Of mammals and milk: how maternal stress affects nursing offspring

1. A large body of research shows that maternal stress during an offspring’s early life can impact its phenotype in both the short and long term. In the Vertebrata, most research has been focused on maternal stress during the prenatal period. However, the postnatal period is particularly important in mammals because maternal milk provides a conduit by which maternal hormones secreted in response to stressors (glucocorticoids, GCs) can reach offspring. Moreover, lactation outlasts gestation in many species.
2. Though GCs were first detected in milk over 40 years ago, few studies have explored how they affect nursing offspring, and no reviews have been written on how maternal stress affects nursing offspring in the natural world.
3. We discuss the evolution of milk and highlight its importance in each of the three mammalian lineages: monotremes (subclass Monotremata), marsupials (infraclass Marsupialia), and eutherians (infraclass Placentalia). Most research on the effects of milk GCs on offspring has been focused on eutherians, but monotremes and marsupials rely on their mothers’ milk for a proportionally longer period of time, and so research on these taxa may yield more insight.
4. We show that GCs are important for milk production, both during an individual nursing bout and over the entire lactation period, and review evidence of GCs moving from maternal blood to milk, and eventually to nursing offspring. We examine evidence from rodents and primates of associations between GC levels in lactating females (either blood or milk) and offspring behaviour and growth rates. We discuss ways that maternal stress may impact these offspring phenotypes outside of milk GCs, such as changes to: (1) milk output, (2) other milk constituents (e.g. macronutrients, growth factors, cytokines), and (3) maternal care behaviour.
5. Critical to understanding the fitness impacts of elevated maternal GC levels during lactation is to place this within the context of the natural environment. Species-specific traits and natural histories will help us to understand why such maternal stress produces different offspring phenotypes that equip them to cope with and succeed in the environment they are about to enter.

     

Transgenic milk containing recombinant human lactoferrin modulates the intestinal flora in piglets

Lactoferrin (LF) is a beneficial multifunctional protein in milk. The objective of this study was to determine whether bovine transgenic milk containing recombinant human lactoferrin (rhLF) can modulate intestinal flora in the neonatal pig as an animal model for the human infant. We fed 7-day-old piglets (i) ordinary whole milk (OM), (ii) a 1:1 mixture of OM and rhLF milk (MM), or (iii) rhLF milk (LFM). LFM provided better average daily mass gain than OM (P = 0.007). PCR-denaturing gradient gel electrophoresis and 16S rDNA sequencing analysis revealed that the LFM piglets exhibited more diversity of the intestinal flora than the OM group. Except for the colon in the LFM group, an increasing trend in microbial diversity occurred from the duodenum to the colon. Fecal flora was not different across different ages or different treatment groups, but a cluster analysis showed that the fecal flora of OM- and MM-fed piglets had a higher degree of similarity than that of LFM-fed piglets. Based on culture-based bacterial counts of intestinal content samples, concentrations of Salmonella spp. in the colon and of Escherichia coli throughout the intestine were reduced with LFM (P < 0.01). Concentrations of Bifidobacterium spp. in the ileum and of Lactobacillus spp. throughout the intestine were also increased with LFM (P ≤ 0.01). We suggest that rhLF can modulate the intestinal flora in piglets.     

Deconstructing the function of maternal stimulation in offspring development: Insights from the artificial rearing model in rats

This article is part of a Special Issue on “Parental Care”.Maternal behavior has an important function in stimulating adequate growth and development of the young. Several approaches have been used in primates and rodents to deconstruct and examine the influence of specific components of maternal stimulation on offspring development. These approaches include observational studies of typical mother–infant interactions and studies of the effects of intermittent or complete deprivation of maternal contact. In this review, we focus on one unique approach using rats that enables the complete control of maternal variables by means of rearing rat pups artificially without contact with the mother or litter, while maintaining stable nutrition, temperature and exposure to stressful stimuli. This artificial rearing model permits the removal and controlled replacement of relevant maternal and litter stimuli and has contributed valuable insights regarding the influence of these stimuli on various developmental outcomes. It also enables the analysis of factors implicated in social isolation itself and their long-term influence. We provide an overview of the effects of artificial rearing on behavior, physiology, and neurobiology, including the influence of replacing maternal tactile stimulation and littermate contact on these outcomes. We then discuss the relevance of these effects in terms of the maternal role in regulating different aspects of offspring development and implications for human research. We emphasize that artificial rearing of rats does not lead to a global insult of nervous system development, making this paradigm useful in investigating specific developmental effects associated with maternal stimulation.     

Effect of maternal obesity on diabetes development in adult rat offspring

This study aimed to evaluate whether maternal obesity leads to the onset of diabetes in adult Wistar rats offspring. MSG solution neonatally administration induced obesity in rats (F(1)MSG group, n=30); and saline solution was also administrated to control rats (F(1)CON group, n=13). In 3rd month of age, both control and MSG groups were mated for offspring (generation F(2)), named as F(2)CON, n=28 and F(2)MSG groups, n=15; and so both generations were studied until 7th month of life. Lee Index was measured for experimental obesity validation from 5th to 7th month. Glycemia was weekly determined during pregnancy and monthly from 3rd to 7th month. In the end of experimental period all rats were submitted to oral glucose tolerance test (OGTT), with estimation of total area under the curve (AUC); and insulin tolerance test (ITT). Rats were then anesthetized and killed. Data were statistically analyzed with significance level of p<0.05. Lee Index has confirmed obesity in all MSG rats. Glycemic levels comparisons between generations showed significant maternal interference in control and MSG groups. OGTT analysis showed higher glycemia in obese rats (F(1)MSG) and their offspring (F(2)MSG) as compared to their respective controls; and MSG groups increased AUC from OGTT. As regards ITT, F(2)MSG showed higher glycemia at 30 and 120 min, suggesting a delay of insulin action decreasing. Although glucose intolerance and insulin resistance clinical conditions represent as a factors for type 2 Diabetes mellitus development, this experimental model proposal was not efficient to induce type 2 Diabetes mellitus, but for obesity developing, glucose intolerance and insulin resistance in successive generations of rats.     

A search for transmission ratio distortions in offspring from crosses between inbred mice

Equal transmission of the two alleles at a locus from a heterozygote parent to the offspring is rarely violated. Beside the differential embryonic mortality, nondisjunction and gene conversion that are rather irregular forms of transmission-ratio distortion (TRD), there are two major forms of departure from Mendelian segregation. The first, found in females, based on the asymmetric nature of female meiosis, is usually referred to as meiotic drive, and has been well documented in a few cases. The second is segregation distortion found in males. There are several known male-related segregation distortion systems that are caused by different fertilizing capacity of sperm cells carrying alternative alleles at a particular locus. Observation of TRD effects requires a sufficient number of offspring produced by a parental pair. As individuals in a population most likely have different genotypes in TRD affecting loci, the total transmission ratio is close to the expected Mendelian ratio and masks potential TRD effects. Highly inbred strains of laboratory mice provide a very good model for studying this phenomenon, because comparing two mice strains is effectively similar as comparison of two individuals in a population. This study tests both forms of TRD in progeny of F1 hybrids from reciprocal crosses of inbred mice. Three previously unknown instances of TRD in females were observed. Therefore, this study concludes that some genes in females may carry alleles that can cause segregation distortion.     

Both high and low maternal salt intake in pregnancy alter kidney development in the offspring

In humans, low glomerular numbers are related to hypertension, cardiovascular, and renal disease in adult life. The present study was designed 1) to explore whether above- or below-normal dietary salt intake during pregnancy influences nephron number and blood pressure in the offspring and 2) to identify potential mechanisms in kidney development modified by maternal sodium intake. Sprague-Dawley rats were fed low (0.07%)-, intermediate (0.51%)-, or high (3.0%)-sodium diets during pregnancy and lactation. The offspring were weaned at 4 wk and subsequently kept on a 0.51% sodium diet. The kidney structure was assessed at postnatal weeks 1 and 12 and the expression of proteins of interest at term and at week 1. Blood pressure was measured in male offspring by telemetry from postnatal month 2 to postnatal month 9. The numbers of glomeruli at weeks 1 and 12 were significantly lower and, in males, telemetrically measured mean arterial blood pressure after month 5 was higher in offspring of dams on a high- or low- compared with intermediate-sodium diet. A high-salt diet was paralleled by higher concentrations of marinobufagenin in the amniotic fluid and an increase in the expression of both sprouty-1 and glial cell-derived neutrophic factor in the offspring's kidney. The expression of FGF-10 was lower in offspring of dams on a low-sodium diet, and the expression of Pax-2 and FGF-2 was lower in offspring of dams on a high-sodium diet. Both excessively high and excessively low sodium intakes during pregnancy modify protein expression in offspring kidneys and reduce the final number of glomeruli, predisposing the risk of hypertension later in life.     

Mapping quantitative trait Loci interactions from the maternal and offspring genomes

The expression of most developmental or behavioral traits involves complex interactions between quantitative trait loci (QTL) from the maternal and offspring genomes. The maternal-offspring interactions play a pivotal role in shaping the direction and rate of evolution in terms of their substantial contribution to quantitative genetic (co)variation. To study the genetics and evolution of maternal-offspring interactions, a unifying statistical framework that embraces both the direct and indirect genetic effects of maternal and offspring QTL on any complex trait is developed. This model is derived for a simple backcross design within the maximum-likelihood context, implemented with the EM algorithm. Results from extensive simulations suggest that this model can provide reasonable estimation of additive and dominant effects of the QTL at different generations and their interaction effects derived from the maternal and offspring genomes. Although our model is framed to characterize the actions and interactions of maternal and offspring QTL affecting offspring traits, the idea can be readily extended to decipher the genetic machinery of maternal traits, such as maternal care. Our model provides a powerful means for studying the evolutionary significance of indirect genetic effects in any sexually reproductive organisms.     

Effect of dietary selenite on development and intestinal absorption in offspring rats

AimThe present study aims to compare selenium (Se) status in offspring rats born to selenium-deficient and selenium supplemented dams and to analyse Se's influence on intestinal parameters and the intestinal absorption of selenomethionine (Se-Met).Main methodsMale and female Wistar rats (150–200 g) were randomised in: control (C) (0.1 ppm Se), Se-deficient (SD) (0.01 ppm Se) and Se-supplemented (SS) (0.5 ppm Se) groups; and were mated to obtain their offspring. Se levels in serum, urine and faeces in offspring and in mothers' milk were measured by graphite-furnace atomic absorption spectrometry. Duodenal transport studies in offspring were performed using an in vivo perfusion of different Se-Met concentrations (2, 5, 10, 25, 75 and 150 μM).Key findingA Se-deficient diet provoked a decrease in the offspring's body weight and intestinal parameters, while the supplemented diet increased these values. Serum Se levels were similar between Se-deficient and control offspring because the urinary excretion of Se was smaller to compensate for Se homeostasis. Intestinal Se-Met absorption obeys the Michaellis–Menten equation with lower apparent constant (K_m) and maximal velocity (V_max) in the SD group. However, the C and SS groups presented similar K_m and different V_max. The V_max showed greater values in the following order of rank: SS > C > SD groups.SignificanceSelenium intake deficiencies in offspring lead to the development of compensatory mechanisms in order to normalise serum selenium levels. These mechanisms, however, do not permit normal body development; nor do they regulate intestinal parameters and Se-Met transport.     

CXCR4 antagonist AMD3100 modulates claudin expression and intestinal barrier function in experimental colitis

Ulcerative colitis is a gastrointestinal disorder characterized by local inflammation and impaired epithelial barrier. Previous studies demonstrated that CXC chemokine receptor 4 (CXCR4) antagonists could reduce colonic inflammation and mucosal damage in dextran sulfate sodium (DSS)-induced colitis. Whether CXCR4 antagonist has action on intestinal barrier and the possible mechanism, is largely undefined. In the present study, the experimental colitis was induced by administration of 5% DSS for 7 days, and CXCR4 antagonist AMD3100 was administered intraperitoneally once daily during the study period. For in vitro study, HT-29/B6 colonic cells were treated with cytokines or AMD3100 for 24 h until assay. DSS-induced colitis was characterized by morphologic changes in mice. In AMD3100-treated mice, epithelial destruction, inflammatory infiltration, and submucosal edema were markedly reduced, and the disease activity index was also significantly decreased. Increased intestinal permeability in DSS-induced colitis was also significantly reduced by AMD3100. The expressions of colonic claudin-1, claudin-3, claudin-5, claudin-7 and claudin-8 were markedly decreased after DSS administration, whereas colonic claudin-2 expression was significantly decreased. Treatment with AMD3100 prevented all these changes. However, AMD3100 had no influence on claudin-3, claudin-5, claudin-7 and claudin-8 expression in HT-29/B6 cells. Cytokines as TNF-α, IL-6, and IFN-γ increased apoptosis and monolayer permeability, inhibited the wound-healing and the claudin-3, claudin-7 and claudin-8 expression in HT-29/B6 cells. We suggest that AMD3100 acted on colonic claudin expression and intestinal barrier function, at least partly, in a cytokine-dependent pathway.     

发酵乳对脓毒症患者肠黏膜屏障功能的影响

观察发酵乳对脓毒症患者肠黏膜屏障功能及炎症指标的影响。

选取60例确诊为脓毒症的患者, 随机分成对照组和发酵乳组, 每组各30例。对照组给予抗生素及营养支持治疗, 治疗组在常规综合治疗的基础上给予口服发酵乳治疗。在治疗前及治疗1周后分别检测并比较两组患者肠黏膜屏障功能、C-反应蛋白(CRP)、降钙素原(PCT)、肿瘤坏死因子-α(TNF-α)和白细胞介素-6(IL-6)水平变化, 记录患者APACHEⅡ评分。采用SPSS 22.0软件进行数据统计。

治疗前两组患者的肠屏障功能、PCT和IL-6水平差异无统计学意义(P > 0.05)。治疗1周后, 发酵乳组血清内毒素(LPS)、血清二胺氧化酶(DAO)、D-乳酸、CRP、PCT、TNF-α、IL-6水平和APACHEⅡ评分较治疗前均显著降低(P < 0.05), 较对照组治疗后也降低(P < 0.05)。

脓毒症患者在常规综合治疗基础上加用发酵乳可改善肠粘膜屏障功能, 减轻患者全身炎症反应。

     

Age affects the expression of maternal care and subsequent behavioural development of offspring in a precocial bird

Variations of breeding success with age have been studied largely in iteroparous species and particularly in birds: survival of offspring increases with parental age until senescence. Nevertheless, these results are from observations of free-living individuals and therefore, it remains impossible to determine whether these variations result from parental investment or efficiency or both, and whether these variations occur during the prenatal or the postnatal stage or during both. Our study aimed first, to determine whether age had an impact on the expression of maternal breeding care by comparing inexperienced female birds of two different ages, and second, to define how these potential differences impact chicks' growth and behavioural development. We made 22 2-month-old and 22 8-month-old female Japanese quail foster 1-day-old chicks. We observed their maternal behaviour until the chicks were 11 days old and then tested these chicks after separation from their mothers. Several behavioural tests estimated their fearfulness and their sociality. We observed first that a longer induction was required for young females to express maternal behaviour. Subsequently as many young females as elder females expressed maternal behaviour, but young females warmed chicks less, expressed less covering postures and rejected their chicks more. Chicks brooded by elder females presented higher growth rates and more fearfulness and sociality. Our results reveal that maternal investment increased with age independently of maternal experience, suggesting modification of hormone levels implied in maternal behaviour. Isolated effects of maternal experience should now be assessed in females of the same age. In addition, our results show, for first time in birds, that variations in maternal care directly induce important differences in the behavioural development of chicks. Finally, our results confirm that Japanese quail remains a great laboratory model of avian maternal behaviour and that the way we sample maternal behaviour is highly productive.     

Role of maternal smoking and maternal reproductive history in the etiology of hypospadias in the offspring

BACKGROUND: This study was undertaken to evaluate some possible risk factors for hypospadias with special regard to parity, subfertility and maternal smoking. METHODS: With the use of the Swedish health registries, 3,262 infants with a diagnosis of hypospadias were identified among 1,413,811 infants born in 1983-96 with prospectively collected smoking exposure during pregnancy. Odds ratios (OR) and 95% confidence intervals (CI) were calculated after adjustment for various possible confounders. RESULTS: A negative association between hypospadias and maternal smoking was found (OR: 0.83 95% CI: 0.76-0.90), but this association was only observed among mothers of Parity 1 or 4+, and the possibility of the results being due to confounding was suspected. Primiparity (vs. Parity 2) was positively associated with hypospadias (OR: 1.29 95% CI: 1.19-1.40), and so was subfertility (defined here as at least 1 year of attempts to conceive) (OR for subfertility: 1.16 95% CI: 1.01-1.33). The OR for smoking and primiparity, respectively, were of the same magnitude irrespective of whether subfertility was present or not, and no evidence was found that subfertility in the parents of infants with hypospadias seriously confounded the analyses. CONCLUSIONS: No explanation was found for the negative association between maternal smoking and hypospadias or the positive association between primiparity and hypospadias. Possible causal mechanisms are discussed.     

Homocysteine-mediated intestinal epithelial barrier dysfunction in the rat model of irritable bowel syndrome caused by maternal separation

Irritable bowel syndrome （IBS）, a common functional gastrointestinal disorder, is characterized by altered bowel evacuation, bloating, and visceral pain in the absence of ana- tomical or biochemical abnormalities [1]. Up to date, the eti- ologies of these symptoms are still not fully understood. The maternal separation （MS） model, rodent pups separated from the dam （3 h/day） during the neonatal period, has been found to display greater anxiety-like behavior, visceral hypersensitivity, increased fecal output, and higher levels of proinflammatory cytokines in adulthood [2], which may constitute a valuable experimental model to investigate the pathophysiology of IBS and to identify novel pharmaco- logical targets. The rat model of IBS caused by MS was established in this study. All of the investigations conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.     

发酵乳对肝硬化失代偿期患者肠黏膜屏障功能的影响

观察发酵乳在改善肝硬化失代偿期患者肠黏膜屏障功能、肝功能及提高患者生活质量方面的作用。

选择我院78例确诊为肝硬化失代偿期的患者,随机分成对照组和发酵乳组,其中对照组42例,发酵乳组36例。对照组患者给予常规综合治疗,发酵乳组在常规综合治疗的基础上给予口服发酵乳治疗,在治疗前及治疗4周后分别检测并比较两组患者肠黏膜屏障功能、血清白蛋白、血浆氨水平及慢性肝病问卷评分（CLDQ）的变化。

治疗前两组患者肠屏障功能、血清白蛋白、氨水平及CLDQ评分差异无统计学意义（均P＞0.05）。治疗4周后,发酵乳组患者血清内毒素、血清二胺氧化酶、D-乳酸及血浆氨水平较治疗前显著降低,较对照组治疗后亦降低（均P＜0.05）。发酵乳组患者血清白蛋白水平及部分CLDQ评分较治疗前显著升高,较对照组治疗后亦升高（均P＜0.05）。

在常规综合治疗的基础上加用发酵乳可调节肝硬化失代偿期患者肠道菌群,改善肠黏膜屏障功能,从而保护肝脏功能,提高患者生活质量。

     

Zinc tolerance and hyperaccumulation in F1 and F2 offspring from intra and interecotype crosses of Thlaspi caerulescens

The relationship between zinc (Zn) tolerance and hyperaccumulation in Thlaspi caerulescens was investigated from F1 and F2 crosses within and among metallicolous and nonmetallicolous Mediterranean populations. F1 offspring were grown on increasingly Zn-enriched soils to test Zn enrichment effects, and many families of F2 offspring were grown on a Zn-rich soil. Tolerance of F1 offspring depended on stress intensity. Tolerance of interecotype crosses was intermediate between that of the intraecotype crosses. No difference in Zn accumulation appeared among the F1 offspring from the three crosses involving metallicolous parents. Otherwise, none of these offspring exceeded the Zn hyperaccumulation threshold (10,000 mg kg(-1)), unlike the nonmetallicolous ones. The latter also showed the highest mortality. In some F2 families from interecotype crosses, hyperaccumulation values exceeded 15,000 mg kg(-1) in nontolerant offspring, whereas tolerant offspring displayed lower values (c. 10,000 mg kg(-1)). There was no difference between tolerant and nontolerant offspring when they showed low hyperaccumulation. Therefore, the relationship between tolerance and hyperaccumulation in F1 and F2 crosses depended on the hyperaccumulation level of plants.     

Specific overexpression of IL-7 in the intestinal mucosa: the role in intestinal intraepithelial lymphocyte development

IL-7 plays a crucial role in controlling T cell development and homeostasis. Since IL-7 may be derived from extraintestinal sources, and exogenous IL-7 broadly affects lymphoid populations, the actions of epithelial cell (EC)-derived IL-7 are not fully understood. The effect of intestinal specific expression of IL-7 on intestinal mucosal lymphocytes was investigated by using an IL-7 transgenic mouse model. We generated an intestinal EC-specific overexpressing IL-7 transgenic mouse model (IL-7(vill)) and compared their phenotype and function to wild-type C57BL/6J mice. EC-derived IL-7 overexpression was found to be exclusively in the small and large intestine. Numbers and subtypes of mucosal lymphocytes, including intraepithelial lymphocytes (IEL) and lamina propria lymphocytes (LPL), significantly changed in IL-7(vill) mice. From a functional standpoint, IEL proliferation also significantly increased in IL-7(vill) mice. IEL cytokine expression significantly changed in both T cell receptor (TCR)-alphabeta(+) and TCR-gammadelta(+) IEL subpopulations, including a significant increase in IFN-gamma and TNF-alpha as well as an increase in keratinocyte growth factor expression. EC expression of CD103 (integrin alpha(E)beta(7)), the ligand of E-cadherin, markedly upregulated and may account for a mechanism of the massive expansion of IEL in transgenic mice. Systemic lymphoid populations did not change in transgenic mice. IL-7 overexpression by intestinal EC significantly affected IEL phenotype and function. These results offer insight into the role of IL-7 in IEL development and suggest a critical role of EC-derived expression of IL-7 in the phenotype and function of IEL.