Exposure to Deoxynivalenol During Pregnancy and Lactation Enhances Food Allergy and Reduces Vaccine Responsiveness in the Offspring in a Mouse Model

Deoxynivalenol (DON), a highly prevalent contaminant of grain-based products, is known to induce reproductive- and immunotoxicities. Considering the importance of immune development in early life, the present study investigated the effects of perinatal DON exposure on allergy development and vaccine responsiveness in the offspring. Pregnant mice received control or DON-contaminated diets (12.5 mg/kg diet) during pregnancy and lactation. After weaning, female offspring were sensitized to ovalbumin (OVA) by oral administration of OVA with cholera toxin (CT). Male offspring were injected with Influvac vaccine. OVA-specific acute allergic skin response (ASR) in females and vaccine-specific delayed-type hypersensitivity (DTH) in males were measured upon intradermal antigen challenge. Immune cell populations in spleen and antigen-specific plasma immunoglobulins were analyzed. In female CT+OVA-sensitized offspring of DON-exposed mothers ASR and OVA-specific plasma immunoglobulins were significantly higher, compared to the female offspring of control mothers. In vaccinated male offspring of DON-exposed mothers DTH and vaccine-specific antibody levels were significantly lower, compared to the male offspring of control mothers. In both models a significant reduction in regulatory T cells, Tbet+ Th1 cells and Th1-related cytokine production of the offspring of DON-exposed mothers was observed. In conclusion, early life dietary exposure to DON can adversely influence immune development in the offspring. Consequently, the immune system of the offspring may be skewed towards an imbalanced state, resulting in an increased allergic immune response to food allergens and a decreased immune response to vaccination against influenza virus in these models.

Download Full-text

Abstract 008: Early Life Stress Induces Renal Pro-inflammatory Immune Responses

Hypertension ◽

10.1161/hyp.66.suppl_1.008 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Carmen De Miguel ◽

Dao H Ho ◽

Analia S Loria ◽

Ijeoma Obi ◽

Jennifer S Pollock

Keyword(s):

Immune Response ◽

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Immune Cell ◽

Early Life Stress ◽

Adult Rats ◽

Activation Markers ◽

Ifn Gamma ◽

Inflammatory Status

We previously reported that maternal separation (MatSep), an animal model of early life stress, sensitizes rats to pro-hypertensive stimuli in adulthood. We hypothesized that MatSep induces a renal pro-inflammatory immune response. Immune cell populations and expression of cytokines were assessed by magnetic bead isolation, FACS analysis, ELISA and RT-PCR in adult male MatSep and normally-reared littermate control rats. Circulating and renal mononuclear or T cell numbers were similar between control and MatSep rats (n=4-11/group, p>0.05). Both groups presented similar percentages of circulating macrophages and T H , T C , and T reg cells (n=4, p>0.05). However, the percentage of circulating B cells was significantly decreased in MatSep rats (23.7±1.2% vs. 20.1±0.7%; n=4, p<0.05). Pro-inflammatory cytokine IL-1Beta was significantly elevated in kidneys from MatSep rats (4.4±0.5 vs. 7.9±1.0 pg/mg prot; n=7-8/group; p<0.05). However, IFN-gamma, IL-6, and IL-4 were not different between control and MatSep rats. To further assess the immune system in MatSep and control rats, we acutely challenged adult rats with lipopolysaccharide (LPS; 2 mg/kg; i.v., 14 h). LPS significantly elevated renal expression of pro-inflammatory chemokine receptors (CCR3, CCR4, CXCR4), cytokines (IFN-gamma, CCL3, CCL4, IL-16), and activation markers (CD40, CD40lg) in MatSep rats (4 to 6 fold increase; n=5/group, p<0.05), suggesting that MatSep induces an exaggerated pro-inflammatory renal immune response to LPS. In conclusion, early life stress induces a renal pro-inflammatory status in adulthood that leads to sensitization to further immune challenges. Funded by P01 HL 69999 to JSP, NIH T32 DK007545 to CDM, F32 HL 116145 to DHH and K99/R00 HL 111354 to ASL.

Download Full-text

Programming effects of maternal and gestational obesity on offspring metabolism and metabolic inflammation

Scientific Reports ◽

10.1038/s41598-019-52583-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 10

Author(s):

E. Chang ◽

H. Hafner ◽

M. Varghese ◽

C. Griffin ◽

J. Clemente ◽

...

Keyword(s):

Body Composition ◽

Adipose Tissue ◽

Maternal Obesity ◽

Immune Cell ◽

Female Offspring ◽

Normal Diet ◽

Male Offspring ◽

Reproductive Age ◽

Metabolic Inflammation ◽

Significant Difference

Abstract With the increasing prevalence of obesity in women of reproductive age there is a need to understand the ramifications of this on offspring. The purpose of this study is to investigate the programming effects of maternal obesity during preconception and the preconception/gestational period on adiposity and adipose tissue inflammation in offspring using an animal model. Adult female C57Bl/6J mice were assigned either normal diet, high fat diet (HFD) prior to pregnancy, or HFD prior to and through pregnancy. Some offspring were maintained on normal diet while others started HFD later in life. Offspring were assessed for body composition and metabolic responses. Lipid storing tissues were evaluated for expansion and inflammation. Male offspring from the preconception group had the greatest weight gain, most subcutaneous adipose tissue, and largest liver mass when introduced to postnatal HFD. Male offspring of the preconception/gestation group had worsened glucose tolerance and an increase in resident (CD11c−) adipose tissue macrophages (ATMs) when exposed to postnatal HFD. Female offspring had no significant difference in any parameter between the diet treatment groups. In conclusion, this study demonstrates that prenatal and pregnancy windows have independent programming effects on offspring. Preconception exposure affects body composition and adiposity while gestation exposure affects metabolism and tissue immune cell phenotypes.

Download Full-text

Maternal vitamin D deficiency increases the risk of obesity in male mice offspring by affecting the immune response

10.1101/2020.03.23.004721 ◽

2020 ◽

Author(s):

Pei Li ◽

Ping Li ◽

Yuanlin Liu ◽

Weijiang Liu ◽

Lanlan Zha ◽

...

Keyword(s):

Immune Response ◽

Immune Cells ◽

Immune Cell ◽

Male Offspring ◽

Inflammatory Factors ◽

Cell Populations ◽

Male Mice ◽

Gene Expressions ◽

M1 Macrophage ◽

Obese Male

AbstractRecently, many epidemiological and animal studies have indicated that obesity have their origin in the early stages of life including the inappropriate balance of some nutrients, the objective of this study is to determine the risk of obesity in male mice offspring as a consequence of maternal VD deficiency-mediated disordering of the immune response. Four-week-old C57BL/6J female mice were fed VD-deficient or normal reproductive diets during pregnancy and lactation. Their male offspring were weighted and euthanized after being fed control and high-fat diets (HFD) for 16 weeks starting at the weaning. The serum was collected for biochemical analyses. Epididymal (eWAT) and inguinal (iWAT) white adipose tissues were excised for histological examination, immunohistochemistry, gene expressions of inflammatory factors, and for determining the proportions of immune cells by flow cytometry. Insufficient maternal VD intake exacerbated the development of obesity both in non-obese and obese male offspring as evidenced by larger adipose cells and abnormal glucose and lipid metabolisms. Also, the expression of proinflammatory cytokine genes was increased and that of anti-inflammatory cytokines was decreased in maternal VD-deficient groups in the eWAT and/or iWAT. This was accompanied by higher levels of TNF-α or/and INF-β, and lower levels of IL-4 and IL-10. Insufficient maternal VD intake was also observed to induce a shift in the profiles of immune cells in the eWAT and/or iWAT, resulting in increased percentages of M1 macrophage, ATDCs, and CD4+ and CD8+ T cells, but caused a significant decrease in the percentage of M2 macrophages, both in non-obese and obese male offspring. All these changes in the immune cell profile were more obvious in the eWAT than in the iWAT. These results indicated that insufficient maternal VD intake promoted the development of obesity in male offspring by modulating the immune cell populations and causing a polarization in the adipose depots.ImportanceEvidence in this study has indicated that insufficient maternal VD intake promotes the development of obesity in the male offspring by modulating the recruitment of immune cell populations and their polarization as well as the expression and secretion of proinflammatory adipokines in the adipose depots in a weight-independent manner, which is more obvious in eWAT than that in the iWAT.

Download Full-text

Environmental Pollution as a Risk Factor in Testicular Tumour Development: Focus on the Interaction between Bisphenol A and the Associated Immune Response

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16214113 ◽

2019 ◽

Vol 16 (21) ◽

pp. 4113 ◽

Cited By ~ 1

Author(s):

Karen Elizabeth Nava-Castro ◽

Ricardo Ramírez-Nieto ◽

Lucía Angélica Méndez-García ◽

Manuel Iván Girón-Pérez ◽

Mariana Segovia-Mendoza ◽

...

Keyword(s):

Immune Response ◽

Bisphenol A ◽

Tumour Growth ◽

Immune Cell ◽

Breast Cancer Incidence ◽

Pregnant Female ◽

Male Offspring ◽

Testicular Tumour ◽

Female Mice ◽

Tnf Α

Bisphenol A (BPA) is an endocrine disruptor to which animals and humans are highly exposed. Many reports have established a relationship between BPA exposure and breast cancer incidence, especially during critical periods of development. However, its effects on the immune response in testicular tumour growth have not yet been described. Thus, we wanted to analyse the effect of perinatal BPA exposure in pregnant female mice and the immune response modulation and tumour growth in an intratesticular cancer model in offspring male mice. Pregnant female mice were exposed to a dose of 250 mg/kg/day/body weight of BPA in their drinking water. In adulthood, male offspring underwent intrascrotal inoculation with 4T1 cancer cells. On day 21 after inoculation, mice were euthanised, and serum was obtained to measure BPA levels using HPLC coupled to mass spectrometry. The percentages of immune cell populations in peripheral lymph nodes (PLN), the spleen and tumours were evaluated by flow cytometry. In addition, the tumour expression of IL-10, TNF-α and TGF-β was analysed by RT-PCR. Of note, we found detectable circulating levels of BPA in the offspring of mothers exposed to it while pregnant. Remarkably, BPA treatment promoted tumour growth by about 75% compared to mice coming from female mice that did not receive the compound. Perinatal exposure to BPA modulated the percentages of different immune cells in the spleen and PLN. In addition, the expression of inflammatory-related cytokines (IL-10 and TNF-α) in the tumours was significantly enhanced compared to control and vehicle groups. In conclusion, the perinatal BPA administration in pregnant female mice modulated different cellular and molecular immune components that resulted in outstanding testicular tumour size in male offspring.

Download Full-text

Early life stress induces immune priming in kidneys of adult male rats

AJP Renal Physiology ◽

10.1152/ajprenal.00590.2016 ◽

2018 ◽

Vol 314 (3) ◽

pp. F343-F355 ◽

Cited By ~ 5

Author(s):

Carmen De Miguel ◽

Ijeoma E. Obi ◽

Dao H. Ho ◽

Analia S. Loria ◽

Jennifer S. Pollock

Keyword(s):

Gene Expression ◽

Immune Response ◽

Life Stress ◽

Early Life ◽

Low Dose ◽

Immune Cell ◽

Early Life Stress ◽

Male Rats ◽

Activation Markers ◽

Gene Expression Response

Early life stress (ELS) in humans is associated with elevated proinflammatory markers. We hypothesized that ELS induces activation of the immune response in a rat model of ELS, maternal separation (MatSep), in adulthood. MatSep involves separating pups from the dam from postnatal day 2 to postnatal day 14 for 3 h/day. Control rats are nonseparated littermates. We determined circulating and renal immune cell numbers, renal immune cell activation markers, renal cytokine levels, and the renal inflammatory gene expression response to low-dose lipopolysaccharide (LPS) in male MatSep and control rats. We observed that MatSep did not change the percentage of gated events for circulating CD3+, CD4+, CD8+, and CD4+/Foxp3+ cells or absolute numbers of mononuclear and T cells in the circulation and kidneys; however, MatSep led to an increase in activation of renal neutrophils as well as CD44+ cells. Renal toll-like receptor 4 (TLR4) and interleukin 1 beta (IL-1β) was significantly increased in MatSep rats, specifically in the outer and inner medulla and distal nephron, respectively. Evaluation of renal inflammatory genes showed that in response to a low-dose LPS challenge (2 mg/kg iv) a total of 20 genes were significantly altered in kidneys from MatSep rats (17 genes were upregulated and 3 were downregulated), as opposed to no significant differences in gene expression in control vs. control + LPS groups. Taken together, these findings indicate that MatSep induces priming of the immune response in the kidney.

Download Full-text

Liver choline metabolism and gene expression in choline-deficient mice offspring differ with gender

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbaa047 ◽

2021 ◽

Vol 85 (2) ◽

pp. 447-451

Author(s):

Yukino Miyachi ◽

Kei Akiyama ◽

Yoshiko Tsukuda ◽

Thanutchaporn Kumrungsee ◽

Noriyuki Yanaka

Keyword(s):

Gene Expression ◽

Female Offspring ◽

Male Offspring ◽

Mrna Levels ◽

Choline Deficiency ◽

Deficient Diet ◽

Choline Metabolism ◽

Pregnancy And Lactation ◽

Gender Specific ◽

Deficient Mice

ABSTRACT Choline is an important nutrient during pregnancy and lactation. Maternal choline deficiency in CD-1 mice lowers liver betaine levels in male offspring. By contrast, it increases elovl3 and vanin-1 mRNA levels in female offspring. Taken together, these observations suggest gender-specific responses to a choline-deficient diet.

Download Full-text

Maternal Consumption of a Diet Rich in Maillard Reaction Products Accelerates Neurodevelopment in F1 and Sex-Dependently Affects Behavioral Phenotype in F2 Rat Offspring

Foods ◽

10.3390/foods8050168 ◽

2019 ◽

Vol 8 (5) ◽

pp. 168 ◽

Cited By ~ 2

Author(s):

Melinda Csongová ◽

Emese Renczés ◽

Veronika Šarayová ◽

Lucia Mihalovičová ◽

Jakub Janko ◽

...

Keyword(s):

Early Development ◽

Hind Limb ◽

Dietary Exposure ◽

Later Life ◽

Female Offspring ◽

Behavioral Phenotype ◽

Control Group ◽

Maillard Reaction Products ◽

Reaction Products ◽

Pregnancy And Lactation

Thermal processing of foods at temperatures > 100 °C introduces considerable amounts of advanced glycation end-products (AGEs) into the diet. Maternal dietary exposure might affect the offspring early development and behavioral phenotype in later life. In a rat model, we examined the influence of maternal (F0) dietary challenge with AGEs-rich diet (AGE-RD) during puberty, pregnancy and lactation on early development, a manifestation of physiological reflexes, and behavioral phenotype of F1 and F2 offspring. Mean postnatal day of auditory conduit and eye opening, or incisor eruption was not affected by F0 diet significantly. F1 AGE-RD offspring outperformed their control counterparts in hind limb placing, in grasp tests and surface righting; grandsons of AGE-RD dams outperformed their control counterparts in hind limb placing and granddaughters in surface righting. In a Morris water maze, female AGE-RD F1 and F2 offspring presented better working memory compared with a control group of female offspring. Furthermore, male F2 AGE-RD offspring manifested anxiolysis-like behavior in a light dark test. Mean grooming time in response to sucrose splash did not differ between dietary groups. Our findings indicate that long-term maternal intake of AGE-RD intergenerationally and sex-specifically affects development and behavioral traits of offspring which have never come into direct contact with AGE-RD.

Download Full-text

EFEITO ADJUVANTE DO CLORETO DE DIMETILDIOCTADECILAMÔNIO EM PREPARAÇÕES DE TOXÓIDE TETÂNICO

Archives of Veterinary Science ◽

10.5380/avs.v8i1.4019 ◽

2003 ◽

Vol 8 (1) ◽

Cited By ~ 1

Author(s):

L.C. SILVA ◽

E. TAKIUCHI ◽

A.F. ALFIERI ◽

A.A. ALFIERI

Keyword(s):

Immune Response ◽

Ammonium Chloride ◽

Aluminum Hydroxide ◽

Guinea Pigs ◽

Neutralizing Antibodies ◽

Immune Cell ◽

Delayed Type Hypersensitivity ◽

Cell Immune Response ◽

Adjuvant Effect ◽

Group B

Foram formuladas duas vacinas contendo a mesma concentração de toxina, com o intuito de se avaliar a habilidade do adjuvante cloreto de demetiloctadecilamônio (DDA cloreto) em potencializar a resposta imune em cobaias imunizada com o toxóide tetânico. A vacina A foi adsorvida com hidróxido de alumínio e a vacina B cmpreendia a associação do hidróxido de alumínio e DDA cloreto. Os títulos de antitoxina no soro dos cobaios imunizados foram quantificados por soroneutralização em camundongos frente a uma dose contendo 1 Lp/10 (limite paralítico) de toxina tetânica. A inclusão do DDA cloreto em vacinas constituídas por toxóide tetânico adsorvido com hidróxido de alumínio promoveu maior ativação das respostas imunes humoral e celular de cobaios, quando comparada à resposta imune dos animais que receberam o antígeno adsorvido apenas com o hidróxido de alumínio. Os animais recebedores da vacina B apresentaram títulos de anticorpos neutralizantes 2,66 vezes maiores que os que recebedores a vacina A, demonstrando a potencialização da resposta imune humoral promovida pelo DDA cloreto. A resposta imune celular, avaliada pela reação de hipersensibilidade cutânea tardia, foi 17,8 maior no grupo B. Esses resultados demonstram que o DDA cloreto é um potente ativador da resposta imune humoral e celular de cobaios imunizados com o toxóide tetânico. Adjuvant effect of dimethyl dioctadecyl ammonium chloride in tetanic toxoid preparations Abstract Two vaccines were formulated with the same concentration of antigen and different adjuvants to assess the performance of dimethyl dioctadecyl ammonium chloride (DDA chloride) in boosting the immune response in guinea pigs immunized with tetanic toxoid. Vaccine A was adsorbed with aluminum hydroxide and vaccine B contained an association of aluminum hydroxide and DDA chloride. The antitoxin titres in the immunized guinea pig sera were assessed serum neutralization in mice using a toxin containing one Lp/10 dose (paralytic limit). The inclusion of DDA chloride in vaccines made up of tetanic toxoid adsorbed with aluminum hydroxide causes a greater activation of the humoral and cell immune response in guinea pigs when compared with the animals which received the antigen adsorbed only with aluminum hydroxide. The animals which received vaccine B had 2.66 times more neutralizing antibodies than those which received vaccine A, showing the boosting of the humoral immune response caused by DDA chloride. The animals from group B also had a strong immune cell response by the delayed type hypersensitivity reaction, which was 17.8 times higher than group A. These results show that DDA chloride is a potent activator of the humoral and cell immune response in guinea pigs immunized with tetanic toxoid.

Download Full-text

The high-fructose intake of dams during pregnancy and lactation exerts sex-specific effects on adult rat offspring metabolism

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174420000501 ◽

2020 ◽

pp. 1-9

Author(s):

Francisca A. Tobar-Bernal ◽

Sergio R. Zamudio ◽

Lucía Quevedo-Corona

Keyword(s):

Metabolic Syndrome ◽

Water Intake ◽

Female Offspring ◽

Male Offspring ◽

Standard Diet ◽

Liver Lipids ◽

The Metabolic Syndrome ◽

High Fructose ◽

Pregnancy And Lactation ◽

Food And Water Intake

Abstract Experimental studies have demonstrated the effects of maternal fructose consumption during pregnancy and lactation on metabolic alterations in their offspring, especially male offspring. However, few studies have focused on female offspring after providing fructose in food to dam rats. Here, we studied whether offspring of both sexes were differentially affected by a maternal high-fructose diet (HFD). For this purpose, Sprague-Dawley rats were fed during pregnancy and lactation with a standard diet (SD) or a HFD (50% w/w). After weaning, offspring were fed an SD; 3 days later, dams were sacrificed, and their offspring were sacrificed on postnatal day 90. Body weight (BW), food and water intake (only for dams), and various biomarkers of metabolic syndrome were measured. When compared to the SD-fed dams, HFD-fed dams had a reduction in BW and food and water intake. Conversely, adiposity, liver weight, liver lipids, and plasma levels of glucose, insulin, cholesterol, triglycerides, and uric acid were increased in HFD-fed dams. Moreover, the BW, food consumption, weight of retroperitoneal fat pads, and liver lipids increased in female and male offspring of HFD-fed dams. Interestingly, the pups of HFD-fed mothers showed increased levels of leptin and insulin resistance and decreased levels of adiponectin which were more pronounced in male offspring than in female offspring. In contrast, a higher increase in BW was shown earlier in female offspring. Thus, high-fructose consumption by dams during pregnancy and lactation led to sex-specific developmental programming of the metabolic syndrome phenotype in adult offspring.

Download Full-text

Stereotypic expansion of Tregulatory and Th17 cells during infancy is disrupted by HIV exposure and gut epithelial damage.

10.1101/2021.05.03.442468 ◽

2021 ◽

Author(s):

Sonwabile Dzanibe ◽

Katie Lennard ◽

Agano Kiravu ◽

Melanie S.S. Seabrook ◽

Berenice Alinde ◽

...

Keyword(s):

T Cell ◽

Early Life ◽

Th17 Cells ◽

Immune Cell ◽

Treg Cells ◽

Cell Populations ◽

Immune Development ◽

Hiv Exposure ◽

Gut Damage ◽

Cell Ontogeny

Few studies have investigated immune cell ontogeny throughout the period of increased vulnerability to infections in early life. Here, we evaluated the dynamics of two critical T cell populations, regulatory T (Treg) cells and Th17 cells, over the first 9 months of life. We observed that Treg and Th17 cells developed in a synchronous fashion. Infants exposed to HIV in utero (iHEU), who are more likely to develop infections, had a lower frequency of Tregs at birth and 36 weeks compared to HIV unexposed infants. This increased Th17/Treg ratio in iHEU was associated with impaired gut integrity at birth. These findings suggest that gut damage disrupts the Th17/Treg ratio during infant immune development, likely by attracting Treg cells to regulate inflammation occurring in the gut, so revealing an immune-gut nexus influenced by HIV exposure.

Download Full-text