The Environment
Arsenic, the Microbiome & Health Outcomes: Mechanisms to Forms of Intervention
Principal Investigator: George A. O'Toole, PhD
Funding: National Institute of Environmental Health Sciences
Project Number: 5R01ES033988-03
Project Narrative: Exposure to arsenic early in life results in the loss of key gut microbiota that tune local and systemic immunity. Here, we propose to use a combination of human-focused studies, molecular studies with lab cell models, and animal work to understand how the arsenic-mediated loss of Bacteroides impacts immunity and health outcomes, and how arsenic-mediated effects can be mitigated. The goal of this project is to assess the impact of arsenic exposure on the gut microbiome and respiratory outcomes.
Highlighted Publications
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Publication Link: Arsenic is related to neurodevelopmental outcomes and is associated with the composition of the gut microbiome. Data on the modifying role of the microbiome are limited. Our findings indicate the infant gut microbiome may alter neurodevelopmental susceptibility to environmental exposures.
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Publication Link: In utero and early life exposure to inorganic arsenic (iAs) alters immune response in experimental animals and is associated with an increased risk of infant infections. iAs exposure is related to differences in the gut microbiota diversity, community structure, and the relative abundance of individual microbial taxa both in laboratory and human studies. Metabolomics permits a direct measure of molecular products of microbial and host metabolic processes. We conducted NMR metabolomics analysis on infant stool samples and quantified the relative concentrations of 34 known microbial-related metabolites. We examined these metabolites in relation to both in utero and infant log2 urinary total arsenic concentrations (utAs, the sum of iAs and iAs metabolites) collected at approximately 6 weeks of age using linear regression models, adjusted for infant sex, age at sample collection, type of delivery (vaginal vs. cesarean section), feeding mode (breast milk vs. any formula), and specific gravity. Increased fecal butyrate (b = 214.24), propionate (b = 518.33), cholate (b = 8.79), tryptophan (b= 14.23), asparagine (b = 28.80), isoleucine (b = 65.58), leucine (b = 95.91), malonate (b = 50.43), and uracil (b = 36.13), concentrations were associated with a doubling of infant utAs concentrations (p< 0.05). These associations were largely among infants who were formula fed. No clear associations were observed with maternal utAs and infant fecal metabolites. Metabolomic analyses of infant stool samples lend further evidence that the infant gut microbiota is sensitive to As exposure, and these effects may have functional consequences.
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Publication Link: Gut bacteria are at the interface of environmental exposures and their impact on human systems, and may alter host absorption, metabolism, and excretion of toxic chemicals. We investigated whether arsenic-metabolizing bacterial gene pathways related to urinary arsenic concentrations. Our findings suggest associations between arsenic-metabolizing bacteria in the infant gut microbiome and urinary arsenic excretion.
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Publication Link: Arsenic is a ubiquitous environmental toxicant with antimicrobial properties that can be found in food and drinking water. The influence of arsenic exposure on the composition of the human microbiome in US populations remains unknown, particularly during the vulnerable infant period. We investigated the relationship between arsenic exposure and gut microbiome composition in 204 infants prospectively followed as part of the New Hampshire Birth Cohort Study. Infant urine was analyzed for total arsenic concentration using inductively coupled plasma mass spectrometry. Stool microbiome composition was determined using sequencing of the bacterial 16S rRNA gene. Infant urinary arsenic related to gut microbiome composition at 6 weeks of life (p = 0.05, adjusted for infant feeding type and urine specific gravity). Eight genera, six within the phylum Firmicutes, were enriched with higher arsenic exposure. Fifteen genera were negatively associated with urinary arsenic concentration, including Bacteroides and Bifidobacterium. Upon stratification by both sex and feeding method, we found detectable associations among formula-fed males (p = 0.008), but not other groups (p > 0.05 for formula-fed females and for breastfed males and females). Our findings from a US population indicate that even moderate arsenic exposure may have meaningful, sex-specific effects on the gut microbiome during a critical window of infant development.
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Publication Link: Emerging evidence points to a critical role of the developing gut microbiome in immune maturation and infant health; however, prospective studies are lacking.
Our findings suggest that intestinal microbial diversity and the relative abundance of key taxa in early infancy may influence susceptibility to respiratory infection, wheezing, and diarrhea.
Impact of early life fluoride exposure on neurodevelopmental outcomes among children in the New Hampshire Birth Cohort
Principal Investigator: Christine Till
Funding: York University
Sponsor Award ID: 524827
Project Narrative: The goal of this project is to assess the impact of fluoride exposure on children’s neurodevelopmental outcomes. The purpose of this renewal application is to provide scientific expertise and leadership to investigate new hypotheses while contributing critical data and biospecimens to address major gaps in our knowledge about early life environmental influences on child health and development in a US pregnancy cohort. Together, the unique strengths of our rural birth cohort and the national ECHO consortium will allow us to address health disparities, emerging public health crises, foster workforce diversity and ensure responsiveness of the program to a broad range of stakeholders.
Highlighted Publications
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Summary: Research is needed on potential susceptibility factors, because from a policy perspective regarding risk, EPA is required to consider setting standards that provide a margin of safety, currently dramatically exceeded by EPA’s regulatory limit of 4 mg/L, to protect potentially susceptible individuals. This includes pregnant women and children and, arguably, individuals who may be genetically susceptible (such as those recently found to have variants related to dopamine metabolism that are associated with amplified fluoride neurotoxicity effects22). Research is also needed that, apart from water fluoridation, compares the benefits in terms of caries prevention and risk of systemic ingestion of fluoride via various modes of fluoride application (e.g., the use of toothpastes, gels, and mouth rinses). New methods of fluoride application could potentially be developed that further minimize the risk of ingesting fluoride, especially in young children, while maximizing the benefit of fluoride for caries prevention.
Parabens at the maternal-child interface: impacts on the milk microbiota and child health
Principal Investigators: Anne Hoen, PhD | Megan Romano, PhD
Funding: National Institute of Environmental Health Sciences
Project Number: 1R01ES037343-01A1
Project Narrative: Parabens are antimicrobial preservatives frequently used in food, pharmaceuticals and personal care products, and infants are exposed to parabens through human milk. We will study the connection between maternal paraben exposure and child health and examine a probable underpinning in the human milk microbiome. This research will resolve a potential and previously unstudied mechanism of the adverse health effects of widespread paraben use.
Project Abstract
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Project Summary/Abstract: Parabens are broad-spectrum antimicrobial chemicals commonly used as preservatives in personal care products, pharmaceuticals, and food. Humans are exposed to parabens through ingestion and inhalation, and parabens are rapidly absorbed through the skin. US women of reproductive age have greater exposure to parabens than men, likely due to greater use of personal care products. Parabens are found in human milk and infants are exposed to parabens through breastfeeding. The period coinciding with breastfeeding is a critical window in infants for major developmental processes that can inform risk of a range of outcomes throughout the lifespan. Also found in human milk are complex microbial communities that have the potential to be perturbed by the antimicrobial properties of parabens. These microbes are a major source of commensal microorganisms shaping the character of the infant gut and airway microbiomes. The microbial taxa comprising these microbiomes are regulators of early life immune development, with consequences for risk for respiratory and allergic conditions among other immune-mediated health outcomes. There is an urgent need for research on the human milk microbiome, its potential to be disrupted by ubiquitous antimicrobial environmental contaminants such as parabens, and the subsequent effects on child health. Our study has three specific aims: First, to evaluate associations of maternal urinary and milk paraben concentrations with early-life respiratory and allergic outcomes. Second, to examine associations between maternal urinary and milk paraben concentrations and human milk microbiota taxonomic composition and functional character. And third, to examine associations between the milk microbiome and early-life respiratory and allergic outcomes. Finally, we will explore our long-term, overarching hypothesis that any effect of maternal paraben exposure on respiratory and allergic outcomes in young children is mediated by the milk microbiome. The contribution of this research will be to fill in the missing links of a hypothesized and highly compelling yet understudied pathway between maternal paraben exposure and child health. This research will set the stage for research on other antimicrobial environmental toxicants found in human milk; advance knowledge of the bioactive properties of human milk in general; and resolve a potential and previously unstudied mechanism of the adverse health effects of widespread paraben use.