Restricting microbial exposure in early life negates the immune benefits associated with gut colonization in environments of high microbial diversity

Background: Acquisition of the intestinal microbiota in early life corresponds with the development of the mucosal immune system. Recent work on caesarean-delivered infants revealed that early microbial composition is influenced by birthing method and environment. Furthermore, we have confirmed that early-life environment strongly influences both the adult gut microbiota and development of the gut immune system. Here, we address the impact of limiting microbial exposure after initial colonization on the development of adult gut immunity. Methodology/Principal Findings: Piglets were born in indoor or outdoor rearing units, allowing natural colonization in the immediate period after birth, prior to transfer to high-health status isolators. Strikingly, gut closure and morphological development were strongly affected by isolator-rearing, independent of indoor or outdoor origins of piglets. Isolator-reared animals showed extensive vacuolation and disorganization of the gut epithelium, inferring that normal gut closure requires maturation factors present in maternal milk. Although morphological maturation and gut closure were delayed in isolatorreared animals, these hard-wired events occurred later in development. Type I IFN, IL-22, IL-23 and Th17 pathways were increased in indoor-isolator compared to outdoor-isolator animals during early life, indicating greater immune activation in pigs originating from indoor environments reflecting differences in the early microbiota. This difference was less apparent later in development due to enhanced immune activation and convergence of the microbiota in all isolator-reared animals. This correlated with elevation of Type I IFN pathways in both groups, although T cell pathways were still more affected in indoor-reared animals. Conclusions/Significance: Environmental factors, in particular microbial exposure, influence expression of a large number of immune-related genes. However, the homeostatic effects of microbial colonization in outdoor environments require sustained microbial exposure throughout development. Gut development in high-hygiene environments negatively impacts on normal succession of the gut microbiota and promotes innate immune activation which may impair immune homeostasis.

Variation in rice cadmium related to human exposure.

Cereal grains are the dominant source of cadmium in the human diet, with rice being to the fore. Here we explore the effect of geographic, genetic, and processing (milling) factors on rice grain cadmium and rice consumption rates that lead to dietary variance in cadmium intake. From a survey of 12 countries on four continents, cadmium levels in rice grain were the highest in Bangladesh and Sri Lanka, with both these countries also having high per capita rice intakes. For Bangladesh and Sri Lanka, there was high weekly intake of cadmium from rice, leading to intakes deemed unsafe by international and national regulators. While genetic variance, and to a lesser extent milling, provide strategies for reducing cadmium in rice, caution has to be used, as there is environmental regulation as well as genetic regulation of cadmium accumulation within rice grains. For countries that import rice, grain cadmium can be controlled by where that rice is sourced, but for countries with subsistence rice economies that have high levels of cadmium in rice grain, agronomic and breeding strategies are required to lower grain cadmium.

Aluminium and breast cancer: sources of exposure, tissue measurements and mechanisms of toxicological actions on breast biology

This review examines recent evidence linking exposure to aluminium with the aetiology of breast cancer. The human population is exposed to aluminium throughout daily life including through diet, application of antiperspirants, use of antacids and vaccination. Aluminium has now been measured in a range of human breast structures at higher levels than in blood serum and experimental evidence suggests that the tissue concentrations measured have the potential to adversely influence breast epithelial cells including generation of genomic instability, induction of anchorage-independent proliferation and interference in oestrogen action. The presence of aluminium in the human breast may also alter the breast microenvironment causing disruption to iron metabolism, oxidative damage to cellular components, inflammatory responses and alterations to the motility of cells. The main research need is now to investigate whether the concentrations of aluminium measured in the human breast can lead in vivo to any of the effects observed in cells in vitro and this would be aided by the identification of biomarkers specific for aluminium action.

Exposure to parabens at the concentration of maximal proliferative response increases migratory and invasive activity of human breast cancer cells in vitro

Alkyl esters of p–hydroxybenzoic acid (parabens) are widely used as preservatives in personal care products, foods and pharmaceuticals. Their oestrogenic activity, their measurement in human breast tissue and their ability to drive proliferation of oestrogen-responsive human breast cancer cells has opened a debate on their potential to influence breast cancer development. Since proliferation is not the only hallmark of cancer cells, we have investigated the effects of exposure to parabens at concentrations of maximal proliferative response on migratory and invasive properties using three oestrogen-responsive human breast cancer cell lines (MCF-7, T-47-D, ZR-75-1). Cells were maintained short-term (1 week) or long-term (20±2 weeks) in phenol-red-free medium containing 5% charcoal-stripped serum with no addition, 10-8M 17-oestradiol, 1-5x10-4M methylparaben, 10-5M n-propylparaben or 10-5M n-butylparaben. Long-term exposure (20±2 weeks) of MCF-7 cells to methylparaben, n-propylparaben or n-butylparaben increased migration as measured using a scratch assay, time-lapse microscopy and xCELLigence technology: invasive properties were found to increase in matrix degradation assays and migration through matrigel on xCELLigence. Western immunoblotting showed an associated downregulation of E-cadherin and -catenin in the long-term paraben-exposed cells which could be consistent with a mechanism involving epithelial to mesenchymal transition. Increased migratory activity was demonstrated also in long-term paraben-exposed T-47-D and ZR-75-1 cells using a scratch assay and time-lapse microscopy. This is the first report that in vitro, parabens can influence not only proliferation but also migratory and invasive properties of human breast cancer cells.