the first month, the
contrast, milk secretion from lactocytes is regulated by a concentration of macronutrients in breast milk remains rela-
complex hormonal milieu that includes numerous reproductive tively constant over the course of lactation, with gradual
hormones (e.g., prolactin) and metabolic hormones [e.g., glu- increases in milk fat content over the course of one feeding
cocorticoids, insulin, insulin-like growth factor 1 (IGF-I), (17). However, it is important to note that milk composition, as
growth hormone, and thyroid hormone]. These hormones can well as mammary gland number, location, and architecture, is
act directly on the lactocyte or indirectly by altering endocrine different between humans and animals, which is a limitation to
response and nutrient delivery to the mammary gland for milk extrapolating information on human lactation from animal
production (34). The main stimulus for the initiation of studies (2). For example, cattle have a total of four inguinal
lactation is infant suckling and milk removal, which acti- mammary glands producing milk that is higher in protein
vates the milk ejection reflex through the release of oxytocin compared with humans, and mice have four thoracic, two
from the posterior pituitary gland, leading to the contraction abdominal, and four inguinal mammary glands producing milk
of the myoepithelial cells around the alveoli and ducts, ulti- that is higher in protein, fat, and energy compared with humans
mately forcing milk into the alveolar lumen and out the nipple, (2, 128).
providing milk to the developing infant (225). Once lactation As a result of this complex mixture of nutritive and nonnu-
has been established, prolactin secretion from the pituitary tritive factors, numerous studies have shown that breastfed
gland decreases, but milk removal from the mammary gland infants have a lower risk for adverse health consequences,
promotes continuous milk production or galactopoesis (5, 19, including gastroenteritis, pneumonia, childhood obesity, leu-
86, 138, 221). However, as discussed below, both genetic and kemia, and sudden infant death syndrome (124). Therefore, the
modifiable factors may play important roles in the ability of the American Academy of Pediatrics recommends exclusive
breast to respond to infant demand and provide optimal nutri- breastfeeding for the first 6 mo of life. Although breastfeeding
tion for growth and development. initiation rates have increased to ⬃75% in the US, the duration
Breast milk is considered the gold standard for infant feed- of exclusive breastfeeding continues to fall below national
ing, as it provides a perfect combination of nutrient and goals; only 47% of infants are breastfed at all by 6 mo of age,
nonnutritive factors that are essential for infant growth and and of those, only 14% are exclusively breastfed as recom-
development. Breast milk contains a diverse array of proteins, mended (89). For the most part, it is assumed that once
lipids, and carbohydrates that provide energy, bioactive pro- lactation is initiated, a breastfeeding woman can produce
teins (e.g., bile salt stimulated lipase, lactoferrin, lysozyme, enough breast milk that meets the nutritional needs of her
secretory IgA, and ␣-lactalbumin), and both group I (vitamins infant, unless she is severely malnourished. Yet, as noted
A, E, B1, B2, B6, B12, and D as well as choline, selenium, and above, ⬃50% of mothers cite concerns about insufficient milk
iodine) and group II (calcium, iron, copper, zinc, and folate) volume or poor milk quality as motivation to wean their infants
AJP-Endocrinol Metab • doi:10.1152/ajpendo.00495.2015 • www.ajpendo.org

Review
ROLE OF GENETICS, DIET, AND ENVIRONMENT ON LACTATION E407
early. Addressing this issue of lactation insufficiency is ham- Surprisingly, little is currently known about the genes that
pered by a lack of reliable tools to both accurately measure govern lactation physiology in humans. Recent studies using
milk volume and diagnose mothers with molecular defects that transcriptomic analysis of isolated milk fat globules (199) and
impair lactation physiology and performance. Many studies milk fat (159) have begun to reveal changes in the patterns of
use the validated approach of maternal report of breast fullness gene expression that occur during secretory activation and
to assess the onset of secretory activation (52, 176, 255), but across the course of lactation, respectively. In addition, Daniels
this approach may be somewhat imprecise due to variability in et al. (70), Lemay et al. (160), and Rijnkels et al. (250) have
perception and the dependency upon neonate sucking and milk shown that epigenetic regulation is important in lactation
removal for robust secretory activation. The most widely physiology, using the mouse as a model. Further transcriptomic
accepted method for measuring milk production is test-weigh- and epigenetic studies will be critical to identify and under-
ing, in which the infant is weighed before and after each stand the regulation of genes that are vital to human lactation.
feeding using an electronic scale (71, 183). However, this Studies in production animals suggest that genetic variation
approach can be cumbersome, requires a sensitive scale, and may also play an important role in modifying lactation success
also depends upon neonate suckling and milk removal. An in humans. The role of genetics as a key modifier of milk
alternative is to identify factors in or missing from milk to production in the dairy industry has been recognized for many
assess lactation performance. Studies using preterm milk sug- years (93), as the execution of large genome-wide association
gest that factors such as elevated sodium, citrate, and lactofer- studies (GWAS) and linkage studies has been driven by the
rin (63, 253) may predict suboptimal lactation performance economics of the dairy industry (59, 112, 182, 246). Over the
(i.e., delayed onset of secretory activation, suboptimal milk years, genomic evaluations of dairy cattle have discovered
production). However, much research is needed to identify and more than 43,000 single nucleotide polymorphisms (SNPs),
validate factors in milk that may eventually be useful in which have profoundly improved breeding decisions and milk
assessing lactation performance in breastfeeding women. production traits (51) and have led to the development of SNP
Increasing evidence supports a role for maternal factors such genotyping chips to predict lactation efficiency (302). Several
as genetic variation, diet composition, and environmental ex- different approaches can be used to identify genes involved in
posures in modulating lactation performance, milk volume, and lactation physiology in women. One approach is to conduct
composition. Identifying these factors and understanding their GWAS and select the most abundant or significantly different
molecular and physiological role in lactation performance are genes between two different phenotypes (e.g., low-volume
important in successfully addressing the biological underpin- producers vs. high-volume producers) and then determine the
nings of breastfeeding challenges, which has a substantial functional consequences on mammary gland biology and lac-
impact on human health and disease. tation performance (60). Another approach is to use targeted
exome sequencing to select genes that are involved in specific
Lactation Endocrinology, Physiology, and Potential Genetic biological processes and pathways that are important for mam-
Modifiers mary development and/or milk production and determine
whether variation in these genes is associated with milk pro-
Prolactin-Jak2/STAT5 signaling. As noted above, prolactin duction or composition (246). A third approach is to use
is the principal lactogenic hormone that regulates mammary quantitative trait locus analysis to identify polymorphisms at a
gland differentiation, milk production, and active secretory specific chromosomal locus (e.g., chromosome 22) that is
mechanisms during lactation (116). When secreted into circu- correlated with phenotype variation (e.g., milk fatty acid com-
lation, prolactin binds to its cognate prolactin receptor (PRLR). position) (88).
Upon prolactin binding, the nonreceptor tyrosine kinase Jak2 is Using a variety of these approaches, recent advancements
activated and phosphorylates the transcription factor STAT5 to have identified numerous genetic variants associated with milk
allow dimerization and translocation into the nucleus, where it production traits in production animals. A recent study using
binds to the promoters of prolactin-responsive genes and me- GWAS data collected from 16,812 Holstein and Jersey dairy
diates mammary gland differentiation and milk synthesis. The cattle identified SNPs in key pathways that are critical for
critical importance of this pathway is illustrated in studies in mammary gland development, prolactin signaling, and involu-
which prolactin, PRLR, Jak2, or STAT5 genes are deleted in tion that explained variation in milk production and milk
mice, leading to severe defects in mammary differentiation, composition (246). For example, ⬃50% of SNPs found in
lactogenesis, and lactation outcomes (53, 66, 118, 220). More- genes critical for prolactin signaling, including SOCS2,
over, disruption of stimulatory and inhibitory molecules that STAT3, STAT5A, STAT5B, PRLR, and ␤-casein, were asso-
are directly involved in the prolactin signaling pathway [e.g., ciated with three or more milk production traits (246). Addi-
the tyrosine kinase ErbB4, negative regulators SOCS2 and tionally, a large number of SNPs in genes that are critical for
SOCS3 (109, 120), transcription factors Elf5 (120), Miz1 mammary gland involution, including ATF4, IGFBP4, IRF1,
(258), and SnoN (126), cytosolic protein-tyrosine phosphatases LIFR, OSMR, PTK2, and STAT3, were also associated with
Shp2 and PTP1B (8), and NHERF1/EBP50, which forms a milk production traits (246). It is important to note that there
multimeric complex with PRLR (200)] all compromise differ- are limited data in production animals that actually address the
entiation and lactogenesis or lead to suboptimal lactation out- effect of genetic variation on mammary gland function or
comes in experimental animal models. The complexity of this lactation physiology; these data have been used strictly for
key lactogenic pathway provides numerous opportunities for genetic association studies and breeding for production traits,
(de)activation resulting from genetic variation in the genes that and therefore, further research is required to better understand
encode these molecules in humans. the physiological implications.

Review
We propose that similar variation may govern lactation missing link between factors involved in milk synthesis and
physiology, milk production, and composition in breastfeeding MEC proliferation, such as glycogen synthase kinase 3
women; however, to date, few studies have explored this (GSK-3) and leucyl-tRNA synthetase (LeuRS) (294, 313). In
possibility. As proof of concept, several mutations in prolactin contrast, AMP-activated protein kinase (AMPK) activation by
and PRLR have been identified in humans (155, 215). In energy depletion in bovine MECs inhibits mTOR signaling and
addition, several studies have found that SNPs in PRLR are decreases milk protein synthesis rate (39). Numerous muta-
associated with elevated serum prolactin levels (rs62355518, tions in genes encoding mTOR components have been identi-
rs10941235, rs1610218, rs34024951, and rs9292575) and in- fied, and the reader is referred to an excellent review by Saxena
creased risk for breast cancer (rs249537, rs7718468 and and Sampson (260) on this topic. Another potential target is the
rs13436213) and gestational diabetes (rs10068521 and peroxisome proliferator-activated receptor-␥ (PPAR␥) path-
rs9292578). Collectively, this suggests that SNPs in PRLR may way, which is critical for the maintenance of the secreting
affect breast function; however, to our knowledge, the effects of mammary epithelium (9) and milk quality by suppressing the
SNPs in PRLR on lactation outcomes have not been explored. production of inflammatory lipids (292). Moreover, PPAR␥
Recently, we identified a woman with a “gain-of-function” variant regulates triglycerol synthesis and secretion in cultured breast
in PRLR (I170L, also known as I146L) who had elevated milk cells (284) and in dairy goats (265). Although SNPs in PPAR␥
zinc concentration (2.82 mg/l; normal ⫽ ⬃1 mg/l) (4). have been identified, are associated with enhanced breast
Subsequent analysis of her milk composition determined density, and are modified by diet (157), no clear relationship
that the ratio of sodium to potassium was also elevated with lactation outcomes (226) has yet been identified. Going
(⬃0.9; Kelleher SL, unpublished data), also suggesting forward, it will be important to differentiate between problems
subclinical breast dysfunction (263). Moreover, a “loss-of- resulting from inadequate mammary gland development during
function” variant in PRLR (H188R) results in secondary puberty or inadequate secretory development in pregnancy
hyperprolactinemia and is associated with persistent galac- from those that impact secretory activation or secretion of milk
torrhea (212). Genetic variation in downstream molecules components.
that elicit prolactin signaling may also be important candi- Other hormones and endocrine factors/inhibitors. In addi-
dates. Gain-of-function mutations in Jak2 (V617F) and tion to prolactin, a complex combination of hormones works
STAT5B have been identified in humans (18, 239). Constitu- together to maintain the differentiated epithelium and milk
tive activation of Jak2 through expression of V617F in mice secretion during lactation, including insulin, glucocorticoids,
elevates STAT5 signaling and promotes alveologenesis, al- growth hormone, oxytocin, and thyroid hormone. Secretory
though lactation outcomes in women expressing V617F have activation and milk ejection require insulin and glucocorticoids
not been investigated. Clearly, a profound lack of understand- to synergistically regulate the formation of tight junctions in
ing exists regarding the consequences of genetic variation in the mammary gland (223, 312), stimulate mammary differen-
the prolactin-Jak2/STAT5 signaling pathway on lactation out- tiation (48), and induce milk protein expression (73). Insulin
comes. Collectively, these observations suggest that alterations levels rapidly decrease during early lactation and steadily
in prolactin signaling pathways may affect breast function and increase over time (301). Recent work shows that insulin in the
lactation outcomes and warrant further investigation. The fact presence of prolactin and hydrocortisone plays a pivotal role in
that recombinant prolactin has successfully been used to in- regulating milk protein synthesis in mammary explants from
crease milk volume and lactose, calcium, and oligosaccharide animals by increasing the expression of transcription factors
concentrations in some women, but with limited success in Elf5 and STAT5 (193, 194). Studies in dairy cows show
others (235), suggests that pharmacogenomics targeted at this conflicting effects of exogenous insulin on milk fat levels,
pathway may be an approach to improve lactation outcomes in where long-lasting insulin treatment tends to increase milk fat
some women in the future. content and milk yield (305), whereas hyperglycemic insulin
Other cell signaling pathways. Apart from prolactin signal- clamp reduces milk fat and milk yield (61, 173). Similarly,
ing, the mammary gland possesses a network of signaling women with gestational diabetes who are on insulin therapy
pathways that detect metabolic status, regulate gene transcrip- have a delay in the onset of secretory activation (179), which
tion and milk protein synthesis, and maintain many cellular suggests that insulin treatment may have adverse effects on
processes during lactation. One such pathway is the mamma- milk production or composition in humans.
lian target of rapamycin (mTOR) pathway, which has a well- In contrast, growth hormone deficiency compromises lacta-
established role in regulating protein synthesis by phosphory- tion outcomes in rats, as it reduces milk yield by ⬃24% (83).
lating eukarytoric translation factor 4E binding protein 1 (4E- Moreover, artificial growth hormone or recombinant bovine
BP1), thereby releasing eukaryotic translation initiation factor somatotropin administration to ewes (56, 256) and dairy cows
4E (eiF4E) to regulate translation (296). The mTOR pathway is (91, 188, 230) increases milk protein yield and milk volume,
a well-known therapeutic target for breast cancer (154), and and growth hormone has been used as a pharmacological agent
emerging studies also illustrate the importance of mTOR in to augment milk production in women (100, 198). It is spec-
modulating lactation outcomes. Inhibition of mTOR signaling ulated that this occurs through the activation of cell prolifera-
using RAD001 during lactation markedly impairs lactation tion (174) and through increased STAT5 expression (33).
(87). Moreover, a role for mTOR signaling in milk protein Genetic variation in growth hormone receptors has recently
synthesis has been demonstrated recently (10, 11, 38, 39, 294, been associated with milk production traits in dairy cattle (51,
313), as synthesis of proteins like ␤-lactoglobulin in bovine 240), sheep (175), and water buffalo (264). Although numer-
mammary glands (201) or ␣-s1 casein in bovine mammary ous SNPs in growth hormone, its cognate receptor, placental
cells (309) is upregulated through the phosphorylation of lactogen, and placental growth hormone have been identified in
4E-BP1. The mTOR pathway has also been shown to be the humans, to our knowledge, genetic variation in this pathway

Review
has yet to be explored as a modulator of lactation outcomes in tion, the contribution of several candidate genes on lactation
women (3). outcomes has been explored directly. For example, diacylglyc-
Several studies have shown that SNPs in the oxytocin gene erol O-acyltransferase 1 (DGAT1), which catalyzes the forma-
are associated with shorter breastfeeding duration, which may tion of triglycerides, is the most prominent gene affecting milk
be due to impaired myoepithelial contraction and milk ejection fat composition in cows (172, 261), and a K232A substitution
(131, 233). Finally, thyroid hormones are also galactopoietic very likely represents the causal mutation (282). DGAT1 is an
and help to establish the metabolic priority of the mammary example of a quantitative trait locus candidate gene in the
gland during lactation (43). Hypothyroidism has deleterious centromeric region of chromosome 14 that was demonstrated
effects on milk composition (108) and milk synthesis and to have a major effect on the fat content of cow milk associated
ejection in rats (107). However, there is little information on specifically with higher saturated fat (i.e., C14:0) compared
the effects of hypo- or hyperthyroidism on lactation outcomes with unsaturated fat (i.e., C18:1) (261, 282). Studies of
in women. DGAT1-deficient mice demonstrate that these defects in lipid
In contrast to the factors that promote lactation, feedback metabolism impair mammary development (47). Moreover,
inhibitor of lactation (FIL) is a polypeptide that controls several variants of fibroblast growth factor 2 (FGF2) in Hol-
lactation by reversibly blocking milk synthesis and secretion stein cattle are associated with fat yield and milk quality, as
when the breast is full (229, 249, 303). Specifically, FIL is
measured by somatic cell scores (295). FGF2 is important for
endogenously synthesized in lactocytes and secreted into the
mammary gland development and also regulates the expression
milk as whey protein, which allows for local regulation of milk
of interferon-tau, a key factor in STAT activation for milk
secretion through an autocrine feedback inhibition (229, 303),
and is critical for matching milk supply to infant demand (304). production (295), which suggests that variation in FGF2 could
However, there is very little understanding of the precise be another potential candidate as a modifier of milk production
mechanisms through which FIL may exert its actions. Finally, in women.
serotonin has been proposed to be an additional feedback Genetic variation in a few nutrient-specific genes has
inhibitor of lactation that reduces milk synthesis and milk yield been associated with alterations in milk composition in
(117). However, recent studies demonstrate that serotonin is humans. Polymorphisms in the vitamin D receptor are
also critical for numerous cellular pathways and biological common and are associated with altered breast function and
processes regulating lactation (151). Further studies are needed breast cancer in women (102, 241). Moreover, Bezerra et al.
to understand how factors secreted into milk assist in regulat- (21) found that SNPs in vitamin D receptor are associated
ing milk volume and the onset of mammary gland remodeling with milk calcium concentration. Recently, there has been
during involution. much interest in better understanding the mechanisms
through which zinc is secreted into milk, as there are
Milk Composition and Potential Genetic Modifiers numerous reports in the literature of exclusively breastfed
infants being diagnosed with severe zinc deficiency. We
The discovery of variants in specific milk proteins dates were the first to identify a mutation in the gene SLC30A2
back to 1955 by Aschaffenburg and Drewry (12), in which two that encodes the zinc transporter ZnT2 (58). This mutation
variants of ␤-lactoglobulin were detected in bovine milk. In leads to an amino acid substitution in the NH2 terminus of
this section, we will review our current understanding the role the protein and the secretion of ⬃75% less zinc into breast
of genetic variation of milk components on milk composition. milk than normal, and since then, several other mutations in
Many studies have identified genetic variation in the major SLC30A2 that lead to substitutions in ZnT2 (G87R, W152R,
milk proteins, including ␣-lactalbumin (27, 57, 178), ␣-caseins S296L, R340C) have subsequently been associated with this
[␣-S1 and ␣-S2, (45, 46)], ␤-casein (134, 189), and ␬-casein disorder (125, 152, 196). More recent studies indicate that
(140, 238). Variation in specific milk proteins appears to affect defects in ZnT2 may have much broader implications for
mammary gland function, as they are associated with differ-
mammary gland biology, as ZnT2-null mice have severe
ences in milk production and milk composition. A study in
defects in lactation outcomes, including profound impair-
Holstein dairy cows found that ␣-S1 and ␤-casein variants
ments in mammary gland differentiation, milk production,
were associated with higher milk volume, milk fat, and protein
yield (213). Consequently, such cows with variants in caseins, composition, and secretion (158). Moreover, studies in mice
as well as ␣-lactalbumin and ␤-lactoglobulin, are economically and cultured lactocytes indicate that ZnT2 imports zinc into
favored for selective breeding (29, 30, 119). ␣-Lactalbumin- lysosomes and plays a critical role in activating cell death
deficient mice produce abnormally viscous milk and fail to and mammary gland involution (114). This may be of
expel milk to suckling pups (274); however, it is important to importance to subpopulations of women because ⬃35% of
note that the concentration of ␣-lactalbumin is quite high in otherwise healthy breastfeeding women had nonsynony-
human milk and is likely not a limiting factor. Although one mous genetic variation in ZnT2 (4), which was associated
might speculate that since in humans genetic variation in with both low and high milk zinc concentrations. In addi-
␣-lactalbumin is quite common (57), perhaps variation in tion, two particular variants (D103E and T288S) were found
␣-lactalbumin may alter lactose production and thus affect with high frequency (⬃12%) and were associated with high
milk quality and milk ejection in women. Because these major milk sodium levels, a known a hallmark of breast dysfunc-
milk proteins also have biological functions beyond providing tion (4). Exciting opportunities exist to better understand the
energy (195), genetic variation may have an effect on the role that nutrigenetics plays in modulating lactation physi-
growth and development of offspring; however, to our knowl- ology and breast milk composition so that personalized
edge there is currently no information in this regard. In addi- strategies to optimize lactation outcomes can be developed.

Review
Role of Energy Balance ty-induced inflammation in the mammary gland. Inflammation

in the mammary gland is marked by elevated levels of proin-
The nutritional requirements during lactation increase con- flammatory factors like TNF␣, IL-1B, and Cox2 (277), in-
siderably to maintain maximal mammary gland secretory ca- creased macrophage infiltration (163), perturbed zinc metabo-
pacity and milk production and also to maintain maternal lism (115), and increased NF-kB signaling (42). Moreover,
energy balance for optimal milk production (234). Energy there is some suggestion that obesity increases local estrogen
requirements increase during lactation (40), and the energy production (36), which in turn may function to downregulate
cost of lactation is determined by the amount of milk produc- prolactin signaling, and suppress lactation (reviewed in Ref.
tion and secretion, milk energy content, and the efficiency of 218). In addition, lipid synthesis is impaired, which can result
converting dietary energy to milk energy (41), which usually from 1) interference with dietary lipid transport into and out of
increases over time in women who breastfeed exclusively the mammary gland and 2) suppression of de novo lipogenesis
(234). As a result, early investigations have focused on the role in the mammary gland, resulting in lipid accumulation and low
of diet in maintaining energy balance and milk production and milk triglycerides (254, 291). Fundamentally, the altered mam-
composition during lactation (reviewed in Ref. 92). Because of mary gland microenvironment that occurs in obesity can lead
the epidemic of obesity in Western countries, more recently the to failed secretory activation or suboptimal lactation, whereby
consequences of dietary excess on mammary gland function the mammary gland is incapable of secreting copious milk to
have garnered much interest. In this section, we will focus on nourish the newborn. Therefore, understanding the lactogenic
recent advances in understanding the consequences of obesity mechanisms that are compromised by obesity will assist clini-
and physical activity on mammary gland function and lactation cians in designing strategies to better support these mothers.
outcomes. Physical activity and fasting. A major concern of women
Maternal metabolism and obesity. The World Health Orga- postpartum is the desire to lose excess weight gained during
nization has declared that obesity is one of the most significant pregnancy. The American College of Obstetricians and Gyne-
human health problems, with the expectation that 80% of cologists recommends that women resume physical activity
women will be overweight (BMI of 25–29) or obese (BMI ⬎30) after delivery as soon as it is physically and medically safe.
by 2020 (297). This could have a profound consequence on the However, intensity and duration appear to have important
number of women who breastfeed successfully, and thus the implications on the effects of exercise on lactation. Moderate
health of infants and the US population at large, because levels of exercise do not affect milk production, milk compo-
mothers who are overweight or obese are less likely to initiate sition, or infant growth (68, 166, 167, 276); rather, exercise
lactation, have delayed secretory activation, and are prone to improves the mother’s overall health and sense of well-being
early breastfeeding cessation (15, 130, 161, 244, 245). Biolog- (72, 168, 236). Moreover, short-term weight loss has no effect
ical complications include prolactin resistance and reduced on lactation performance, milk volume, or milk protein con-
STAT5 activation (37), which is linked to delayed initiation centration (187). However, several other reports examining the
and premature cessation of lactation (245), and decreased effects of more intense exercise and starvation (i.e., religious
insulin sensitivity (50), which may result in insufficient glan- fasting) have observed significant changes in specific milk
dular development and reduced milk volume (202, 279). Re- proteins and other essential factors in milk, such as immuno-
cently, many researchers have used dietary-induced obese globulins (94), lactose (315), and micronutrients (zinc, mag-
animal models to further investigate the effects of obesity on nesium, and potassium) (242). This is consistent with studies in
the lactating mammary gland and milk composition that in turn rats, where Matsuno et al. (181) found that chronic low-
affect lactation outcomes. As described by multiple studies, the intensity exercise during lactation decreases milk lactose, in-
consequences of obesity in rodents include increased adipocyte creases milk protein and milk fat, and compromises offspring
size (115, 133) and disturbances in the mammary gland mi- growth. However, it is important to note that lactation is much
croenvironment and impaired development during pubertal more energy demanding in rodents than humans. For example,
stages (133). In addition, the growth hormone/IGF-I axis, rats lactate at their maximum physiological capacity and re-
somatostatin/cortistatin, and ghrelin systems are increased in quire ⱖ100 –300% of their energy to produce milk (237), and
the mammary fat pads of diet-induced obese mice (288), which therefore, changes in maternal diet and metabolism are more
may be involved in the pathophysiology of the mammary gland robustly reflected in their milk composition. However, this
(77, 148). Although growth hormone is known to improve milk concept does not apply to breastfeeding women, who need only
volume (197, 316), obese mice also have increased plasma ⬃20% of their total energy (237). For women, intense exercise
leptin (288), which inhibits the effect of oxytocin on myoepi- or “exhaustive exercise” may have short-term effects on milk
thelial contraction for milk ejection (20). Moreover, during composition, such as increased lactic acid and decreased se-
pregnancy and lactation, obese rodents have significant defects cretory IgA concentration; however, this appears to return to
in alveolar development (84, 115), abnormal collagen deposi- normal levels within 1 h (44, 94). It is important to note that
tion, and incomplete myoepithelial lining around ductal struc- increased milk lactic acid secretion after moderate- or high-
tures (133). During lactation, the mammary glands of obese intensity exercise is common and does not impede infant
mice accumulate lipid in the MECs, consistent with secretory acceptance of breast milk (307). Likewise, short-term starva-
inactivation (84, 156). Growing evidence suggests that in tion decreases amino acid supply to the mammary gland and
addition to systemic inflammation, obesity is also associated lowers free amino acid concentration in the milk of fasted rats
with an inflammatory microenvironment in the mammary (289) and also decreases expression and activity of essential
gland (22, 36, 277), which has recently been associated with enzymes such as fatty acid synthase, glucose-6-dehydrogenase,
premature involution in murine models (115). A few studies and lipoprotein lipase, all of which are critical for fatty acid
provide insight into the possible mechanism underlying obesi- production (95, 129). However, these effects are easily re-

Review
versed with refeeding or resumption of normal activity. An riboflavin (B2), and niacin (B3) are critical for energy metab-
additional concern is that with severe calorie restriction, fad olism, and folate and B12 are essential for DNA synthesis.
diets and rapid weight loss, fat-soluble environmental contam- Although intake of B vitamins (particularly B1, folate, and B12)
inants, and toxins, including polychlorinated biphenyls (PCBs) varies widely, few studies exploring the effects of B vitamin
and pesticides that are stored in body fat, can be secreted into deficiency on mammary gland biology have been described.
milk (149). Moreover, it is hard to make generalized recom- Dangat et al. (69) found that B12 deficiency may reduce milk
mendations regarding diet and exercise during lactation due to volume; however, no studies toward understanding the molec-
differences in individual genetics and the changes in gene ular underpinnings have since been described. Given the im-
expression influenced by modulation of energy balance (224). portance of B vitamins in energy metabolism, DNA synthesis,
Nowadays, much interest in understanding the effects of phys- and cell proliferation, understanding the effects of suboptimal
ical activity on breastfeeding has shifted toward studies on the B vitamin nutrition on lactation outcomes warrants further
effects of physical activity on breast cancer progression (205). consideration.
Multiple studies have explored the effects of exercise on the Minerals. Minerals play diverse roles in biology ranging
normal mammary gland in an attempt to identify tumor- from cofactors for protein stability or activity to the transfer of
associated/inhibiting markers. Hopefully, these studies will electrons in numerous biological pathways. The mammary
indirectly provide information regarding the effects of exercise gland has a remarkable capacity to homeostatically regulate
on breast development (298) and function (205) that impact milk concentrations of minerals such as iron and zinc in times
lactation outcomes. of maternal deficiency in these minerals (165). Iron deficiency
is one of the most common nutrient deficiencies in the world.
Role of Diet Iron bound to transferrin in serum is taken into the mammary
gland by transferrin receptors (267) and may be imported into
Nutrient intake: deficiency and supplementation. In recent the endoplasmic reticulum by ferroportin for incorporation of
years, increasing evidence shows not only that adequate nutri- iron into proteins such as lactoferrin in humans and mice or
ent intake and appropriate nutrient homeostasis are important transferrin in rats (165). However, there remains an incomplete
for maintaining maternal energy balance but that suboptimal understanding of the molecular regulation of iron transport in
nutrition has significant effects on breast physiology and milk the mammary gland for secretion into milk. However, due to
production, secretion, and composition. Nutrient deficiencies the role of iron in energy generation (306), it is reasonable to
can result in failed secretory activation from several perspec- assume that iron deficiency may have an impact on mammary
tives, such as inefficient hormone responsiveness, and defects gland biology and lactation outcomes. Although Grill et al.
in cellular processes involved in morphogenesis and secretory (96) found that iron deficiency has minimal effects on pubertal
pathways. Moreover, energy/nutrient imbalance may cause mammary expansion, to our knowledge, no studies have ex-
more perverse effects on immune response and increased risk plored effects of iron deficiency on mammary gland function
of mastitis (127, 203, 204, 216). This next section highlights during lactation. In contrast, the potential impact of zinc
our limited understanding of the role of diet and specific deficiency on lactation outcomes has been better documented.
nutrients and dietary factors on lactation physiology. Because Zinc is a catalytic, structural, or regulatory cofactor for ⬎10%
the ethics of manipulating maternal diet in humans preclude of the proteome (184). Marginal zinc deficiency is common in
randomized clinical studies, much of our current understanding women of reproductive age (262). Studies in mice show that
comes from studies conducted in animal models. marginal zinc deficiency leads to a toxic mammary gland
Vitamins. Vitamin A deficiency remains a major worldwide microenvironment that impairs mammary development and
health problem that leads to blindness, growth retardation, and subsequently affects lactation outcomes, including mammary
death, particularly in developing countries. Its prevalence is gland expansion, milk composition, and milk volume (32).
estimated at ⬃29%, with Sub-Saharan African and Southeast Most studies have not found a relationship between maternal
Asian countries most affected (273), and affects largely pre- zinc status and milk zinc levels (55, 145). However, a recent
school children, pregnant and lactating mothers, and the rural report in Thai mother-infant pairs found that exclusively
poor (101). Whereas vitamin A intake is positively correlated breast-fed infants had the highest prevalence of zinc deficiency
to milk vitamin A concentration (97), vitamin A deficiency did and that maternal zinc status was indeed positively correlated
not appear to have major effects on mammary gland biology in to milk zinc concentration (75). Our current understanding in
a rat model (257). However, vitamin A deficiency in rodent lactocytes is that a complex network of zinc transporters may
models decreases expression of mammary gland iron transport- regulate zinc uptake and export into milk (184). It is not yet
ers and milk iron levels (136), alters zinc transporter expres- understood how the lactocyte takes up zinc from the systemic
sion (137), and leads to pathological damage to the mammary circulation or how this process is regulated; however, we
gland after intramammary challenge with staphylococcus (54). previously proposed roles for ZIP5, ZIP8, and ZIP10 in this
Similarly, vitamin D deficiency is presumed to be very com- process. Much more is known about how zinc is secreted into
mon in pregnant women (177). Studies in rodent models found milk. The important role of ZnT2 in zinc secretion was dis-
that vitamin D deficiency significantly reduces milk protein, cussed above. In addition to ZnT2, several studies have shown
calcium, and lactose levels and impairs milk protein synthesis, that ZnT4 may also play a role in zinc secretion into milk;
suggesting a role in hormone-induced functional differentiation however, there is far less understanding of its relevance. We
of the mammary gland (23). However, studies on the effects of have shown previously that ZnT4 transports zinc into the
vitamin D deficiency on mammary gland function have not trans-Golgi apparatus and across the apical cell surface (185).
been conducted since the 1980s and necessitate more robust Presumably, insufficient zinc in the trans-Golgi apparatus
molecular investigation. Finally, B vitamins like thiamin (B1), impairing galactosyltransferase activity and the production of

Review
lactose may underlie the phenotype of reduced milk secretion development and susceptibility to allergies during infancy
and milk zinc levels in ZnT4-null mice (186). However, a (169, 283, 286). Maternal fatty acid intake not only affects the
much more impressive phenotype in ZnT4-null mice is the fatty acid profile of human milk but has also been shown to be
dramatic loss in alveolar structure and activation of precocious an important dietary determinant of mammary gland function.
involution and early lactation failure (186); thus more research For example, MECs of rats fed a LCPUFA-deficient diet are
is required to understand the role of ZnT4 in lactation physi- unresponsive to prolactin stimulation and have impaired secre-
ology and how the lactocyte regulates zinc transport to meet its tion resulting from low phospholipid levels in the mammary
unique physiological needs. Given the role of genetic variation gland and accumulation of secretory vesicles in the cytoplasm
in ZnT2 (and perhaps other zinc transporters) in modifying (219). This suggests that low intake of LCPUFAs may have
milk zinc levels, further studies are needed to determine the profound effects on milk volume and composition. Moreover,
contribution of maternal genetics to regulating zinc homeosta- medium-chain fatty acids (C:8 –C14:0) are found in breast
sis during times of zinc deficiency or excess. Finally, the other milk, and the concentration increases over the duration of
mineral that is of global concern is iodine. In the mammary lactation (13, 82, 104). Medium-chain fatty acids are synthe-
gland, iodide transport is mediated by the sodium/iodide sym- sized in the mammary gland through de novo fatty acid
porter (NIS) (251, 281), and the concentration of milk iodine synthesis, which is catalyzed by the enzyme fatty acid synthase
varies widely, ranging from 5.4 to 2,170 ␮g/l, reflecting the (FASN) (278, 314). In addition to reduced milk fatty acids,
lack of homeostasis (74). This not only affects infant iodine FASN-deficient mice showed defects in mammary develop-
nutrition but can also have profound effects on breast physi- ment and underwent precocious involution (278). Recent stud-
ology, resulting in mammary dysplasia and atypia due to ies reveal genomic variability and functional expression of the
atrophy and necrosis in the alveolar cells (78, 275), most likely FASN gene in buffalo and found the highest expression of
through alterations in the production, secretion, and activity of FASN1 in mammary gland during lactation when fat turnover
thyroid hormones. As noted above, further studies are needed is the greatest (214), which implicates its importance in the
to better understand effects of hypo- and hyperthyroidism on active stage of milk production (190). Genetic variations in
lactation outcomes and milk composition. In contrast to iodine, other genes that govern fatty acid metabolism have been shown
maternal intake of calcium does not directly affect calcium to have a profound impact on milk composition and infant
levels in breast milk (123) because a large amount of calcium health outcomes. A T347S variant of apolipoprotein A4, which
is drawn from the bone (144) to transfer ⬃300 – 400 mg is involved in dietary fat absorption, is present in about one-
calcium/day into milk (142). Therefore, dietary calcium intake third of the US population, and women with this variant have
prior to pregnancy may be most critical for providing calcium a greater level of DHA in their breast milk (98, 222). More-
for milk secretion during lactation and has been reviewed over, 20% of the population carries one or two copies of the E4
recently by Kovacs (143). This large amount of calcium is variant of the apoliprotein E gene, which regulates circulating
secreted by forming a complex with citrate, casein, or phos- fat metabolism, and women with the E4 variant have signifi-
phates that are packaged into secretory vesicles for exocytosis cantly less milk fat than women without this variant (132, 268).
(208) or by direct transport across the apical membrane The most well-studied genetic variants are SNPs in fatty acid
through calcium ATPase type 2 (248). For an excellent review desaturase 1 and 2 (FADS1 and FADS2), which encode the
on calcium transport in the breast during lactation, the reader is enzymes ⌬5 and ⌬6 desaturases, respectively, and are rate-
referred to Cross et al. (65). limiting enzymes in the synthesis of polyunsaturated ␻-3 and
Protein and amino acids. In addition to vitamins and min- ␻-6 fatty acids (arachidonic acid, eicosapentaenoic acid, and
erals, protein deficiencies have been reported to reduce milk DHA). Several SNPs in FADS1 and FADS2 in Canadian
production (14). Rats fed an arginine-deficient diet had im- Holstein cows (121) and breastfeeding women (308) are asso-
paired mammary gland growth (228). Moreover, excess protein ciated with alterations in milk fatty acid composition. Impor-
intake in lactating mice decreases mammary gland mass, re- tantly, these alterations have critical implications for infant
duces expression of major milk constituents, and lowers milk health and development, as an interaction between exclusive
lactose concentration (146). Milk lactose and milk fat are breastfeeding and asthma modified by FADS genotypes in
essential components in milk that reflect the capacity for children has been noted (271). Furthermore, breastfeeding,
secretory activation, milk synthesis, and milk quality; there- FADS genotype, and fish intake are important determinants of
fore, when dietary glucose (a precursor for lactose synthesis) or DHA status in late infancy (110). This may be particularly
fatty acids are restricted, substantial impacts on milk compo- important given the role of EPA and DHA in neurological
sition (protein, fat, and glucose) and mammary gland growth development during infancy, which has been elegantly re-
occur in lactating rat dams (150). However, it is not clear viewed by Innis (122).
whether dietary glucose restriction will affect lactation in
women, because studies in developing countries of women Role of Environmental Factors on Mammary Gland
with poor diets have shown no effect on milk output (62). Physiology
Fatty acids. Milk fat is a major source of energy and
fat-soluble vitamins as well as essential fatty acids (31, 82) In addition to genetics and diet, environmental factors may
Fatty acid composition in milk is species specific and is contribute to suboptimal lactation (26, 35, 79, 211). Many of
extremely sensitive to maternal nutrition and dietary alterations these environmental chemicals have become a part of our daily
(82, 227). In particular, long-chain polyunsaturated fatty acids diet and exposures, especially since they are often found at
(LCPUFAs) such as docosahexaenoic acid (DHA), ecosopen- high concentrations in fat-containing food such as red meat and
tanoic acid (EPA), and arachidonic acid in breast milk are dairy products (191). Constant exposure to various chemicals
obtained from maternal diet and are implicated in neurological in the environment can put a toxic burden upon the body, and

Review
many such chemicals are stored in the mother’s adipose tissue child health, the reader is referred to several recent reviews
and then found in breast milk, which is then transferred to the (171, 285). However, in this section we will review the evi-
nursing infant (191). This suggests that analysis of milk fat dence that exposure to environmental toxins may also have
from breastfeeding women might be useful in assessing envi- important effects on mammary gland physiology. In particular,
ronmental contaminants in populations. For a more in-depth several studies have shown that exposure to chemicals or
review of the transfer of toxins into breast milk and effects on endocrine-disrupting compounds (EDCs) during gestation can
A Successful Lactation B Lactation Insufficiency
Milk Milk
Functional Impaired mammary gland

mammary gland differentiation and milk secretion
Genetics Diet Environment

Prolactin Receptor signaling: Micronutrients: Environmental toxins:
PRLr, Jak2, SOCS2, STAT3, Vitamins A, D, B1, B2, B3 Atrazine, dioxin , BPA,
STAT5A, STAT5B, ATF4, IGFBP4, Iron, Zinc, Iodine, Calcium Dibutylphthalate, Nonylphenol,
IRF1, LIFR, OSMR, PTK2 PBDE, PFOA, PCDD,
Macronutrients: PCDF, PCB, DDE
Other signaling pathways: Protein, Lactose, Glucose
mTOR, Gsk3, LeuRS, PPAR Fatty Acids (LCPUFA, DHA, EPA, Heavy Metals:
GH, OXTR, FGF2 AA, MCFA) Copper, Zinc, Selenium,
Lead, Cadmium, Mercury
Milk protein: Energy Balance:
-lactalbumin, -casein, Obesity
-casein, -casein, Fasting/Starvation
Physical Activity
Nutrient Transport:
VDR, ZnT2, DGAT1
Apo4, ApoE, FADS1, FADS2
Fig. 1. Maternal factors that can lead to lactation insufficiency. Lactation insufficiency is a condition in which lactation is insufficient or unsuccessful due to
inadequate milk production. A and B: images of hematoxylin and eosin-stained mouse mammary gland tissues represent a functional mammary gland undergoing
successful lactation (A) and a mammary gland with impaired mammary differentiation and milk secretion that results in lactation insufficiency (B). C: list
summarizing genetic, dietary, and environmental factors that have been shown to affect lactation outcomes. PRLR, prolactin receptor; Jak2, Janus kinase 2;
SOCS2, suppressor of cytokine signaling 2; STAT, signal transducer and activator of transcription; ATF4, activating transcription factor 4; IGFBP-4, insulin-like
growth factor-binding protein 4; IRF1, interferon regulatory factor 1; LIFR, leukemia inhibitory factor receptor; OSMR, oncostatin M receptor; PTK2, protein
tyrosine kinase 2; mTOR, mammalian target of rapamycin; Gsk3, glycogen synthase kinase 3; LeuRS, leucyl-tRNA synthetase; PPAR␥, peroxisome
proliferator-activated receptor-␥; GH, growth hormone; OXTR, oxytocin receptor; FGF2, fibroblast growth factor 2; VDR, vitamin D receptor; ZnT2, zinc
transporter 2; DGAT1, diacylglycerol O-acyltransferase 1; apo4, apolipoprotein 4; apoE, apolipoprotein E; FADS, fatty acid desaturase; LCPUFA, long-chain
polyunsaturated fatty acids; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; MCFA, medium-chain fatty acid; AA, arachidonic Acid; BPA, bisphenol
A; PBDE, polybrominated diphenyl ethers (PBDE); PFOA, perfluorooctanoic acid; PCDD, polychlorinated dibenzo-p-dioxins; PCDF, polychlorinated
dibenzofurans; PCB, polychlorinated biphenyls; DDE, dichlorodiphenyl dichloroethene.

Review
cause adverse effects on mammary gland development and to investigate potential ways to reduce transfer into milk or to
lactation (80). Numerous chemicals such as atrazine and dioxin buffer these harmful factors in infants (191).
(in herbicides), bisphenol A (BPA), and dibutylphthalate (in
plastics), nonylphenol (in laundry and dish detergent), poly- Conclusion
brominated diphenyl ethers (a flame retardant), and perfluo- Breast milk clearly provides optimal nutrition for the grow-
rooctanoic acid (PFOA; in cleaning products and pesticides) ing infant as long as the mother is capable of producing and
have been observed to disrupt mammary gland function. Di- secreting an adequate volume of high-quality milk. Epidemi-
oxins or dioxin-like compounds are comprised of members of ological studies suggest that many breastfeeding women may
three structurally related families of chemicals: polychlorinated suffer from suboptimal lactation, and increasing evidence im-
dibenzo-p-dioxins, polychlorinated dibenzofurans, and poly- plicates maternal genetics, diet, and environmental toxins as
chlorinated biphenyls (PCBs). Dioxins activate the aryl hydro- modifiers of reproductive endocrinology, mammary gland
carbon receptor, which increases expression of numerous physiology, lactation, and milk composition (Fig. 1). Although
genes, including ABCG2, which is the main xenobiotic trans- infant formula meets the nutritional needs of infants, there
porter in the mammary gland (106). PFOA is a known agonist remain clear differences in short- and long-term health out-
of PPAR␣, which profoundly impairs normal differentiation of comes between breast-fed and formula-fed infants. Clearly,
lobular-alveolar units during lactation (310). Studies in rodents understanding factors that impact lactation and developing
show that gestational exposure to dioxins (290), PFOA (299, methods to accurately assess lactation outcomes before a
300), atrazine (247), and BPA (180) leads to changes in breast-fed infant becomes ill will directly inform the develop-
mammary gland development that include mammary hypopla- ment of therapeutic strategies to improve poor lactation per-
sia, reduced apoptosis in terminal end buds, altered gene or formance. Importantly, these advancements will have a major
protein expression, and accelerated alveolar differentiation. In impact on increasing the number of exclusively breastfed
addition, mice exposed to dioxins during gestation have acti- infants and decreasing the burden of noncommunicable dis-
vated aryl hydrocarbon receptor, severe defects in mammary ease. Moreover, understanding these factors and improving
gland differentiation during lactation, and reduced milk protein lactation success will be important to develop novel nutrig-
expression that leads to offspring death within 24 h postpartum enomic or pharmacogenomic approaches for reducing breast
(290). PFOA exposure in mice during early gestation or lac- disease and cancer.
tation permanently impairs mammary gland differentiation,
GRANTS
reduces milk protein expression, and decreases pup survival
over the lactation period (300). Finally, exposure to BPA This work was supported in part by NIHD058614 to S. L. Kelleher,
intramural support from the Penn State Hershey Department of Surgery to S. L.
during pregnancy in mice leads to lactation insufficiency and Kelleher, and the Huck Dissertation Research Award from the Huck Institute
offspring death (180). Thus far, only a few studies in women of Life Sciences at Penn State University to S. Lee.
have shown an association between toxins like PCBs and
dichlorodiphenyl dichloroethene and lactation defects such that DISCLOSURES
exposure to these toxins is associated with shorter breastfeed- No conflicts of interest, financial or otherwise, are declared by the authors.
ing duration (67, 252). Given the burden of these often hidden
AUTHOR CONTRIBUTIONS
environmental toxins in daily life, understanding the conse-
quences of these environmental toxins on mammary gland S.L. and S.L.K. prepared figures; S.L. and S.L.K. drafted manuscript; S.L.
physiology in humans is an important area for future research. and S.L.K. edited and revised manuscript; S.L. and S.L.K. approved final
version of manuscript.
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Am J Physiol Endocrinol Metab 311: E405–E422, 2016.

First published June 28, 2016; doi:10.1152/ajpendo.00495.2015. Review

Biological underpinnings of breastfeeding challenges: the role of genetics,

Lee S, Kelleher SL. Biological underpinnings of breastfeeding challenges: the

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Role of Energy Balance ty-induced inflammation in the mammary gland. Inflammation

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A Successful Lactation B Lactation Insufficiency

Functional Impaired mammary gland

Genetics Diet Environment

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