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. 2017 Mar;125(3):437-446.
doi: 10.1289/EHP360. Epub 2016 Sep 16.

Sex-Dependent Effects of Cadmium Exposure in Early Life on Gut Microbiota and Fat Accumulation in Mice

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Free PMC article

Sex-Dependent Effects of Cadmium Exposure in Early Life on Gut Microbiota and Fat Accumulation in Mice

Qian Ba et al. Environ Health Perspect. .
Free PMC article

Abstract

Background: Environmental cadmium, with a high average dietary intake, is a severe public health risk. However, the long-term health implications of environmental exposure to cadmium in different life stages remain unclear.

Objectives: We investigated the effects of early exposure to cadmium, at an environmentally relevant dosage, on adult metabolism and the mechanism of action.

Methods: We established mouse models with low-dose cadmium (LDC) exposure in early life to examine the long-term metabolic consequences. Intestinal flora measurement by 16S rDNA sequencing, microbial ecological analyses, and fecal microbiota transplant was conducted to explore the potential underlying mechanisms.

Results: Early LDC exposure (100 nM) led to fat accumulation in adult male mice. Hepatic genes profiling revealed that fatty acid and lipid metabolic processes were elevated. Gut microbiota were perturbed by LDC to cause diversity reduction and compositional alteration. Time-series studies indicated that the gut flora at early-life stages, especially at 8 weeks, were vulnerable to LDC and that an alteration during this period could contribute to the adult adiposity, even if the microbiota recovered later. The importance of intestinal bacteria in LDC-induced fat accumulation was further confirmed through microbiota transplantation and removal experiments. Moreover, the metabolic effects of LDC were observed only in male, but not female, mice.

Conclusions: An environmental dose of cadmium at early stages of life causes gut microbiota alterations, accelerates hepatic lipid metabolism, and leads to life-long metabolic consequences in a sex-dependent manner. These findings provide a better understanding of the health risk of cadmium in the environment. Citation: Ba Q, Li M, Chen P, Huang C, Duan X, Lu L, Li J, Chu R, Xie D, Song H, Wu Y, Ying H, Jia X, Wang H. 2017. Sex-dependent effects of cadmium exposure in early life on gut microbiota and fat accumulation in mice. Environ Health Perspect 125:437-446; http://dx.doi.org/10.1289/EHP360.

Conflict of interest statement

The authors declare they have no actual or potential competing financial interests.

Figures

Figure 1
Figure 1
Effect of early-LDC exposure on body composition. (A) Study design: C57BL/6J mice received LDC (100 nM in drinking water) continuously for life beginning either at weaning (day 28, LDC-w, = 6 males and = 5 females), or from fertilization (LDC-m, = 6 males and = 5 females). Control mice received water alone (= 6 males and = 6 females). (BD) Body composition was measured by NMR at week 20; *p < 0.05 compared with the control. (E) Body fat percentage in male and female mice was measured; *p < 0.05 compared with the control. Note: F, female; M, male.
Figure 2
Figure 2
Early-life LDC exposure disturbed lipid homeostasis. (AF) The plasma levels of TG (A), TC (B), free fatty acids (C), leptin (D), HDL (E) and VLDL&LDL (F) in male and female mice were measured at week 30; *p < 0.05, **p < 0.01 compared with the control group. (G) The contents of liver TG in male mice was measured at week 30; *p < 0.05 compared with the control group. (H) Representative images of Oil Red O staining of liver sections from control and LDC male mice. The arrows indicate the lipid deposits in liver cells. Magnification, ×40.
Figure 3
Figure 3
Effect of early-life LDC exposure on hepatic gene expressions. (A) Number of LDC-induced differentially expressed hepatic genes (p < 0.05 or 0.01, fold change ≥ 2) in male and female mice. (B) The differential expression of hepatic genes was comparatively analyzed. A Venn diagram represents the numbers of overlapping genes between two separate pairwise comparisons: male mice [LDC vs. Control (Ctrl)] and female mice (LDC vs. Control). (CE) The expression values of genes in Venn regions I–III were shown in heatmaps. (F) The lipid metabolism-related biological processes enriched by up-regulated differential genes in LDC male mice were represented in the GO analysis network. Node size shows the number of genes annotated in each GO term and the node color represents the significance of the enrichment.
Figure 4
Figure 4
Dynamics of adiposity and microbiota changes after LDC exposure. (A) Study design: C57BL/6J mice received LDC (= 6 males and = 5 females) or only water (= 6 males and = 6 females) from fertilization to 30 weeks of age. (B) Body fat percentage in male and female mice was measured over time by magnetic resonance spectroscopy (NMR); **< 0.01 compared with the control group. (C-F) Fecal specimens at weeks 4, 8, and 20, and the terminal (week 30) cecal specimens from male mice were collected and the intestinal floras were examined by 16S rDNA sequencing. (C) Alpha diversity of control and LDC community was analyzed by Shannon diversity index; *p < 0.05 compared with the control group. (D) Intragroup β-diversity of control and LDC community was measured by weighted UniFrac distance. (E) The plots generated by the weighted UniFrac-based PCoA at each time point. (F) LDC affected the relative abundance of predominant bacteria at the phylum level in control and LDC male mice. Note: PCoA1 and PCoA2 are the two dimensions with the most significant differences in the analysis.
Figure 5
Figure 5
Characteristics of microbial community composition in 8-week male mice. (A) The enriched taxa in control and LDC 8-week fecal microbiota were represented in Cladogram. The central point represents the root of the tree (Bacteria), and each ring represents the next lower taxonomic level (phylum to genus: p, phylum; c, class; o, order; f, family; g, genus). The diameter of each circle represents the relative abundance of the taxon. (B) The most differentially abundant taxa between control and LDC groups were identified through the LDA score which was generated from LEfSe analysis. (C) Relative abundance of dominant phyla was compared between control and LDC groups; *p < 0.05 significantly different by Mann–Whitney U test. (D) Relative abundance at the bacterial genus level between control and LDC groups was compared; *p < 0.05, **p < 0.01 significantly different by Mann–Whitney U test.
Figure 6
Figure 6
Effect of microbiota transplant on body compositions. (A) Study design: 3-week-old control or LDC male mice (control, = 8; LDC, = 10) were used as donors. The fecal contents were collected, pooled, and transferred to age-matched male recipient mice (= 8 for each group) by oral gavage twice a week. No recipient mice received LDC during the experiment. (BD) Body composition in the control- and LDC-microbiota recipient mice was measured by NMR at 8, 12, 16, and 20 weeks of age. *p < 0.05 compared with the control-recipient group. (E) Body fat percentage in control- and LDC-microbiota recipient mice was measured over time. *p < 0.05 compared with the control-recipient group.

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