Animal Models for In Vivo Lactation Studies: Anatomy, Physiology and Milk Compositions in the Most Used Non-Clinical Species: A Contribution from the ConcePTION Project

Abstract

The present review aims to summarize the main features of mammary gland anatomy, and the physiology of lactation and colostrum/milk in the most commonly used animal species for regulatory toxicity. The final goal is the selection of a preferred animal species to be enrolled in studies investigating the potential transfer of drugs and exogenous molecules through milk, within the Innovative Medicines Initiative (IMI) funded project ConcePTION. Reference data regarding humans were also collected and analyzed in order to highlight critical similarities and differences with the studied species. Additional practical considerations were also taken into account, such as ethical consideration regarding the chosen species which affects the group size, financial implications and technical feasibility of lactation trials (e.g., ease of sampling, volume of sampling, husbandry requirements and scientific recognition). In conclusion, the present analysis of the literature confirms the complexity of the decisional process behind the choice of an animal model for in vivo trials. For some of the evaluated species, data were either poor or missing, highlighting the necessity to generate more physiological background studies for species that are routinely used in laboratory settings. Overall, when taking into consideration ethical factors, feasible group size, milk volume and ease of milk collection, and physiological similarities with humans, minipigs seem to represent the most appropriate choice.

A Comparative Review of the Cell Biology, Biochemistry, and Genetics of Lactose Synthesis

“…In a similar way, lactose in bovine milk (44 to 56 mg/ ml) provides approximately 30% of the calories required by newborn calves [1,6]. Milk produced by rodents has a lower content of lactose, ranging from 24 to 28 mg/ml in mice, and 11 to 41 mg/ml in rats [7]. Aquatic Pinnipeds, like the otariid species, produce milk devoid of lactose that enables them to avoid involution induced by milk stasis [8], while others like the phocids, vary their production of lactose [9][10][11][12].…”

“…Data for fat and lactose content in the milk of the human, cow, goat, mouse, rat, dog, minipig are presented as the mean of published ranges. Tammar wallaby: Fat (40 mg/ ml) was measured at 26 weeks of lactation and lactose (39 mg/ml) between 13 and 34 weeks of lactation [25,140]; Florida manatee: Fat (190 mg/ml) and lactose (not detected) at 30 weeks and at 2 years of lactation [9]; Human: fat (28-44 mg/ml) and lactose (61-79 mg/ml) between 40 and 180 days postpartum [5]; Lemur: fat (18 mg/ml) and lactose (81 mg/ml) at 72 days postpartum [5]; Cow: fat (33-54 mg/ ml) and lactose (44-56 mg/ml) during mid-lactation [6]; Horse: fat (12.1 mg/ml, range 50-200) and lactose (63.7 mg/ml, range 58-70) during mid-lactation [141]; Goat: fat (40 mg/ml) and lactose (32-50 mg/ml) during mid-lactation [6]; Mouse: fat (190-220 mg/ ml) and lactose (24-28 mg/ml) in mature milk samples [7]; Rat: fat (140-159 mg/ml) and lactose (11-41 mg/ml) in mature milk samples [7]; Rabbit: fat (152 mg/ml) and lactose (18 mg/ml) in mature milk samples [7]; Dog: fat (24-134 mg/ml) and lactose (29-40 mg/ml) in mature milk samples [7]; (mini)Pig: fat (77-100 mg/ml) and lactose (43-56 mg/ml) in mature milk samples [7]; Subantarctic fur seal: fat (510 mg/ml) and lactose (not detected) in mid-lactation samples [12]; Polar bear: fat (278 mg/ml) and carbohydrate (26 mg/ml) in yearlings mid-lactation sample [142] lactose is considerably higher than that found in human or bovine milk. For example, the ratio of oligosaccharides to free lactose ranges from 7:1 for the striped skunk and 5:1 for mink, to 31:1 for polar bears and 52:1 for the Japanese bear [18,20].…”

Modulation of Milk and Lipid Synthesis and Secretion in a3-Dimensional Mouse Mammary Epithelial Cell Culture Model: Effects of Palmitate and Orlistat

“…The findings of the palmitate-mediated increased MEC synthesis and production of “milk” triglycerides and its prevention by a lipase inhibitor provide evidence that the 3-D mouse MEC primary culture can be used to modulate milk production/composition in vitro. Nonetheless, due to differences in milk production/composition in mice and humans [ 69 , 70 , 71 ], it is of utmost importance to establish similar 3-D human MEC cultures to investigate the mechanisms of human milk production and the contribution of serum substrates and MEC enzymatic pathways to milk FAs, protein, as well as lactose and oligosaccharides. An understanding of the mechanisms of mammary cell substrate uptake, milk synthesis, and milk secretion which result in the marked variability of human milk composition will lead to the development of mechanism-based therapies that may include pharmacologic interventions, to optimize human milk composition.…”

Maternal amoxicillin affects piglets colon microbiota: microbial ecology and metabolomics in a gut model

“…In the last decades, the swine has been acknowledged as one of the most important preclinical species for a wide variety of physiological patterns. Indeed, the swine species show close similarities with humans, and the employment of pigs in research trials seems to be more widely accepted by society in terms of ethical values (Ventrella et al 2021 ).…”