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The mammary gland has an incredible level of organization and a remarkable ability to convert circulating nutrients into milk components. This review highlights four areas of high interest in the biology of milk synthesis where advances over the last quarter-century have resulted in new understanding or revealed new opportunities. First, advances in our understanding of the mechanisms of milk secretion has led to a substantial increase in our knowledge of the intracellular origin of lipid droplets and the identity and potential function of milk fat globule membrane proteins in milk-lipid secretion. Second, recent breakthroughs have advanced our understanding of the nutritional regulation of milk fat and highlighted the interrelations between dietary components, digestive processes in the rumen, and the regulation of mammary synthesis of milk fat. Third, nutritional quality is becoming increasingly important in food choices because of consumer awareness of the links between diet and health. The traditional nutritional value of milk and dairy products is well established, but recent discoveries have identified a number of “bioactive” components in milk with potential to improve human health. Finally, the concept of genetic engineering and the use of animals as “bioreactors” and the “pharming” of proteins not normally found in milk have gained recognition, with the dairy industry ideally suited to take advantage of advances in these areas.

Lactation represents an important element of the life history strategies of all mammals, whether monotreme, marsupial, or eutherian. Milk originated as a glandular skin secretion in synapsids (the lineage ancestral to mammals), perhaps as early as the Pennsylvanian period, that is, approximately 310 million years ago (mya). Early synapsids laid eggs with parchment-like shells intolerant of desiccation and apparently dependent on glandular skin secretions for moisture. Mammary glands probably evolved from apocrine-like glands that combined multiple modes of secretion and developed in association with hair follicles. Comparative analyses of the evolutionary origin of milk constituents support a scenario in which these secretions evolved into a nutrient-rich milk long before mammals arose. A variety of antimicrobial and secretory constituents were co-opted into novel roles related to nutrition of the young. Secretory calcium-binding phosphoproteins may originally have had a role in calcium delivery to eggs; however, by evolving into large, complex casein micelles, they took on an important role in transport of amino acids, calcium and phosphorus. Several proteins involved in immunity, including an ancestral butyrophilin and xanthine oxidoreductase, were incorporated into a novel membrane-bound lipid droplet (the milk fat globule) that became a primary mode of energy transfer. An ancestral c-lysozyme lost its lytic functions in favor of a role as α-lactalbumin, which modifies a galactosyltransferase to recognize glucose as an acceptor, leading to the synthesis of novel milk sugars, of which free oligosaccharides may have predated free lactose. An ancestral lipocalin and an ancestral whey acidic protein four-disulphide core protein apparently lost their original transport and antimicrobial functions when they became the whey proteins β-lactoglobulin and whey acidic protein, which with α-lactalbumin provide limiting sulfur amino acids to the young. By the late Triassic period (ca 210 mya), mammaliaforms (mammalian ancestors) were endothermic (requiring fluid to replace incubatory water losses of eggs), very small in size (making large eggs impossible), and had rapid growth and limited tooth replacement (indicating delayed onset of feeding and reliance on milk). Thus, milk had already supplanted egg yolk as the primary nutrient source, and by the Jurassic period (ca 170 mya) vitellogenin genes were being lost. All primary milk constituents evolved before the appearance of mammals, and some constituents may have origins that predate the split of the synapsids from sauropsids (the lineage leading to ‘reptiles’ and birds). Thus, the modern dairy industry is built upon a very old foundation, the cornerstones of which were laid even before dinosaurs ruled the earth in the Jurassic and Cretaceous periods.

Three experiments were conducted on Martina Franca jennies. Experiment 1 tested Wood’s model for evaluating the lactation curve. Data from the entire lactation period of 12 jennies were used. The results showed that Wood’s model was able to recognize the shape of the lactation curve from pooled data (r2 = 0.11; P < 0.01), with the lactation peak occurring at 48 d. Individual curves showed wide variability. Experiment 2 aimed to evaluate the effects of the daily number of milkings (1, 3, or 6) and the interval between the separation of foals from dams and milking (2 or 3 h) on milk yield and udder health. Four groups of jennies (n = 5) were considered: 1 x 3H, milked once per day (1x) with a 3-h interval from the time of foal removal (3H) from the dams to mechanical milking (3-h interval); 3 x 3H, milked 3 times per day with 3-h intervals; 3 x 2H, milked 3 times per day with 2-h intervals; and 6 x 2H, milked 6 times per day with 2-h intervals. The milk somatic cell count (SCC) was monitored. Better efficiency was observed for 3 vs. 1 milking per day and for 3-h vs. 2-h intervals. The regimen of 6 daily milkings at 2-h intervals did not increase milk yield and was related to an increase in the SCC compared with 3 daily milkings. In Exp. 3, the effects of the interval from foal removal to milking (3, 5, or 8 h) on yield, gross chemical composition, organoleptic characteristics of the milk, and udder health of the jennies were evaluated. The effects of milking time were also evaluated. Twenty jennies milked twice daily (2x) were subdivided into 4 groups (n = 5): 2 x 3H, with milkings at 1200 h and 1900 h and an interval of 3 h; 2 x 5H, milked at 1200 h and 1900 h with a 5-h interval; 2 x 8H1, milked at 1200 h and 2200 h with an 8-h interval; and 2 x 8H2, milked at 0700 h and 1900 h with an 8-h interval. Milk yield was greater by 28.4% when an 8-h interval was used compared with a 3-h interval and at the morning vs. the evening milking. The milk yield per milking was greatest at 0700 h, indicating the existence of a circadian rhythm in milk secretion processes. Intervals of 5 and 8 h caused significant decreases in the fat and lactose content and organoleptic characteristics of the milk, whereas an 8-h interval led to an increase in the SCC. In conclusion, a milking regimen of twice-daily milking at 0700 h and 1900 h with an 8-h interval provided the maximum yield per day. In terms of milk quality, a 3-h interval yielded the best results.

Twenty-four lactating ewes (Manchega, n = 12; Lacaune, n = 12) in mid lactation were used to assess the short-term effects of different machine milking intervals (4, 8, 12, 16, 20, and 24h) on milk yield, milk composition, and tight junction (TJ) permeability of mammary epithelia. Milk samples were analyzed for chemical composition, somatic cell count (SCC), and plasmin activity. Plasma lactose, and milk Na and K concentrations were used as indicators of TJ permeability. Milk accumulated linearly for up to 24h, showing a different rate according to the milk yield of the breed (Manchega, 38mL/h; Lacaune, 87mL/h). Milking interval affected milk fat content, which decreased markedly from 4 to 24h in both breeds, but no differences were observed in milk protein content. The milk contents of casein, true protein, lactose, and total solids also varied according to milking interval. Values of SCC did not vary by breed (175×103cells/mL, on average), showing the lowest log10 values for the 4-and 24-h milking intervals in both breeds. Plasmin activity in milk increased with milking interval until 20h of udder filling in both breeds, and was poorly but positively correlated with SCC content (r = 0.39). Plasma lactose increased dramatically after 20h of milk accumulation, indicating enhanced permeability of mammary TJ. As a result, an increase in Na concentration and in the Na:K ratio, and a decrease in K concentration, were observed in the milk of Manchega ewes. On the contrary, no differences in Na and K concentrations in milk were detected in Lacaune ewes. In conclusion, our results proved that Manchega and Lacaune dairy sheep could maintain high rates of milk secretion during extended milking intervals in the short term, with no effects on udder health and few negative effects on milk yield. Increased TJ permeability, caused by the effect of udder filling, induced changes in milk composition that were more marked in Manchega than in Lacaune ewes.

A recently developed biological model of lactation described changes in daily milk yield throughout lactation as the result of 3 processes, secretory cell differentiation, cell death, and secretion rate per cell. This paper extends the model to describe the production of milk components (fat, protein, lactose, and water) throughout lactation by replacing milk secretion rate of the original model with the secretion rates of the four components. The milk component model approach was used to examine the relationship between milk yield and the major determinants of its production, using the secretion of milk components throughout lactation. Newly derived models were tested on 461 lactations from a single Holstein herd and used to estimate variability of secretion rates throughout lactation. Because the pattern of cell numbers throughout lactation is not precisely known, an alternative pattern of cell numbers was modeled and the concomitant change in secretion rates outlined. Fat secretion rate was the most variable, as measured by its weekly coefficient of variation throughout lactation. Secretion rates of lactose and water were nearly constant throughout lactation and highly correlated (0.94). Fat and protein secretion rates also were well correlated (0.53). The known biochemistry of milk component production related well to the secretion rate observations derived from the model. Lactose secretion rate and numbers of active secretory cells primarily determined daily milk yield.

It is well established that milk production of the dairy cow is a function of mammary epithelial cell (MEC) number and activity and that these factors can be influenced by diverse environmental influences and management practises (nutrition, milk frequency, photoperiod, udder health, hormonal and local effectors). Thus, understanding how the mammary gland is able to respond to these environmental cues provides a huge potential to enhance milk production of the dairy cow. In recent years our understanding of molecular events within the MEC underlying bovine lactation has been advanced through mammary microarray studies and will be further advanced through the recent availability of the bovine genome sequence. In addition, the potential of epigenetic regulation (non-sequence inheritable chemical changes in chromatin, such as DNA methylation and histone modifications, which affect gene expression) to manipulate mammary function is emerging. We propose that a substantial proportion of unexplained phenotypic variation in the dairy cow is due to epigenetic regulation. Heritability of epigenetic marks also highlights the potential to modify lactation performance of offspring. Understanding the response of the MEC (cell signaling pathways and epigenetic mechanisms) to external stimuli will be an important prerequisite to devising new technologies for maximising their activity and, hence, milk production in the dairy cow.

Modeling extended lactations for the US Holsteins is useful because a majority (>55%) of the cows in the present population produce lactations longer than 305 d. In this study, 9 empirical and mechanistic models were compared for their suitability for modeling 305-d and 999-d lactations of US Holsteins. A pooled data set of 4,266,597 test-day yields from 427,657 (305-d complete) lactation records from the AIPL-USDA database was used for model fitting. The empirical models included Wood (WD), Wilmink (WIL), Rook (RK), monophasic (MONO), diphasic (DIPH), and lactation persistency (LPM) functions; Dijkstra (DJ), Pollott (POL), and new-multiphasic (MULT) models comprised the mechanistic counterparts. Each model was separately tested on 305-d (>280 days in milk) and 999-d (>800 days in milk) lactations for cows in first parity and those in third and greater parities. All models were found to produce a significant fit for all 4 scenarios (2 parity groups and 2 lactation lengths). However, the resulting parameter estimates for the 4 scenarios were different. All models except MONO, DIPH, and LPM yielded residuals with absolute values smaller than 2kg for the entire period of the 305-d lactations. For the extended lactations, the prediction errors were larger. However, the RK, DJ, POL, and MULT models were able to predict daily yield within a±3kg range for the entire 999-d period. The POL and MULT models (having 6 and 12 parameters, respectively) produced the lowest mean square error and Bayesian information criteria values, although the differences from the other models were small. Conversely, POL and MULT were often associated with poor convergence and highly correlated, unreliable, or biologically atypical parameter estimates. Considering the computational problems of large mechanistic models and the relative predictive ability of the other models, smaller models such as RK, DJ, and WD were recommended as sufficient for modeling extended lactations unless mechanistic details on the extended curves are needed. The recommended models were also satisfactory in describing fat and protein yields of 305-d and 999-d lactations of all parities.

A quantitative trait locus (QTL) underlying different milk production traits has been identified with a high significance threshold value in the genomic region containing the acylCoA:diacylglycerol acyltransferase (DGAT1) gene, in the 3 main French dairy cattle breeds: French Holstein, Normande, and Montbéliarde. Previous studies have confirmed that the K232A polymorphism in DGAT1 is responsible for a major QTL underlying several milk production traits in Holstein dairy cattle and several other bovine breeds. In this study, we estimate the frequency of the 2 alternative alleles, K and A, of the K232A polymorphism in French Holstein, Normande, and Montbéliarde breeds. Although the K allele segregates in French Holstein and Normande breeds with a similar effect on production traits, the existence of additional mutations contributing to the observed QTL effect is strongly suggested in both breeds by the existence of sires heterozygous at the QTL but homozygous at the K232A polymorphism. One allele at a variable number of tandem repeats (VNTR) locus in the 5′ noncoding region of DGAT1 has been recently proposed as a putative causative variant. In our study, this marker was found to present a high mutation rate of 0.8% per gamete and per generation, making the allele diversity observed compatible with that expected under neutrality. Moreover, among the sires homozygous at the K232A polymorphism, no allele at the VNTR can fully explain their QTL status. Finally, no allele at the VNTR was found to be significantly associated with the fat percentage variation in the 3 breeds simultaneously after correction for the effect of the K232A polymorphism. Therefore, our results suggest the existence of at least one other causative polymorphism not yet described. Because the A allele is nearly fixed in the Montbéliarde breed, this breed represents an interesting model to identify and confirm other mutations that have a strong effect on milk production traits.

Fatty acid composition influences the nutritional quality of milk and the technological properties of butter. Using a prediction of fatty acid (FA) contents by mid-infrared (MIR) spectrometry, a large amount of data concerning the FA profile in bovine milk was collected. The large number of records permitted consideration of more complex models than those used in previous studies. The aim of the current study was to estimate the effects of season and stage of lactation as well as genetic parameters of saturated (SAT) and monounsaturated (MONO) fatty acid contents in bovine milk and milk fat, and the ratio of SAT to unsaturated fatty acids (UNSAT) that reflect the hardness of butter (SAT:UNSAT), using 7 multiple-trait, random-regression test-day models. The relationship between these FA traits with common production traits was also studied. The data set contained 100,841 test-day records of 11,626 Holstein primiparous cows. The seasonal effect was studied based on unadjusted means. These results confirmed that milk fat produced during spring and summer had greater UNSAT content compared with winter (63.13 vs. 68.94% of SAT in fat, on average). The effect of stage of lactation on FA profile was studied using the same methodology. Holstein cows in early first lactation produced a lower content of SAT in their milk fat. Variance components were estimated using a Bayesian method via Gibbs sampling. Heritability of SAT in milk (0.42) was greater than heritability of SAT in milk fat (0.24). Estimates of heritability for MONO were also different in milk and fat (0.14 vs. 0.27). Heritability of SAT:UNSAT was moderate (0.27). For all of these traits, the heritability estimates and the genetic and phenotypic correlations varied through the lactation.

Researchers have recently called for human lactation research to be conceptualized as a biological framework where maternal and infant factors impacting human milk, in terms of composition, volume and energy content are studied along with relationships to infant growth, development and health. This approach allows for the development of evidence-based interventions that are more likely to support breastfeeding and lactation in pursuit of global breastfeeding goals. Here we summarize the seminal findings of our research programme using a biological systems approach traversing breast anatomy, milk secretion, physiology of milk removal with respect to breastfeeding and expression, milk composition and infant intake, and infant gastric emptying, culminating in the exploration of relationships with infant growth, development of body composition, and health. This approach has allowed the translation of the findings with respect to education, and clinical practice. It also sets a foundation for improved study design for future investigations in human lactation.