Perinatal Lead Exposure Alters Gut Microbiota Composition and Results in Sex-specific Bodyweight Increases in Adult Mice

Abstract

Heavy metal pollution is a principle source of environmental contamination. Epidemiological and animal data suggest that early life lead (Pb) exposure results in critical effects on epigenetic gene regulation and child and adult weight trajectories. Using a mouse model of human-relevant exposure, we investigated the effects of perinatal Pb exposure on gut microbiota in adult mice, and the link between gut microbiota and bodyweight changes. Following Pb exposure during gestation and lactation via maternal drinking water, bodyweight in A(vy) strain wild-type non-agouti (a/a) offspring was tracked through adulthood. Gut microbiota of adult mice were characterized by deep DNA sequencing of bacterial 16S ribosomal RNA genes. Data analyses were stratified by sex and adjusted for litter effects. A Bayesian variable selection algorithm was used to analyze associations between bacterial operational taxonomic units and offspring adult bodyweight. Perinatal Pb exposure was associated with increased adult bodyweight in male (P < .05) but not in female offspring (P = .24). Cultivable aerobes decreased and anaerobes increased in Pb-exposed offspring (P < .005 and P < .05, respectively). Proportions of the 2 predominant phyla (Bacteroidetes and Firmicutes) shifted inversely with Pb exposure, and whole bacterial compositions were significantly different (analysis of molecular variance, P < .05) by Pb exposure without sex bias. In males, changes in gut microbiota were highly associated with adult bodyweight (P = .028; effect size = 2.59). Thus, perinatal Pb exposure results in altered adult gut microbiota regardless of sex, and these changes are highly correlated with increased bodyweight in males. Adult gut microbiota can be shaped by early exposures and may contribute to disease risks in a sex-specific manner.

Perinatal lead (Pb) exposure results in sex and tissue‐dependent adult DNA methylation alterations in murine IAP transposons

“…It is notable that both HMGA2 and FOXO are transcription factors that have been linked to metabolic‐related conditions. In a recent series of studies, which used the same longitudinal mouse cohort referenced in the current manuscript, we observed that perinatal Pb exposure leads to metabolic‐related physiological effects including increased food intake, body weight, body fat, activity changes, and insulin resistance in adult mice (Faulk et al, ; Wu et al, ). Although Pb toxicity research has traditionally focused on neurological‐related outcomes, other studies investigating developmental Pb exposure have also observed persistent physiological changes including decreased fetal and childhood growth in humans and late onset obesity in rodents (Gonzalez‐Cossio et al, ; Iavicoli et al, ; Leasure et al, ; Little et al, ; Afeiche et al, ).…”

Sexually Dimorphic Effects of Early-Life Exposures to Endocrine Disruptors: Sex-Specific Epigenetic Reprogramming as a Potential Mechanism

“…Further, the altered insulin response was non-monotonic in relation to exposure. Using the same cohort of mice, the gut microbiota was compared between control mice and the high Pb exposure group of 10-month-old mice, finding that perinatal Pb exposure induced changes in gut microbiota in adult male and female mice, but microbiota changes were correlated to increases in body weight in male mice only [48]. …”

Endocrine Disruptors in Food: Impact on Gut Microbiota and Metabolic Diseases

“…In addition, reduced aerobic bacteria and increased anaerobic bacteria were observed in the exposed offspring. Lastly, Pseudomonas, Enterobacter, and Desulfovibrio were found in higher abundances in exposed adult mice than in controls (p < 0.05) [43]. Ba et al (2017) [42] demonstrated the sex-specific effects of low-dose exposure to cadmium and found that early exposure to 100 nM induced fat accumulation in adult male C57BL/6J mice.…”

“…These changes in metabolite homeostasis are important risk factors involved in tissue dysfunctions, which may cause diseases such as obesity and diabetes [139]. [43] reported that perinatal lead (Pb) exposure (32 ppm) in the drinking water, in wild-type non-agouti (a/a) mice of the Avy strain isogenic mouse model of perinatal environmental exposure, induced changes in the adult offspring gut microbiota. These changes were sex-independent, but a strong association was found between male offspring and increased body weight.…”