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International audience; Antibiotic excretion into milk depends on several factors such as the compound's physicochemical properties, the animal physiology, and the milk composition. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model describing the passage of drugs into the milk of lactating species. The udder is described as a permeability limited compartment, divided into vascular, extracellular water (EW), intracellular water (IW) and milk, which was stored in alveolar and cistern compartments. The pH and ionization in each compartment and the binding to IW components and to milk fat, casein, whey protein, calcium, and magnesium were considered. Bidirectional passive diffusion across the blood-milk barrier was implemented, based on in vitro permeability studies.The model application used to predict the distribution of oxytetracycline in cow and goat milk, after different doses and routes of administration, was successful. By integrating inter-individual variability and uncertainty, the model also allowed a suitable estimation of the withdrawal periods.Further work is in progress to evaluate the predictive ability of the PBPK model for compounds with different physico-chemical properties that are potentially actively transported in order to extrapolate the excretion of xenobiotics in milk of various animal species including humans.

International audience; BACKGROUND: Food allergies affect 4-8% of children and are constantly on the rise, thus making allergies a timely issue. Most importantly, prevention strategies are nonexistent, and current therapeutic strategies have limited efficacy and need to be improved. One alternative to prevent or reduce allergies, particularly during infancy, could consist of modulating maternal immunity and microbiota using nondigestible food ingredients, such as prebiotics. For this purpose, we studied the preventive effects of prebiotics in Balb/c mothers during pregnancy and breastfeeding on food allergy development in offspring mice. METHODS: After weaning, the offspring from mothers that were exposed to GOS/inulin mixture or fed a control diet were intraperitoneally sensitized to wheat proteins to induce a systemic allergic response and orally exposed to the same allergen. Immunological, physiological, and microbial parameters were analyzed. RESULTS: GOS/inulin mixture diet modified the microbiota of mothers and their offspring. Offspring from mothers that received GOS/inulin prebiotics were protected against food allergies and displayed lower clinical scores, specifically of IgE and histamine levels, compared to offspring from mothers fed a control diet. Moreover, GOS/inulin supplementation for the mother resulted in stronger intestinal permeability in the offspring. Enhancement of the regulatory response to allergic inflammation and changes in the Th2/Th1 balance toward a dampened Th2 response were observed in mice from GOS/inulin mixture-exposed mothers. CONCLUSION: The treatment of pregnant and lactating mice with nondigestible GOS/inulin prebiotics promotes a long-term protective effect against food allergies in the offspring.

WOS: 000301474900013; International audience; The early nursing-sucking relationship is not to be taken for granted in humans. A number of factors can either facilitate or mitigate its optimal establishment on the mother's or newborn's sides. Among these factors, a morphological feature of human mothers' breasts--the areolar glands (AG)--has been identified as potentially important. Three day-old infants display attraction during the presentation of the native secretions of the AG, suggesting that they could influence the newborn's behaviour during breastfeeding. The present study assessed this topic in a sample of 121 Caucasian mother-infant dyads. The areolae of these women were screened during the first 3 postnatal days in parallel with the infant's sucking performance, body weight fluctuations and time to lactation onset. On average, 97% of the women bore AG, 80.2% having 1-20 units per areola and 33% showing AG excreting a visible fluid. The endowment in AG appeared positively linked with neonatal growth after birth and with the speed of lactation onset: infants of primiparous women with lower AG numbers had a lower weight gain than those of mothers with higher AG numbers. Further, it took longer to primiparae with lower AG counts to set on lactation. This study confirms and extends the fact that AG, in interaction with maternal experience, might influence the initiation of the breastfeeding relationship.

Little is known about modifications of the mammary utilization of nutrients circulating in blood plasma when milk yield is strongly decreased by once-daily milking. A trial was carried out to describe the mammary nutritional adjustments linked to the downregulation of milk synthesis as milk accumulated over an extended milking interval in the bovine udder. Three Holstein dairy cows yielding 34.0 kg/d of milk were fitted with an ultrasound flow probe around the left external pudic artery and with catheters inserted into the left carotid and milk vein to estimate mammary blood flow (MBF) and mammary uptake of acetate, β-hydroxybutyrate, nonesterified fatty acids, glycerol, glucose, O(2), and CO(2) release. The trial was carried out over 2 consecutive weeks, with wk 2 repeating wk 1. Cows were milked twice daily at 12-h milking intervals. On d 3, cows were milked at 0630 h and were not milked for 36 h until d 4 at 1830 h. Over the following days, twice-daily milking was resumed using 12-h milking intervals. Each half-udder was milked separately. Secretion rates of milk and milk proteins decreased 67% during the 12-to-36-h interval of milk accumulation, whereas that of milk fat fell 30%. Timing of changes in MBF and lactose levels in blood plasma was concomitant and significant after 19.5 and 21.5h of milk accumulation in the udder, respectively. The MBF decreased, most likely because the usual increases in MBF no longer occurred when the udder was full of milk. After 24h of milk accumulation, MBF did not increase further when cows lay down, and did not increase as usual 3h after a meal, suggesting a possible physical effect of milk accumulated in the udder on MBF, complementing metabolic regulation. Mammary uptake or release of nutrients was lowered before 24h for glucose, acetate, and β-hydroxybutyrate and after 24h for total glycerol, O(2), and CO(2), mostly associated with the impaired MBF. However, these decreases ranged from 12 to 17%, and cannot entirely explain the -45 and -20% decreases in milk secretion rates observed during the entire 36 h of milk accumulation, thus confirming the primary role of intramammary metabolic regulation in the downregulation of milk secretion. The larger amount of nutrients taken up by the udder could explain the enhanced milk fat levels, involving a strongly modified metabolic fate of nutrients.

The aim of this study was to investigate the effects of a severe nutrient restriction on mammary tissue morphology and remodeling, mammary epithelial cell (MEC) turnover and activity, and hormonal status in lactating dairy cows. We used 16 Holstein × Normande crossbred dairy cows, divided into 2 groups submitted to different feeding levels (basal and restricted) from 2 wk before calving to wk 11 postpartum. Restricted-diet cows had lower 11-wk average daily milk yield from calving to slaughter than did basal-diet cows (20.5 vs. 33.5 kg/d). Feed restriction decreased milk fat, protein, and lactose yields. Restriction also led to lower plasma insulin-like growth factor 1 and higher growth hormone concentrations. Restricted-diet cows had lighter mammary glands than did basal-diet cows. The total amount of DNA in the mammary gland and the size of the mammary acini were smaller in the restricted-diet group. Feed restriction had no significant effect on MEC proliferation at the time of slaughter but led to a higher level of apoptosis in the mammary gland. Gelatin zymography highlighted remodeling of the mammary extracellular matrix in restricted-diet cows. Udders from restricted-diet cows showed lower transcript expression of α-lactalbumin and kappa-casein. In conclusion, nutrient restriction resulted in lower milk yield in lactating dairy cows, partly due to modulation of MEC activity and a lower number of mammary cells. An association was found between feed restriction-induced changes in the growth hormone-insulin-like growth factor-1 axis and mammary epithelial cell dynamics.

In most mammals, prolactin (PRL) is essential for maintaining lactation, and yet the short-term suppression of PRL during established lactation by bromocriptine has produced inconsistent effects on milk yield in cows and goats. To assess the effect of the long-term inhibition of PRL release in lactating dairy cows, 5 Holstein cows in early lactation received daily intramuscular injections of 1mg of the PRL-release inhibitor quinagolide for 9 wk. Four control cows received the vehicle (water) only. During the last week of the treatments, one udder half was milked once a day (1×) and the other twice a day (2×). Blood samples were harvested at milking in wk -1, 1, 4, and 8. The daily injections of quinagolide reduced milking-induced PRL release but not the basal PRL concentration. Quinagolide induced a faster decline in milk production, which was about 5.3 kg/d lower in the quinagolide-treated cows during the last 4 wk of treatment. During wk 9, the inhibition of milk production by quinagolide was maintained in the udder half that was milked 2× but not in the half milked 1×. Milk production was significantly correlated with the quantity of PRL released at milking. Quinagolide did not affect the release of oxytocin at milking. Serum concentration of insulin-like growth factor-1 was not affected by treatment or correlated with milk production. Serum concentrations of leptin and the calciotropic hormone stanniocalcin were not affected by the treatment. In conclusion, the chronic administration of the PRL-release inhibitor quinagolide decreases milk production in dairy cows. The effect is likely the result of the reduced release of milking-induced PRL and is modulated at the level of the gland by milking frequency.

International audience; Neonatal mammals are exposed to an outstandingly powerful selective pressure at birth, and any mean to alleviate their localization effort and accelerate acceptance to orally grasp a nipple and ingest milk should have had advantageous consequences over evolutionary time. Thus, it is essential for females to display a biological interface structure that is sensorily conspicuous and executively easy for their newborns. Females' strategy to increase the conspicuousness of nipples could only exploit the newborns' most advanced and conserved sensory systems, touch and olfaction, and selection has accordingly shaped tactilely and olfactorily conspicuous mammary structures. This evolutionary modification has worked either by affecting structural features of mammaries or indirectly by affecting maternal behavioral propensities to create olfactory traces on them. These predictions are considered here in mammalian cases that have received empirical attention among marsupials, rodents, lagomorphs, ungulates, carnivores, and primates. It appears that broadcasting chemical cues and/or signals from the mammae is a pan-mammalian reproductive strategy to pilot neonatal arousal, motivation and attraction to the mother, provide assistance in localizing and orally grasping the mammae, and boost up learning. But the ways by which these chemical cues are produced and assembled on the mammae are both diverse between species and complex within species, offering an outstanding opportunity for comparative analyses in chemical communication.

Although it is known that disruption of the cell junctions in the mammary gland induces a decrease in milk yield, the cellular mechanisms involved in milk secretion reduction during mammary cell junction disruption are not well understood. The aim of this study was to investigate the cellular regulations taking place after cell junction disruption in the mammary gland of goats. We performed intramammary infusions of Ca chelators to induce cell junction disruption. In a first group of 5 goats, intramammary infusions of ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) in the right gland halves and saline as a control in the left gland halves were performed after 4 consecutive milkings. A second group of 4 goats received 4 intramammary infusions of citrate solution in the right gland halves and lactose solution as a control in the left halves. Intramammary infusion of EGTA and lactose induced a disruption of cell junctions, whereas citrate infusions failed to modify mammary epithelium integrity. The effect of the infused solutions was also tested in vitro via the measurement of transepithelial resistance, confirming mammary epithelium disruption by the EGTA, lactose, and citrate solutions at high concentrations. The disruption of mammary epithelium integrity by EGTA induced a decrease in the expression of the cell junction protein E-cadherin. Both the EGTA and lactose infusions induced a decrease in milk secretion that was accompanied by cellular modifications. We observed a decrease in milk casein, which was associated with a decrease in the mRNA level of kappa-casein in the lactose-infused glands, and a decrease in milk lactose, which was associated with a downregulation of alpha-lactalbumin transcripts in both the EGTA- and lactose-treated glands. Both the EGTA and lactose infusions increased terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling (TUNEL) in the mammary tissue, indicating an induction of apoptosis. Lactose infusion increased the mRNA level of Bax, suggesting that apoptosis was regulated at the transcriptional level. The results obtained in these experiments suggest that disruption of mammary epithelium integrity was associated with both reduced synthetic activity and apoptosis induction in the mammary gland.

This study analyzed the effect of propionate (C3) and casein (CN) on whole-body and mammary metabolism of energetic nutrients. Three multiparous Holstein cows fitted with both duodenal and ruminal cannulas were used in 2 replicated Youden squares with 14-d periods. Effects of CN (743 g/d in the duodenum) and C3 (1,042 g/d in the rumen) infusions, either separately or in combination as supplements to a grass silage diet, were tested in a factorial arrangement. The control diet provided 97% of energy and protein requirements. Within each period, blood samples were taken (d 11) from the carotid artery and the right mammary vein to determine net uptake of energetic nutrients. Plasma blood flow was calculated using the Fick principle (based on Phe and Tyr). On d 13, [6,6-(2)H(2)]glucose was infused in the jugular vein to determine whole-body glucose rate of appearance (Ra) based on enrichments in arterial plasma. Both C3 and CN treatments increased whole-body Ra (17% and 13%, respectively) but only CN increased milk (18%) and lactose (14%) yields, suggesting no direct link between whole-body Ra and milk yield. When CN was infused alone, the apparent ratio of conversion of CN carbon into glucose carbon was 0.31 but, when allowance was made for the CN required to support the extra milk protein output, the ratio increased to 0.40, closer to the theoretical ratio (0.48). This may relate to the observed increases in arterial glucagon concentrations for CN alone. Conversely, the apparent conversion of infused C3 carbon alone to glucose was low (0.31). With C3, mammary plasma flow increased as did uptakes of lactate, Ala, and Glu whereas the uptake for beta-hydroxybutyrate (BHBA) decreased. Mammary net carbon balance suggested an increase with C3 treatment in glucose, lactate, Ala, and Glu oxidation within the mammary gland. Mammary glucose uptake did not increase with CN treatment, despite an increase in glucose arteriovenous difference and extraction rate, because plasma flow decreased (-17%). Whereas CN, alone or in combination with C3, increased both lactose and protein yields, only mammary AA (and BHBA in CN alone) uptake increased because plasma flow decreased (-17%). These data suggest that the observed variations of milk lactose yield (and other milk components) are linked to metabolic interchanges between several energetic nutrients at both the whole-body and mammary levels and are not explained by increases in whole-body glucose availability.

Two experiments were conducted to determine the milk loss of high-yielding Alpine goats resulting from once-daily milking (ODM) and its relationship to udder cisternal size. We investigated the effects of application of this management strategy on milk yield, composition, and technological parameters: lipolysis, fat globule size, and cheese yield. In a second experiment, we investigated the effect of repeated periods of ODM management during lactation. Goats at the beginning of both experiments were at 25 d in milk on average and were previously milked twice daily (twice-daily milking; TDM). In experiment 1, which was conducted for 2 periods (P) of 9 wk (P1, P2), 48 goats were grouped (1, 2, 3, and 4) according to milk yield, parity, and somatic cell count (SCC). Over the 2 periods, goats from group 1 were managed with TDM and those from group 2 were managed with ODM. In group 3, goats were assigned to TDM during P1 and ODM during P2, conversely, those in group 4 were assigned to ODM in P1 and TDM in P2. During P1, the 12 goats from group 3 underwent 2 distinct morning machine milkings to measure milk repartition (cisternal and alveolar) in the udder based on the "atosiban method." On P1 plus the P2 period of 18 wk, milk loss caused by ODM (compared with TDM) was 16%. In our condition of 24-h milk accumulation, there was no correlation between milk loss and udder cisternal size. Milk fat content, fat globule size, or apparent laboratory cheese yield was not modified by ODM, but milk protein content (+2.7 g/kg), casein (+1.8 g/kg), milk soluble protein concentration (+1.0 g/kg), and SCC increased, whereas lipolysis decreased (-0.3 mEq/100 g of oleic acid). In experiment 2, which was conducted for 4 periods (P1, P2, P3, P4) of 5 wk each, 8 goats, blocked into 2 homogenous groups (5 and 6), were used to study the effects of a double inversion of milking frequency (TDM or ODM) for 20 wk of lactation. Milk loss was 17% and ODM did not modify milk fat or protein contents, SCC, casein, or milk soluble protein concentration, but lipolysis was decreased (-0.3 mEq/100 g of oleic acid). Neither experiment showed the effects of period of ODM management on milk yield, milk fat or protein content, SCC, fat globule size, lipolysis, casein, milk soluble protein concentration, or apparent laboratory cheese yield.

As oestrous expression of dairy cows has decreased over the last decades oestrus detection has become more difficult. The objective of this study is to identify the main factors that affect oestrus detection in seasonal calving dairy cows, and to establish their relative importance. In each of 5 years 36 Normande and 36 Holstein cows were assigned to a Low or High winter-feeding level group. Half of each group was then assigned to a Low or High pasture-feeding group. The Low-Low strategy resulted in the lowest milk yield and the greatest body condition (BC) loss from calving to nadir BC score (6302 kg; -0.98 unit). The High-High strategy had the converse effect (7549 kg; -0.75 units). Low-High and High-Low strategies had intermediate values. The Normande cows had lower milk yield and BC loss than Holstein cows (6153 kg versus 7620 kg; -0.82 unit versus -1.20 unit). A database of 415 observed spontaneous oestruses was created. Oestruses were classified according to detection signs: (1) standing to be mounted, (2) mounting without standing, (3) other signs without standing or mounting (slight signs). Presence of another cow in oestrus, access to pasture, Normande breed and Low-Low strategy increased standing detection. In the Normande breed, 97% of oestruses were detected by standing while combining the presence of a herdmate in oestrus and access to pasture with a milk production of less than 6550 kg. Holstein cows had a higher frequency of slight signs oestruses than Normande ones, which was associated with a decreased subsequent calving rate (P

Milk production and hormonal responses to milking in Holstein cows that were milked twice daily, and that either also nursed calves twice daily 2 h after milking for 9 wk after calving (n = 10) or that served as nonnursing controls (n = 8) were examined to assess how nursing affected responses to machine milking. Milk yield at milking during the 9 wk of nursing was lower in nursing cows compared with control cows (26.1 +/- 1.0 vs. 35.5 +/- 1.1 kg) that were only machine milked. During nursing, the amount drunk by calves increased from 6.5 +/- 0.7 kg/d on wk 1 to 12.5 +/- 1.4 kg/d on wk 9. When this was added to the amount of milk obtained at milking, nursing cows did not differ from control cows in total milk produced (35.5 +/- 1.0 vs. 35.5 +/- 1.0 kg). Residual milk yield, after i.v. injection of oxytocin after milking, was higher in nursing cows than in control cows (8.7 +/- 0.8 vs. 3.2 +/- 0.8 kg). During the 6 wk after weaning, milk production was the same for the nursing and control cows (34.0 +/- 1.35 vs. 34.7 +/- 1.42 kg). Plasma oxytocin levels during milking were greater for control cows than for nursing cows (31.7 +/- 5.4 vs. 18.0 +/- 2.8 pg/mL), but were equivalent to concentrations in nursing cows during nursing (35.5 +/- 7.5 pg/mL). Plasma concentrations of prolactin and cortisol increased after both milking (control vs. nursing: prolactin: 40.2 +/- 6.8 vs. 32.9 +/- 6.1 ng/mL; cortisol: 6.4 +/- 1.23 vs. 7.4 +/- 1.10 ng/mL) and nursing (control vs. nursing: prolactin: 18.6 +/- 7.3 vs. 38.9 +/- 6.6 ng/mL; cortisol: 2.34 +/- 1.15 vs. 7.37 +/- 1.04 ng/mL). In contrast to previous studies, there was no obvious advantage for milk production by keeping a calf with the cow. This appears to result from the reduced oxytocin secretion during milking for the nursing cows.

8th International Workshop on the Biology of Lactation in Farm Animals. Pirassununga, Brazil. 2006/08/21-23; This paper aims to compare different adaptive responses of the mammary gland of cows, ewes, and goats submitted to extended milking intervals in different systems of management. Depending on the species, these extended milking intervals can be characterized by the following milk removal approaches; 3 milkings every 2 d, elimination of 1 milking per week (i.e., 13 vs. 14 milkings per week), and once-daily milking with additional suckling (i.e., dual purpose system of suckling and milking) or without suckling (exclusive once-daily milking). All the high-yielding animals and breeds adapted without problems to being submitted to intervals between milking less than 20 to 21 h. Under these conditions, all ruminant species demonstrated only low and transitory variations in milk production and quality. Thus, management systems using such an interval are good tools for the dairy producer who wants to save time without important adverse economic impact. When animals have good mammary gland health, these management systems can be applied without preliminary adaptation. However, goats and some breeds of dairy ewes seem to adapt to once-daily milking better than cows. Additionally, goats and ewes with higher production levels demonstrate a lower reduction in milk yield. With goats, there is only a limited variation in milk quality and cheese-making capacity of the milk produced, but ewes and cows show a significant enrichment of milk constituents, especially in fat. This indicates some differences in the regulation of lactose, protein, and fat synthesis depending on the duration of the milking interval and provides interesting models for physiological studies on milk secretion and synthesis regulation. Anatomical and physiological characteristics of lactating cows and ewes, in terms of cisternal vs. alveolar volumes within the mammary glands, could contribute to different abilities in adaptation to different milking systems. In goats, however, other mechanisms, such as compliancy of the mammary gland and regulation of tight junction impermeability, could be involved in milk secretion regulation and, thus, could become new targets for genetic selection of animals better adapted to accept extended milking intervals.

Allergic asthma is a chronic disease characterized by airway obstruction in response to allergen exposure. It results from an inappropriate T helper type 2 response to environmental airborne antigens and affects 300 million individuals. Its prevalence has increased markedly in recent decades, most probably as a result of changes in environmental factors. Exposure to environmental antigens during infancy is crucial to the development of asthma. Epidemiological studies on the relationship between breastfeeding and allergic diseases have reached conflicting results. Here, we have investigated whether the exposure of lactating mice to an airborne allergen affects asthma development in progeny. We found that airborne antigens were efficiently transferred from the mother to the neonate through milk and that tolerance induction did not require the transfer of immunoglobulins. Breastfeeding-induced tolerance relied on the presence of transforming growth factor (TGF)-beta during lactation, was mediated by regulatory CD4+ T lymphocytes and depended on TGF-beta signaling in T cells. In conclusion, breast milk-mediated transfer of an antigen to the neonate resulted in oral tolerance induction leading to antigen-specific protection from allergic airway disease. This study may pave the way for the design of new strategies to prevent the development of allergic diseases.

International audience; This paper aims to compare different adaptive responses of the mammary gland of cows, ewes, and goats submitted to extended milking intervals in different systems of management. Depending on the species, these extended milking intervals can be characterized by the following milk removal approaches; 3 milkings every 2d, elimination of 1 milking per week (i.e., 13 vs. 14 milkings per week), and once-daily milking with additional suckling (i.e., dual purpose system of suckling and milking) or without suckling (exclusive once-daily milking). All the high-yielding animals and breeds adapted without problems to being submitted to intervals between milking less than 20 to 21 h. Under these conditions, all ruminant species demonstrated only low and transitory variations in milk production and quality. Thus, management systems using such an interval are good tools for the dairy producer who wants to save time without important adverse economic impact. When animals have good mammary gland health, these management systems can be applied without preliminary adaptation. However, goats and some breeds of dairy ewes seem to adapt to once-daily milking better than cows. Additionally, goats and ewes with higher production levels demonstrate a lower reduction in milk yield. With goats, there is only a limited variation in milk quality and cheese-making capacity of the milk produced, but ewes and cows show a significant enrichment of milk constituents, especially in fat. This indicates some differences in the regulation of lactose, protein, and fat synthesis depending on the duration of the milking interval and provides interesting models for physiological studies on milk secretion and synthesis regulation. Anatomical and physiological characteristics of lactating cows and ewes, in terms of cisternal vs. alveolar volumes within the mammary glands, could contribute to different abilities in adaptation to different milking systems. In goats, however, other mechanisms, such as compliancy of the mammary gland and regulation of tight junction impermeability, could be involved in milk secretion regulation and, thus, could become new targets for genetic selection of animals better adapted to accept extended milking intervals.

International audience; Metal concentrations measured in the organs of beached whales are published regularly. Few of these, however, describe metal levels in nursing females. In the present study, mercury, lead, copper and zinc levels were measured in the milk and tissues of a female Bottlenose dolphin. Results reveal that metal pollutants pass from the tissue into the milk.

International audience; Mice carrying a germ-line null mutation of the prolactin receptor gene have been produced by gene targeting in embryonic stem cells. Heterozygous females showed almost complete failure of lactation attributable to greatly reduced mammary gland development after their first, but not subsequent, pregnancies. Homozygous females were sterile owing to a complete failure of embryonic implantation. Moreover, they presented multiple reproductive abnormalities, including irregular cycles, reduced fertilization rates, defective preimplantation embryonic development, and lack of pseudopregnancy. Half of the homozygous males were infertile or showed reduced fertility. This work establishes the prolactin receptor as a key regulator of mammalian reproduction, and provides the first total ablation model to further study the role of the prolactin receptor and its ligands.