Biology subjects

Ritz, B.

Publications and source records attributed to Ritz, B..

3 recordsLinked to original sources

bioRxiv2022

Coupling comprehensive pesticide-wide association study to iPSC dopaminergic screening identifies and classifies Parkinson-relevant pesticides

Parkinsons disease (PD) is a complex, multi-factorial neurodegenerative disease, known to involve genetic, aging-related components, but also to be highly sensitive to environmental factors. In particular, ample evidence links pesticides to PD etiology. Here, establishing a field-to-bench paradigm, we have combined record-based exposure assessment in a population-based epidemiologic study of PD with testing in dopaminergic neurons produced from iPSCs to further identify and classify PD-relevant pesticides. First, agricultural pesticide-application records in California enabled us to investigate exposure to nearly 300 specific pesticides and PD risk in a comprehensive, pesticide-wide association study (PWAS). We implicated long-term exposure to 53 pesticide active ingredients in PD risk and identified their relevant co-exposure profiles. Second, to identify which of these pesticides might contribute to PD through direct effects on dopaminergic neurons, we employed a live-cell imaging screening paradigm in which neurons, definitively identified with a tyrosine hydroxylase reporter, were exposed to 43 of the high-risk pesticides. Using detailed morphometric measures, we found 10 pesticides were directly toxic to these neurons. Further, we analyzed pesticides typically used in combinations in cotton farming. Among these "cotton cluster" pesticides, co-exposures resulted in markedly greater toxicity than any single pesticide. Trifluralin was a pivotal driver of toxicity to dopaminergic neurons and led to marked mitochondrial dysfunction. Our field-to-bench paradigm may prove useful to mechanistically dissect pesticide exposure implicated in PD risk, and guide agricultural policy in the future.

neuroscience↗

bioRxiv2020

A survey of rare epigenetic variation in 23,116 human genomes identifies disease-relevant epivariations and novel CGG expansions

There is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles from 23,116 individuals using the Illumina 450k array. Using a robust outlier approach, we identified 4,452 unique autosomal epivariations, including potentially inactivating promoter methylation events at 384 genes linked to human disease. For example, we observed promoter hypermethylation of BRCA1 and LDLR at population frequencies of ~1 in 3,000 and ~1 in 6,000 respectively, suggesting that epivariations may underlie a fraction of human disease which would be missed by purely sequence-based approaches. Using expression data, we confirmed that many epivariations are associated with outlier gene expression. Analysis of SNV data and monozygous twin pairs suggests that approximately two thirds of epivariations segregate in the population secondary to underlying sequence mutations, while one third are likely sproradic events that occur post-zygotically. We identified 25 loci where rare hypermethylation coincided with the presence of an unstable CGG tandem repeat, and validated the presence of novel CGG expansions at several of these, identifying the molecular defect underlying most of the known folate-sensitive fragile sites in the genome. Our study provides a catalog of rare epigenetic changes in the human genome, gives insight into the underlying origins and consequences of epivariations, and identifies many novel hypermethylated CGG repeat expansions.

genomics↗

bioRxiv2018

Prenatal Bisphenol A Exposure in Mice Induces Multi-tissue Multi-omics Disruptions Linking to Cardiometabolic Disorders

The health impacts of endocrine disrupting chemicals (EDCs) remain debated and their tissue and molecular targets are poorly understood. Here we leveraged systems biology approaches to assess the target tissues, molecular pathways, and gene regulatory networks associated with prenatal exposure to the model EDC Bisphenol A (BPA). Prenatal BPA exposure led to scores of transcriptomic and methylomic alterations in the adipose, hypothalamus, and liver tissues in mouse offspring, with cross-tissue perturbations in lipid metabolism as well as tissue-specific alterations in histone subunits, glucose metabolism and extracellular matrix. Network modeling prioritized main molecular targets of BPA, including Pparg, Hnf4a, Esr1, and Fasn. Lastly, integrative analyses identified the association of BPA molecular signatures with cardiometabolic phenotypes in mouse and human. Our multi-tissue, multi-omics investigation provides strong evidence that BPA perturbs diverse molecular networks in central and peripheral tissues, and offers insights into the molecular targets that link BPA to human cardiometabolic disorders.\n\nAuthor summaryThe inability to pinpoint the mechanistic underpinnings of environmentally-induced diseases likely stems from the pleiotropic effects of chemicals such as BPA on diverse tissues and molecular space (transcriptome, epigenome, etc.). This makes it challenging to fully dissect their health impact and merits a call for modern big data approaches to examine environmental factors. Our data-driven study is the first unbiased, multi-tissue multiomic systems biology investigation of the molecular circuitry and mechanisms underlying offspring response to prenatal BPA exposure. Importantly, the incorporation of network-based modeling allows us to capture novel players in the regulation of BPA activities in vivo, and the integration with human disease association datasets helps bridge the molecular pathways affected by BPA with diverse human diseases. In doing so, our study provides compelling molecular evidence that developmental BPA exposure significantly perturbs metabolic and endocrine systems in the offspring, and supports BPA as one of the environmental factors involved in the developmental origins of health and disease (DOHaD).

systems biology↗