Biology subjects

Goodrich, J. M.

Publications and source records attributed to Goodrich, J. M..

4 recordsLinked to original sources

bioRxiv2025

Perinatal Lead (Pb) Exposure Increases Mouse Embryonic Weight and Alters Neuronal Gene Expression

Acute and chronic exposure to lead (Pb) during pregnancy is linked to adverse health outcomes, including delayed neurodevelopment in offspring. However, the pathways by which Pb exposure influences long-term health remain poorly understood. To address this, we measured the effects of perinatal Pb exposure on gene expression including imprinted genes, X-linked genes, and sexually dimorphic genes. Female mice were given control or Pb acetate dosed (32 ppm) drinking water two weeks prior to timed mating until embryonic day (E)10-12, upon which whole embryos were collected, weighed, and sexed at E13-15. From a subset of embryo heads (n[≥]9 per sex per group), we extracted and sequenced RNA. We used linear regression to assess Pb impacts on embryonic weight and gene expression across all mice and stratified by sex. Among the differentially expressed genes, we identified significantly enriched pathways. Pb-exposed embryos weighed more than controls (p=0.007), across both sexes. Collectively, we identified 2,920 differentially expressed genes (FDR<0.05), including 31 imprinted genes and 120 X-linked genes upon Pb exposure. Pb exposure altered expression in gene pathways related to neuronal structure and function as well as sexually dimorphic genes (44 for females; 76 for males). These findings highlight perinatal Pb-linked alterations that may drive later-life health outcomes.

genetics↗

bioRxiv2022

Epigenetic biomarkers of autoimmune risk and protective antioxidant signaling in methylmercury-exposed adults

I.BackgroundEpigenome-wide association studies (EWAS) are a highly promising approach that can inform precision environmental health. However, current EWAS are underpowered for biomarker detection and increasing sample sizes will require substantial resources. Therefore, alternative approaches for identifying candidate biomarkers through EWAS are critical for moving the field forward. ObjectivesTo provide proof-of-principle that maximizing exposure variance in EWAS by selecting participants from disproportionately exposed global populations enables effective candidate biomarker detection, even in small sample sizes. MethodsWe profiled genome-wide DNA methylation using Illumina Infinium MethylationEPIC BeadChip in whole blood from N=32 individuals from Madre de Dios, Peru with high methylmercury (MeHg) exposure due to artisanal and small-scale gold mining. We compared DNA methylation in N=16 individuals with high (>10 g/g) vs. N=16 individuals with low (<1 g/g) total hair mercury (a proxy for methylmercury exposure), matched on age and sex. ResultsWe identified nine differentially methylated CpG sites (FDR<0.05), including several with known links to MeHg toxicity. The most significantly different CpG site was in an intronic enhancer of the SLC5A7 gene, which encodes the L-type amino acid transporter 1 (LAT1) that facilitates MeHg transport into protein-rich tissue, including muscle and brain. Our Gene Ontology and transcription factor motif enrichment analyses identified differential methylation of genes involved in several outcomes with established links to MeHg, including immune response, neurotoxicity, and type 2 diabetes (T2D) risk. Last, we identified candidate epigenetic biomarkers of PUFA-mediated protection against MeHg toxicity. DiscussionHere, we show that a small EWAS on samples with high MeHg exposure variance can detect candidate differentially methylated CpGs and pathways of interest relevant to MeHg biology. Similar EWAS in global populations with known high exposure variance can be leveraged to develop targeted, custom sequencing panels and microarrays limited to replicated, validated biomarkers of a given exposure.

genomics↗

bioRxiv2021

Placental gene expression-based cell type deconvolution: Cell proportions drive preeclampsia gene expression differences

The placenta mediates adverse pregnancy outcomes, including preeclampsia, which is characterized by gestational hypertension and proteinuria. Placental cell type heterogeneity in preeclampsia is not well-understood and limits mechanistic interpretation of bulk gene expression measures. We generated single-cell RNA-sequencing samples for integration with existing data to create the largest deconvolution reference of 19 fetal and 8 maternal cell types from placental villous tissue at term (n=15,532 cells). We deconvoluted eight published microarray case-control studies of preeclampsia (n=330). Deconvolution revealed excess extravillous trophoblasts and fewer mesenchymal cells. Adjustment for cellular composition reduced preeclampsia-associated differentially expressed genes (FDR<0.05) from 1,224 to 0, whereas pathway alterations exhibiting a metabolic adaptation to hypoxia were robust to cell type adjustment. Cellular composition explained 35.1% of the association between preeclampsia and FLT1 overexpression. Our findings indicate substantial placental cellular heterogeneity in preeclampsia that predicts previously observed bulk gene expression differences. Our deconvolution reference lays the groundwork for cellular heterogeneity-aware investigation into placental dysfunction and adverse birth outcomes.

developmental biology↗

bioRxiv2019

Perinatal exposure to lead results in altered DNA methylation in adult mouse liver and blood: Implications for target versus surrogate tissue use in environmental epigenetics

BackgroundDNA methylation is a critical epigenetic mechanism linking early developmental environment to long-term health. In humans, the extent to which toxicant-induced changes in DNA methylation in surrogate tissues, such as blood, mirror those in the target tissues is unclear. The Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET II) consortium was established by the National Institute of Environmental Health Sciences to address the utility of surrogate tissues as proxies for toxicant-induced epigenetic changes in target tissues.\n\nObjectivesThe objective of this study was to investigate the effects of perinatal exposure to a human environmentally relevant level (32 ppm in maternal drinking water) of lead (Pb) on liver and blood DNA methylation in adult male and female mice. We hypothesized that developmental Pb exposure would lead to persistent changes in DNA methylation, and that a subset of differentially methylated loci would overlap between liver and blood.\n\nMethodsEnhanced reduced-representation bisulfite sequencing was used to assess DNA methylation in 5 month old Pb-exposed and control mice. Sex-stratified modeling of differential methylation by Pb exposure was conducted using an established bioinformatics pipeline.\n\nResultsAlthough Pb exposure ceased at 3 weeks of age, we observed thousands of stably modified, sex-specific differentially methylated regions in the blood and liver of Pb-exposed animals, including 44 genomically imprinted loci. In males, we discovered 5 sites that overlapped between blood and liver, and exhibited changes in DNA methylation in the same direction in both tissues.\n\nConclusionsThese data demonstrate that perinatal exposure to Pb induces sex-specific changes in hepatic DNA methylation in adulthood, some of which are also present in blood. Ongoing studies will provide additional exposure-specific insights, and include other epigenetic marks that will enable further refinement of the design and analysis of human studies where target tissues are inaccessible.

genomics↗