The ABCG2 Transporter Affects Plasma Levels, Tissue Distribution and Milk Secretion of Lumichrome, a Natural Derivative of Riboflavin.

The ABCG2 membrane transporter affects bioavailability and milk secretion of xenobiotics and natural compounds, including vitamins such as riboflavin. We aimed to characterize the in vitro and in vivo interaction of ABCG2 with lumichrome, the main photodegradation product of riboflavin, which has proven in vitro anti-cancer activity and a therapeutical role in antibacterial photodynamic therapy as an efficient photosensitizer. Using MDCK-II polarized cells overexpressing murine Abcg2 and human ABCG2 we found that lumichrome was efficiently transported by both variants. After lumichrome administration to wild-type and Abcg2-/- mice, plasma AUC20-120 min was 1.8-fold higher in Abcg2-/- mice compared with wild-type mice. The liver and testis from Abcg2-/- mice showed significantly higher lumichrome levels compared with wild-type, whereas lumichrome accumulation in small intestine content of wild-type mice was 2.7-fold higher than in Abcg2-/- counterparts. Finally, a 4.1-fold-higher lumichrome accumulation in milk of wild-type versus Abcg2-/- mice was found. Globally, our results show that ABCG2 plays a crucial role in plasma levels, tissue distribution and milk secretion of lumichrome potentially conditioning its biological activity.

Secretion into Milk of the Main Metabolites of the Anthelmintic Albendazole Is Mediated by the ABCG2/BCRP Transporter.

Albendazole (ABZ) is an anthelmintic with a broad-spectrum activity, widely used in human and veterinary medicine. ABZ is metabolized in all mammalian species to albendazole sulfoxide (ABZSO), albendazole sulfone (ABZSO2) and albendazole 2-aminosulphone (ABZSO2-NH2). ABZSO and ABZSO2 are the main metabolites detected in plasma and all three are detected in milk. The ATP-binding cassette transporter G2 (ABCG2) is an efflux transporter that is involved in the active secretion of several compounds into milk. Previous studies have reported that ABZSO was in vitro transported by ABCG2. The aim of this work is to correlate the in vitro interaction between ABCG2 and the other ABZ metabolites with their secretion into milk by this transporter. Using in vitro transepithelial assays with cells transduced with murine Abcg2 and human ABCG2, we show that ABZSO2 and ABZSO2-NH2 are in vitro substrates of both. In vivo assays carried out with wild-type and Abcg2-/- lactating female mice demonstrated that secretion into milk of these ABZ metabolites was mediated by Abcg2. Milk concentrations and milk-to-plasma ratio were higher in wild-type compared to Abcg2-/- mice for all the metabolites tested. We conclude that ABZ metabolites are undoubtedly in vitro substrates of ABCG2 and actively secreted into milk by ABCG2.

Hoxd10 Is Required Systemically for Secretory Activation in Lactation and Interacts Genetically with Hoxd9.

Targeted disruption of the murine Hoxd10 gene (ΔHoxd10) leads to a high frequency of localized (gland-to-gland or regionally within a gland) lactation impairment in homozygous mutant mice as a single gene mutation. The effect of Hoxd10 disruption was enhanced by simultaneous disruption of Hoxd9 (ΔHoxd9/d10), a mutation shown previously to have no effect on mammary function as a single gene alteration. Mammary glands of homozygous ΔHoxd10 and ΔHoxd9/d10 females were indistinguishable from those of wild type littermate and age-matched control mice in late pregnancy. However, in lactation, 47% of homozygous ΔHoxd10 females, and 100% of homozygous ΔHoxd9/d10 females, showed localized or complete failure of two or more glands to undergo lactation-associated morphological changes and to secrete milk. Affected regions of ΔHoxd10 and ΔHoxd9/d10 mutants showed reduced prolactin receptor expression, reduced signal transducer and activator transcription protein 5 (STAT5) phosphorylation, reduced expression of downstream milk proteins, mislocalized glucose transporter 1 (GLUT1), increased STAT3 expression and phosphorylation, recruitment of leukocytes, altered cell cycle status, and increased apoptosis relative to unaffected regions and wild type control glands. Despite these local effects on alveolar function, transplantation results and hormone analysis indicate that Hoxd10 primarily has systemic functions that confer attenuated STAT5 phosphorylation on both wild type and ΔHoxd10 transplants when placed in ΔHoxd10 hosts, thereby exacerbating an underlying propensity for lactation failure in C57Bl/6 mice.

Suppression of prolactin and reduction of milk secretion by effect of cabergoline in lactating dairy ewes.

The effects of cabergoline, an ergot derivative and dopamine receptor agonist, were investigated in 30 ewes of 2 dairy breeds (Manchega; MN, n = 15; Lacaune; LC, n = 15). Ewes were in a similar late-lactation stage, but differed in milk yield according to breed (MN vs. LC, 1.02 ± 0.03 vs. 2.27 ± 0.05 kg/d). Treatments consisted of a single intramuscular injection of cabergoline at different doses per ewe. Cabergoline doses (per ewe) were: low (0.56 mg), high (1.12 mg), and control (CON; 0 mg; 1 mL of saline). Milk yield was recorded daily (d -14 to 25), milk and blood were sampled, and udder traits were measured from d -2 to 14 after injection. No local reaction at the injection site, nor behavior and metabolic indicators of the ewes were detected after the cabergoline injection, but milk yield fell rapidly in both breeds (MN vs. LC, -54% vs. -27%) when compared with CON ewes. Cabergoline effects progressively disappeared after d 5, and no milk yield differences between treatments were detected from d 8 to 25 after injection. Milk fat and protein contents increased similarly (22% and 23%; respectively) in both breeds and at both cabergoline doses until d 5, and the effects disappeared thereafter. Plasma prolactin (PRL) decreased dramatically in the low- and high-treated ewes the day after injection when compared with the CON ewes, and reached values below the detection limit of the assay between d 1 and 5, increasing similarly thereafter. On d 14, PRL values were 58% greater in the low- and high-treated than in the CON ewes, showing that PRL concentrations rebounded when the cabergoline effects ceased. Total udder volume correlated with milk accumulated in the udder (r = 0.77) of all groups of ewes throughout the experiment, suggesting its use as a noninvasive method for the estimation of milk stored in the udder. Udder volume was similar for the low and high ewes, but both values were lower than those of the CON ewes from d 1 to 14 after injection. No other effects on udder size were detected. Cabergoline dramatically inhibited PRL secretion and decreased milk yield and udder volume of lactating dairy ewes. The low dose of cabergoline was as effective as the high dose in the 2 breeds of dairy ewes. These results suggest the use of cabergoline to facilitate the decrease of milk production in dairy ewes (e.g., dry-off, illness care), although further research in pregnant dairy ewes and during the following lactation is still needed.

Milk yield did not decrease in large herds of high-producing Holstein cows in semi-arid climate of Mexico.

This study aimed to determine the trends in milk production, fertility, temperature-humidity index (THI), and herd size in dairy herds from the Laguna region in northern Mexico. Records of 16 dairy herds of Holstein cows from January 2002 to December 2016 were used. Milk production was categorized in low and high levels. Milk production and fertility were analyzed using generalized equation estimation procedures by a model of repeated measures that included the effect of year, month, and productive level, an interaction for month × productive level, and herd effect was nested in productive level. For THI, a generalized linear model that included the effects of year and month was used. Dairy herds with high levels of milk production yielded more milk than those with low levels (P < 0.001). Milk production in 2002 and 2016 was 27.4 ± 0.6 and 32.3 ± 0.7 L/cow/day, respectively. Fertility fluctuated throughout the study. Dairy herds with high levels of milk production recorded higher fertility than those with low levels (P < 0.001). From October to April, THI was < 70, whereas it was > 73 from May to September, indicating that cows were in heat stress (20 h/day). The median herd size was 995 and 2569 cows in 2002 and 2016, respectively. In conclusion, in large herds, milk production increased over the years of study, whereas fertility showed a wave cycle; nonetheless, when THI was > 73, both milk production and fertility decreased.

Role of Phospholipid Flux during Milk Secretion in the Mammary Gland.

Lipids are a complex group of chemical compounds that are a significant component of the human diet and are one of the main constituents of milk. In mammals, lipids are produced in the milk-secreting cells in the form of milk fat globules. The chemical properties of these compounds necessitate developing separate processes for effective management of non-polar substances in the polar environment of the cell, not only during their biosynthesis and accumulation in the cell interior and secretion of intracytoplasmic lipid droplets outside the cell, but also during digestion in the offspring. Phospholipids play an important role in these processes. Their characteristic properties make them indispensable for the secretion of milk fat as well as other milk components. This review investigates how these processes depend on the coordinated flux and availability of phospholipids and how the relationship between the surface area (phospholipids) and volume (neutral lipids) of the cytoplasmic lipid droplets must be in biosynthetic balance. The structure formed as a result (i.e. a milk fat globule) is therefore a result of specified structural limitations inside the cell, whose overcoming enables the coordinated secretion of milk components. This structure and its composition also reflects the nutritional demands of the developing infant organism as a result of evolutionary adaptation.

Short communication: The gain-of-function Y581S polymorphism of the ABCG2 transporter increases secretion into milk of danofloxacin at the therapeutic dose for mastitis treatment.

The ATP-binding cassette transporter ABCG2 restricts the exposure of certain drugs and natural compounds in different tissues and organs. Its expression in the mammary gland is induced during lactation and is responsible for the active secretion of many compounds into milk, including antimicrobial agents. This particular function of ABCG2 may affect drug efficacy against mastitis and the potential presence of drug residues in the milk. Previous in vitro and in vivo studies showed increased transport of several compounds, including fluoroquinolones, by the bovine ABCG2 Y581S polymorphism. Our main purpose was to study the potential effect of this bovine ABCG2 polymorphism on the secretion into milk of the antimicrobial danofloxacin administered at the therapeutic dose of 6mg/kg used for mastitis treatment. In addition, the effect of this polymorphism on the relative mRNA and protein levels of ABCG2 by quantitative real-time PCR and Western blot were studied. Danofloxacin 18% (6mg/kg) was administered to 6 Y/Y homozygous and 5 Y/S heterozygous cows. Danofloxacin levels in milk and milk-to-plasma concentration ratios were almost 1.5- and 2-fold higher, respectively, in Y/S cows compared with the Y/Y cows, showing a higher capacity of this variant to transport danofloxacin into milk. Furthermore, the higher activity of this polymorphism is not linked to higher ABCG2 mRNA or protein levels. These results demonstrate the relevant effect of the Y581S polymorphism of the bovine ABCG2 transporter in the secretion into milk of danofloxacin after administration of 6mg/kg, with potentially important consequences for mastitis treatment and for milk residue handling.

Genetic variations in the SPP1 promoter affect gene expression and the level of osteopontin secretion into bovine milk.

Osteopontin (OPN) is now recognized as an important cytokine and extracellular integrin-binding protein at the crossroads of inflammation and homeostasis. In a previous study, we found that OPN gene (SPP1) polymorphisms are associated with milk performance traits and somatic cell score (SCS), a parameter used to estimate the genetic value of udder health in dairy cattle. In this study, we assessed whether the genetic variations had an impact on SPP1 promoter activity, immune response and the level of OPN secreted into milk. The influence of DNA polymorphisms on the promoter activity of SPP1 was confirmed in vitro. To measure the impact of the genetic variations on OPN secretion into milk, we measured OPN levels in both plasma and milk throughout lactation. Cows were grouped by the OPN haplotypes associated with a high (H2 × H3) or low (H1 × H4) SCS. For both H2 × H3 and H1 × H4, the OPN level in plasma remained low throughout lactation, although the concentration in the milk of H1 × H4 cows increased more in late lactation. Moreover, the macrophages of H1 × H4 cows expressed a lower SPP1 and proinflammatory IL6 in response to infection. Regarding the immune cell response, cows with the genetic potential to secrete higher OPN levels during late lactation had macrophages expressing fewer proinflammatory cytokines, a situation that might explain the genetic association with low somatic cells. Although OPN's favorable roles during late lactation remain to be elucidated, the tissue remodeling properties associated with OPN may be beneficial for reducing the incidence of infection during the transition period in lactating cows.

Role of the Abcg2 transporter in plasma, milk, and tissue levels of the anthelmintic monepantel in mice.

Breast cancer resistance protein/ATP-binding cassette subfamily G2 (BCRP/ABCG2) is an ATP-binding cassette efflux (ABC) transporter expressed in the apical membrane of cells in tissues, such as the liver, intestine, kidney, testis, brain, and mammary gland. It is involved in xenobiotic pharmacokinetics, potentially affecting the efficacy and toxicity of many drugs. In this study, the role of ABCG2 in parasiticide monepantel (MNP) and its primary metabolite, monepantel sulfone (MNPSO2)'s systemic distribution and excretion in milk, was tested using female and male wild-type and Abcg2-/- mice. Liquid chromatography coupled with a tandem mass spectrometer (LC-MS/MS) was used for the analysis in a 10-min run time using positive-mode atmospheric pressure electrospray ionization (ESI+) and multiple reaction monitoring (MRM) scanning. For the primary metabolite tested, milk concentrations were 1.8-fold higher in wild-type mice than Abcg2-/- female lactating mice (P = 0.042) after intravenous administration of MNP. Finally, despite the lack of a difference between groups, we investigated potential differences in MNP and MNPSO2's plasma and tissue accumulation levels between wild-type and Abcg2-/- male mice. In this study, we demonstrated that MNPSO2 milk levels were affected by Abcg2, with potential pharmacological and toxicological consequences, contributing to the undesirable xenobiotic residues in milk.

The ABCG2 protein in vitro transports the xenobiotic thiabendazole and increases the appearance of its residues in milk.

Thiabendazole (TBZ) is a broad-spectrum anthelmintic and fungicide used in humans, animals, and agricultural commodities. TBZ residues are present in crops and animal products, including milk, posing a risk to food safety and public health. ABCG2 is a membrane transporter which affects bioavailability and milk secretion of xenobiotics. Therefore, the aim of this work was to characterize the role of ABCG2 in the in vitro transport and secretion into milk of 5-hydroxythiabendazole (5OH-TBZ), the main TBZ metabolite. Using MDCK-II polarized cells transduced with several species variants of ABCG2, we first demonstrated that 5OH-TBZ is efficiently in vitro transported by ABCG2. Subsequently, using Abcg2 knockout mice, we demonstrated that 5OH-TBZ secretion into milk was affected by Abcg2, with a more than 2-fold higher milk concentration and milk to plasma ratio in wild-type mice compared to their Abcg2-/- counterpart.

Effects of traditional Chinese medicine-assisted intervention on improving postpartum lactation: A systematic review and meta-analysis.

Importance: Breast milk is the safest food for infants and has many psychological and physical benefits for infants and mothers. However, problems encountered during the breastfeeding process can reduce postpartum women's willingness to breastfeed. Lactation and engorgement may be improved through Traditional Chinese Medicine auxiliary therapy. However, the overall efficacy of various Traditional Chinese Medicine auxiliary therapies and the relevant meridians and acupuncture points for treating breast milk deficiency remain unclear. Objective: To investigate Traditional Chinese Medicine auxiliary therapy's effectiveness and acupoints for postpartum women who experience problems during the breastfeeding process. Methods: Data were sourced from Embase, Web of Science, CINAHL, Cochrane, CNKI, PubMed, and the Airiti Library Central Register of Controlled Trials and Clinical Trials from the database inception to October 2022. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Main outcome measures: The primary outcomes were overall efficiency, prolactin level, milk volume, and breast engorgement in postpartum women with lactation deficiency after-assisted therapies and the correlation between meridian points and milk secretion. Results: A total of 1,516 studies were initially identified, and 357 articles were assessed. In the final analysis, 20 studies were included, covering various Traditional Chinese Medicine therapies (acupuncture, acupressure, scrapping, moxibustion cupping, etc.) to stimulate relative acupoints without any acupoint stimulation. The overall efficiency (odds ratio [OR] = 14.17, 95% confidence interval [CI] = 6.49 to 30.92), prolactin level (standardized mean difference [SMD] = 0.36, 95% CI = 0.074 to 0.64), improvement of milk volume (SMD = 0.94, 95% CI = 0.59 to 1.29), reduction of engorgement level (OR= 18, 95% CI = 8.34 to 38.82) demonstrated that Traditional Chinese Medicine therapies can effectively improve lactation and breast fullness, thereby helping patients with breast milk deficiency. The most common acupuncture points used to treat agalactia were classified as the Stomach Meridian, Small Intestine Meridian, and Conception Vessel, with the common acupoints CV17: Danzhong, ST18: Rugen, SI1: Shaoze, ST36: Zusanli, and ST16: Yingchuang. Conclusion: Adjuvant Traditional Chinese Medicine therapy can improve lactation and breast engorgement, thereby increasing the willingness to breastfeed. Clinical Finding: 1. The best time for Traditional Chinese Medicine acupoint intervention for breast deficiency treatment is within 24 h 2. The most effective acupuncture points for improving milk deficiency and bloating pain are ST18: Rugen, ST16: Yingchuang, ST36: Zusanli, SI1: Shaoze, CV17: Danzhong. 3. Traditional Chinese Medicine is non-invasive and effective techniques such as scraping, cupping, acupressure and ear peas. 4. Traditional Chinese Medicine can be combined with other different acupuncture points according to the different constitutions of post-partum women. Breast acupressure, ear acupuncture, scrapping, cupping, and moxibustion are noninvasive treatments that can effectively help patients during lactation, and their clinical practice should be considered and widely promoted.

Varying the ratio of Lys: Met through enhancing methionine supplementation improved milk secretion ability through regulating the mRNA expression in bovine mammary epithelial cells under heat stress.

Introduction: The ratio of lysine (Lys) to methionine (Met) with 3.0: 1 is confirmed as the "ideal" profile for milk protein synthesis, but whether this ratio is suitable for milk protein synthesis under HS needs to be further studied. Methods: To evaluate the molecular mechanism by which HS and Lys to Met ratios affect mammary cell functional capacity, an immortalized bovine mammary epithelial cell line (MAC-T) is incubated with 5 doses of Met while maintaining a constant concentration of Lys. The MAC-T cells was treated for 6 h as follow: Lys: Met 3.0: 1 (control 37°C and IPAA 42°C) or treatments under HS (42°C) with different ratios of Lys: Met at 2.0: 1 (LM20), 2.5: 1 (LM25), 3.5: 1 (LM35) and 4.0: 1 (LM40). RNA sequencing was used to assess transcriptome-wide alterations in mRNA abundance. Results: The significant difference between control and other groups was observed base on PCA analysis. A total of 2048 differentially expressed genes (DEGs) were identified in the IPAA group relative to the control group. Similarly, 226, 306, 148, 157 DEGs were detected in the LM20, LM25, LM35 and LM40 groups, respectively, relative to the IPAA group. The relative mRNA abundance of HSPA1A was upregulated and anti-apoptotic genes (BCL2L1 and BCL2) was down-regulated in the IPAA group, compared to the control group (p < 0.05). Compared with the IPAA group, the relative mRNA abundance of anti-apoptotic genes and casein genes (CSN1S2 and CSN2) was up-regulated in the LM25 group (p < 0.05). The DEGs between LM25 and IPAA groups were associated with the negative regulation of transcription RNA polymerase II promoter in response to stress (GO: 0051085, DEGs of BAG3, DNAJB1, HSPA1A) as well as the mTOR signaling pathway (ko04150, DEGs of ATP6V1C2, WNT11, WNT3A, and WNT9A). Several DEGs involved in amino acids metabolism (AFMID, HYKK, NOS3, RIMKLB) and glycolysis/gluconeogenesis (AFMID and MGAT5B) were up-regulated while DEGs involved in lipolysis and beta-oxidation catabolic processes (ALOX12 and ALOX12B) were down-regulated. Conclusion: These results suggested that increasing Met supply (Lys: Met at 2.5: 1) may help mammary gland cells resist HS-induced cell damage, while possibly maintaining lactation capacity through regulation of gene expression.

ABCG2 Transports the Flukicide Nitroxynil and Affects Its Biodistribution and Secretion into Milk.

The ABCG2 transporter plays a key role in pharmacological and toxicological processes, affecting bioavailability, tissue accumulation and milk secretion of its substrates. This protein is expressed in several biological barriers acting as a protective mechanism against xenobiotic exposure by pumping out a broad range of compounds. However, its induced expression during lactation in alveolar cells of mammary gland represents a relevant route for active transport of unwanted chemicals into milk. This work aimed to characterize the involvement of ABCG2 in systemic exposure and milk secretion of the flukicide nitroxynil. Using MDCK-II cells overexpressing the transporter, we showed that nitroxynil is an in vitro substrate of different species variants of ABCG2. Moreover, using wild-type and Abcg2-/- mice, we showed that murine Abcg2 clearly affects plasma levels of nitroxynil. We also reported differences in nitroxynil accumulation in several tissues, with almost 2-fold higher concentration in kidney, small intestine and testis of Abcg2-/- mice. Finally, we proved that nitroxynil secretion into milk was also affected by Abcg2, with a 1.9-fold higher milk concentration in wild-type compared with Abcg2-/- mice. We conclude that ABCG2 significantly impacts nitroxynil biodistribution by regulating its passage across biological barriers.

Parental factors that impact the ecology of human mammary development, milk secretion, and milk composition-a report from "Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN)" Working Group 1.

The goal of Working Group 1 in the Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN) Project was to outline factors influencing biological processes governing human milk secretion and to evaluate our current knowledge of these processes. Many factors regulate mammary gland development in utero, during puberty, in pregnancy, through secretory activation, and at weaning. These factors include breast anatomy, breast vasculature, diet, and the lactating parent's hormonal milieu including estrogen, progesterone, placental lactogen, cortisol, prolactin, and growth hormone. We examine the effects of time of day and postpartum interval on milk secretion, along with the role and mechanisms of lactating parent-infant interactions on milk secretion and bonding, with particular attention to the actions of oxytocin on the mammary gland and the pleasure systems in the brain. We then consider the potential effects of clinical conditions including infection, pre-eclampsia, preterm birth, cardiovascular health, inflammatory states, mastitis, and particularly, gestational diabetes and obesity. Although we know a great deal about the transporter systems by which zinc and calcium pass from the blood stream into milk, the interactions and cellular localization of transporters that carry substrates such as glucose, amino acids, copper, and the many other trace metals present in human milk across plasma and intracellular membranes require more research. We pose the question of how cultured mammary alveolar cells and animal models can help answer lingering questions about the mechanisms and regulation of human milk secretion. We raise questions about the role of the lactating parent and the infant microbiome and the immune system during breast development, secretion of immune molecules into milk, and protection of the breast from pathogens. Finally, we consider the effect of medications, recreational and illicit drugs, pesticides, and endocrine-disrupting chemicals on milk secretion and composition, emphasizing that this area needs much more research attention.

Comparative proteomic analysis of human milk fat globules and paired membranes and mouse milk fat globules identifies core cellular systems contributing to mammary lipid trafficking and secretion.

Introduction: Human milk delivers critical nutritional and immunological support to human infants. Milk fat globules (MFGs) and their associated membranes (MFGMs) contain the majority of milk lipids and many bioactive components that contribute to neonatal development and health, yet their compositions have not been fully defined, and the mechanisms responsible for formation of these structures remain incompletely understood. Methods: In this study, we used untargeted mass spectrometry to quantitatively profile the protein compositions of freshly obtained MFGs and their paired, physically separated MFGM fractions from 13 human milk samples. We also quantitatively profiled the MFG protein compositions of 9 pooled milk samples from 18 lactating mouse dams. Results: We identified 2,453 proteins and 2,795 proteins in the majority of human MFG and MFGM samples, respectively, and 1,577 proteins in mouse MFGs. Using paired analyses of protein abundance in MFGMs compared to MFGs (MFGM-MFG; 1% FDR), we identified 699 proteins that were more highly abundant in MFGMs (MFGM-enriched), and 201 proteins that were less abundant in MFGMs (cytoplasmic). MFGM-enriched proteins comprised membrane systems (apical plasma membrane and multiple vesicular membranes) hypothesized to be responsible for lipid and protein secretion and components of membrane transport and signaling systems. Cytoplasmic proteins included ribosomal and proteasomal systems. Comparing abundance between human and mouse MFGs, we found a positive correlation (R 2 = 0.44, p < 0.0001) in the relative abundances of 1,279 proteins that were found in common across species. Discussion: Comparative pathway enrichment analyses between human and mouse samples reveal similarities in membrane trafficking and signaling pathways involved in milk fat secretion and identify potentially novel immunological components of MFGs. Our results advance knowledge of the composition and relative quantities of proteins in human and mouse MFGs in greater detail, provide a quantitative profile of specifically enriched human MFGM proteins, and identify core cellular systems involved in milk lipid secretion.

Organelles coordinate milk production and secretion during lactation: Insights into mammary pathologies.

The mammary gland undergoes a spectacular series of changes during its development and maintains a remarkable capacity to remodel and regenerate during progression through the lactation cycle. This flexibility of the mammary gland requires coordination of multiple processes including cell proliferation, differentiation, regeneration, stress response, immune activity, and metabolic changes under the control of diverse cellular and hormonal signaling pathways. The lactating mammary epithelium orchestrates synthesis and apical secretion of macromolecules including milk lipids, milk proteins, and lactose as well as other minor nutrients that constitute milk. Knowledge about the subcellular compartmentalization of these metabolic and signaling events, as they relate to milk production and secretion during lactation, is expanding. Here we review how major organelles (endoplasmic reticulum, Golgi apparatus, mitochondrion, lysosome, and exosome) within mammary epithelial cells collaborate to initiate, mediate, and maintain lactation, and how study of these organelles provides insight into options to maintain mammary/breast health.

Association of Milk Secretion Volume with Nipple Pain: A Prospective Hypothesis Verification Study.

Background: Many mothers stop breastfeeding due to nipple pain, which is experienced when the baby sucks the mother's nipples during breastfeeding. Objective: To verify how nipple pain during breastfeeding is associated with nipple perfusion and volume of milk secretion. Study Design: Prospective hypothesis verification study. Methods: Fifty-nine lactating women who delivered at term were enrolled. The CS Probe S and laser Doppler ALF21 were used to measure perfusion, and PowerLab 2/26 and LabChart 8 were used to analyze perfusion. The difference in the infant's weight (g) before and after breastfeeding was used to measure milk secretion. Results: The participants' mean age (± standard deviation) was 30.88 ± 3.77 years. Although 80-90% of participants had proper breastfeeding posture and infant attachment, 34 (57.6%) and 30 (42.4%) mothers experienced nipple pain on postpartum days 1 and 4, respectively. For postpartum days 1 and 4, the group with nipple pain exhibited significantly less nipple perfusion than the group without pain. Milk secretion was lower in the group with nipple pain on postpartum day 4 than in the group without pain, although this was not statistically significant. The reduction in nipple perfusion did not differ significantly between the high (75%) and low secretion groups (25%) and between the nipple trauma and nontrauma groups. However, the low secretion group and nipple trauma group had larger reductions in nipple perfusion. Conclusion: Assessing the amount of milk secretion can provide a new perspective on preventive care for nipple pain and trauma.

Long-term chromium picolinate supplementation improves colostrum profile of Santa Ines ewe.

Chromium (Cr) is a micromineral that is involved in the metabolism of carbohydrates, lipids, ammonia, and nucleic acids; thus, its supplementation can influence the nutritional status of ruminants, and consequently, colostrum profile, since this secretion depends on products secreted by the mammary gland and elements of the maternal bloodstream. The present study investigated the influence of supplementation with Cr bound to organic molecule on the nutritional, immune, and antioxidant quality of ewe colostrum. Thirty-two multiparous Santa Ines ewes (55.3 ± 8.00 kg body weight) were randomly assigned into four groups: T1 (0.0 mg of chromium picolinate (CrPic) supplementation per ewe, n = 8), T2 (0.15 mg of CrPic per ewe, n = 9), T3 (0.30 mg of CrPic per ewe, n = 7), and T4 (0.45 mg of CrPic per ewe, n = 8). Supplementation was supplied during the breeding season, pregnancy, and lactation. Shortly after calving, the first milking colostrum was collected to determine its chemical composition, activity of lysozyme, lactoperoxidase, ceruloplasmin, catalase, glutathione peroxidase, and oxygen radical absorbance capacity. The results show that lactoperoxidase activity decreased with CrPic supplementation (P < 0.01), revealing that this micromineral reduces an important component of defense mechanism in the body. Therefore, the results of this work show that supplementation with chromium picolinate influences colostrum quality.

Effects of Domperidone in Increasing Milk Production in Mothers with Insufficient Lactation for Infants in the Neonatal Intensive Care Unit.

Breast milk is the optimum for all infants, but hospitalization in the neonatal intensive care unit can cause separation of mothers and infants, which often interferes with milk secretion. Some reports show that domperidone is effective in promoting milk secretion. However, the Food and Drug Administration in the United States cautioned to not use domperidone for increasing milk volume because domperidone carries some risk of cardiac events, including QT prolongation, cardiac arrest, and sudden death. In contrast, it is used in Canada, Australia, and the United Kingdom with safety. The pharmacodynamics and pharmacokinetics of drugs may vary by race or ethnic origin, and it is not known whether domperidone is effective or safe for Japanese. In this study we report the effects of domperidone for Japanese mothers with insufficient lactation. Ten mothers were enrolled in a pilot study. After confirming that there were no abnormal findings on the electrocardiogram, the mothers were administered domperidone. Seven of 10 who took domperidone increased their milking volume. Prolactin was increased in 9 of 10 mothers. Adverse events were observed in two mothers, one headache and one abdominal pain; all symptoms were mild and improved promptly; and there were no adverse cardiac events. These results are consistent with reports from other countries. Domperidone may tentatively be considered effective for increasing milk secretion in Japanese mothers as in other populations. Our preliminary study of 10 cases indicates the need for further studies with larger sample sizes to assess the efficacy and safety of domperidone.

Effect of bovine ABCG2 polymorphism Y581S SNP on secretion into milk of enterolactone, riboflavin and uric acid.

The ATP-binding cassette transporter G2/breast cancer resistance protein (ABCG2/BCRP) is an efflux protein involved in the bioavailability and milk secretion of endogenous and exogenous compounds, actively affecting milk composition. A limited number of physiological substrates have been identified. However, no studies have reported the specific effect of this polymorphism on the secretion into milk of compounds implicated in milk quality such as vitamins or endogenous compounds. The bovine ABCG2 Y581S polymorphism is described as a gain-of-function polymorphism that increases milk secretion and decreases plasma levels of its substrates. This work aims to study the impact of Y581S polymorphism on plasma disposition and milk secretion of compounds such as riboflavin (vitamin B2), enterolactone, a microbiota-derived metabolite from the dietary lignan secoisolariciresinol and uric acid. In vitro transport of these compounds was assessed in MDCK-II cells overexpressing the bovine ABCG2 (WT-bABCG2) and its Y581S variant (Y581S-bABCG2). Plasma and milk levels were obtained from Y/Y homozygous and Y/S heterozygous cows. The results show that riboflavin was more efficiently transported in vitro by the Y581S variant, although no differences were noted in vivo. Both uric acid and enterolactone were substrates in vitro of the bovine ABCG2 variants and were actively secreted into milk with a two-fold increase in the milk/plasma ratio for Y/S with respect to Y/Y cows. The in vitro ABCG2-mediated transport of the drug mitoxantrone, as a model substrate, was inhibited by enterolactone in both variants, suggesting the possible in vivo use of this enterolignan to reduce ABCG2-mediated milk drug transfer in cows. The Y581S variant was inhibited to a lesser extent probably due to its higher transport capacity. All these findings point to a significant role of the ABCG2 Y581S polymorphism in the milk disposition of enterolactone and the endogenous molecules riboflavin and uric acid, which could affect both milk quality and functionality.