Stimulation of the Immune Response in B6C3F1 Mice by Genistein Is Affected by Exposure Duration, Gender, and Litter Order

Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
Journal of Nutrition (Impact Factor: 3.88). 11/2005; 135(10):2449-56.
Source: PubMed


The objective of this study was to determine whether immune responses could be differentially modulated by the phytoestrogen genistein (GEN) in mice from the 1st and 2nd litters, and whether the effects were persistent or reversible. B6C3F1 mice were exposed to a control or GEN-containing diet at 25, 250, and 1250 microg/g for the 1st litters, and 500 microg/g for the 2nd litters from d 0 of gestation to postnatal day (PND) 22, and through feeding after weaning. At PND42, anti-CD3 antibody-stimulated splenic T-cell proliferation and the percentages of T cells were increased in mice from the 1st litters at 250 and 1250 microg/g GEN but not from the 2nd litters. At PND84, the activity of IL-2-treated NK cells was significantly increased by GEN in mice from the 2nd litters but not from the 1st litters. The activity of cytotoxic T cells (CTLs) was also significantly increased by GEN in male mice from the 2nd litters. However, the increases in the CTL activity were not significant when the male mice were shifted from GEN-containing food to control food at PND22. Additionally, the increases in T-cell activities in female mice from the 1st litters and male mice from the 2nd litters were associated with a decrease in the percentage of CD4+CD25+ T regulatory cells. Overall, the results demonstrated that GEN could enhance the immune responses in mice from the 1st and 2nd litters; however, the effects varied depending on the exposure duration, gender, and litter order.

Download full-text


Available from: Kimber L White, Apr 15, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Developmental immunotoxicity (DIT) recently emerged as a significant concern for drug safety and was the topic of several recent scientific forums in Europe, North America and Asia. The heightened concern is based on several observations: 1) many childhood diseases with recent increases in prevalence, such as asthma, allergic disease, leukemia and certain infections, have clear linkages to the immune system and immune dysfunction, 2) the developing immune system has been shown to be a particularly sensitive target for xenobiotic-induced adverse outcomes, 3) immunotoxicity assessment following adult exposure to xenobiotics is ineffective for predicting immunotoxic risk in the non-adult and 4) in several cases developmental immunotoxicity to low-level xenobiotic exposure can take the form of immune dysfunction in the absence of readily detected morphometric/histological alterations. The present review examines harmonized preclinical drug safety guidelines for immunotoxicity in light of environmentally-mediated childhood disease trends as well as research-based mechanisms for DIT. Because none of the guidelines was designed to address risk of DIT, suggestions are offered for closing the early-life immune dysfunction data gap. A longer-term goal is to help narrow the difference between current guideline expectations and the known sensitivity of the developing immune system for potential adverse outcomes.
    Full-text · Article · Oct 2008 · Current Drug Safety
  • [Show abstract] [Hide abstract]
    ABSTRACT: Developmental immunotoxicity (DIT) is an increasing health concern since DIT outcomes predispose children to those diseases that have been on the rise in recent decades (e.g., childhood asthma, allergic diseases, autoimmune conditions, childhood infections). The enhanced vulnerability of the developing immune system for environmental insult is based on unique immune maturational events that occur during critical windows of vulnerability in early life. The semi-allogeneic pregnancy state, with suppression of graft rejection and associated skewing of the fetal and neonatal immune system, also influences the specific nature of DIT outcomes. In the exposed offspring, targeted immunosuppression can co-exist with an increased risk of allergic and/or autoimmune disease. Because with DIT immune dysfunction rather than profound immunosuppression is the greater concern, testing approaches should emphasize multi-functional assessment. Beyond T-cells, dendritic cells and macrophages are sensitive targets. The last-trimester fetus and the neonate are normally depressed in T(H)1-dependent functions and postnatal acquisition of needed T(H)1 capacity is a major concern with DIT. With this in mind, assessment should include a measure of T(H)1-dependent cell-mediated immunity [cytotoxic T-lymphocyte (CTL) activity or delayed-type hypersensitivity (DTH) response] in conjunction with a multi-isotype T-dependent antibody response (TDAR) and evaluation of innate immunity (e.g., NK activity). Other parameters such as immune histology, immunophenotyping, cytokine responses, and organ weights can be useful when included with immune functional evaluation. A multifunctional DIT protocol using influenza challenge is presented as one example of an approach that permits dysfunction and misregulation to be evaluated.
    No preview · Article · Nov 2008 · Journal of Immunotoxicology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Incidence of childhood allergic disease including asthma (AD-A) has risen since the mid-20th century with much of the increase linked to changes in environment affecting the immune system. Childhood allergy is an early life disease where predisposing environmental exposures, sensitization, and onset of symptoms all occur before adulthood. Predisposition toward allergic disease (AD) is among the constellation of adverse outcomes following developmental immunotoxicity (DIT; problematic exposure of the developing immune system to xenobiotics and physical environmental factors). Because novel immune maturation events occur in early life, and the pregnancy state itself imposes certain restrictions on immune functional development, the period from mid-gestation until 2 years after birth is one of particular concern relative to DIT and AD-A. Several prenatal-perinatal risk factors have been identified as contributing to a DIT-mediated immune dysfunction and increased risk of AD. These include maternal smoking, environmental tobacco smoke, diesel exhaust and traffic-related particles, heavy metals, antibiotics, environmental estrogens and other endocrine disruptors, and alcohol. Diet and microbial exposure also significantly influence immune maturation and risk of allergy. This review considers (1) the critical developmental windows of vulnerability for the immune system that appear to be targets for risk of AD, (2) a model in which the immune system of the DIT-affected infant exhibits immune dysfunction skewed toward AD, and (3) the lack of allergy-relevant safety testing of drugs and chemicals that could identify DIT hazards and minimize problematic exposure of pregnant women and children.
    No preview · Article · Dec 2008 · Birth Defects Research Part B Developmental and Reproductive Toxicology
Show more