About

Sara Elizabeth Pinney, MD, MS, is an Associate Professor of Pediatrics specializing in Endocrinology and Diabetes at the Children's Hospital of Philadelphia. She is a member of several research centers at the University of Pennsylvania School of Medicine, including the Institute of Diabetes, Obesity and Metabolism/Diabetes Research Center, the Center for Excellence in Environmental Toxicology, the Center for Research on Reproduction and Women's Health, and the Institute of Translational Medicine and Therapeutics. Dr. Pinney's work focuses on pediatric endocrinology and diabetes, contributing to research and clinical care in these fields. She holds degrees from the University of Pennsylvania and the University of Cincinnati College of Medicine, including an M.S. in Translational Research.

Research topics

• Computational biology
• Bioinformatics
• Medicine
• Genetics
• Mathematics
• Biology
• Obstetrics

Selected publications

• Pediatric Hepatocyte Nuclear Factor 1B ( <i>HNF1B</i> ) Disease: Diabetes and Endocrine Manifestations

  Pediatric Diabetes · 2025-01-01 · 1 citations

  articleOpen accessSenior authorCorresponding

  Context: Mutations in hepatocyte nuclear factor 1B ( HNF1B ) are rare but they are known to cause structural renal disease and diabetes mellitus. There is limited data on pediatric HNF1B disease. Objective: To analyze the clinical characteristics of HNF1B ‐related disease in a cohort of children identified at a single pediatric tertiary medical center, with a specific focus on endocrine‐related disease. Methods: Subjects with HNF1B genetic variants were identified from the Children’s Hospital of Philadelphia Atypical Diabetes Registry between 2013 and 2022. Results: Of the 11 pediatric subjects with HNF1B mutations or deletions, 7 (64%) initially presented with diabetes, sometimes referred to as MODY5, while 4 (36%) were diagnosed based on family history or a genetic evaluation of renal disease. Only one patient presented with diabetic ketoacidosis, and three presented with diabetic ketosis. Of the four children with HNF1B mutations identified by familial mutation analysis or based on renal disease, two developed diabetes during the course of the study. Abnormalities in fasting lipid profiles were common: 10 with triglycerides &gt;90 mg/dL, 5 with LDL‐C &gt;110 mg/dL, 5 with HDL‐C &lt;45, and 7/11 with non‐HDL cholesterol &gt;120 mg/dL. Over half of the subjects had hyperparathyroidism with PTH (&gt;65 pg/mL) and a calcium concentration &gt;9 mg/dL. Conclusion: This case series represents one of the largest pediatric HNF1B ‐related disease cohorts at a single center. The majority of patients with diabetes presented with clinical features distinct from Type 1 or Type 2 diabetes. Pediatricians should consider genetic testing for HNF1B mutations when children are diagnosed with diabetes and have renal abnormalities, hyperlipidemia, and hyperparathyroidism.

  PublisherOA PDFDOI

• P186: The earliest sign of hypogonadotropic hypogonadism: The importance of genetic screening and evaluation in individuals with microphallus

  Genetics in Medicine Open · 2024-01-01

  articleOpen access

  Microphallus is a congenital difference in male presenting individuals defined as a stretched penile length of less than 2.5 standard deviations (SDs) below the mean for age. As an anomaly affecting the genital system, this is a finding that meets criteria for a variation of sex characteristic/difference of sex development (VSC/DSD). Currently, 37 OMIM genes have microphallus as associations, most of which are related to Hypogonadotropic Hypogonadism (HH). HH can be defined as failure of the normal episodic GnRH secretion.

  PublisherOA PDFDOI

• RF22 | PSUN318 Hepatocytes Exposed to PFOA Prior to Differentiation Leads to Epigenetic Changes in Genes Linked With NAFLD

  Journal of the Endocrine Society · 2022-11-01

  articleOpen access

  Abstract Background Perfluorooctanoic acid (PFOA), is a persistent fluorinated compound with oil and water repelling properties found in cookware, food packaging and municipal water systems. Adult animals exposed to PFOA develop hepatomegaly, fatty liver, peroxisome proliferation, and immunotoxicity. Rodents exposed to PFOA in utero have altered hepatic lipid metabolism, increased hepatic de novo lipogenesis and susceptibility to non-alcoholic fatty liver disease (NAFLD), but underlying molecular mechanisms remain unknown. With increasing rates of obesity, diabetes, and NAFLD it is critical to examine the mechanisms by which in utero exposure to PFOA contributes to the development of metabolic syndrome in offspring. Objectives To characterize how PFOA exposure during hepatocyte differentiation leads to the development of NAFLD through alterations in DNA methylation profiles and changes in the availability of transcription factor binding sites. Methods HepaRG cells (human-derived hepatocyte progenitor cells) were treated with 0.5uM PFOA or vehicle for 48 hours followed by differentiation. Undifferentiated and differentiated hepatocytes exposed to PFOA were assessed relative to controls (n=4). RNASeq was completed; DESeq2 identified differentially expressed genes via false discovery rate (FDR) of &amp;lt;0.05 after Bonferroni correction. Genome-wide DNA methylation analysis via MethylSeq was completed to identify differentially methylated regions (DMRs) defined as minimum number of CpN =5, absolute change in percent methylation &amp;gt;10%, and FDR of &amp;lt;0.05. Enrichment analysis of transcription factor binding motifs within DMRs and single CpG sites (± 200 bp) was performed using HOMER. Results PFOA treatment resulted in decreased expression of the transcription factors early growth response protein 1 (EGR1), nuclear receptor Nur77 (NR4A1), early growth response protein 2 (EGR2), krueppel-like factor 10 (KLF10) and fos-related antigen 1 (FOSL1), which are key genes linked to impaired hepatic insulin signaling, lipid metabolism, steatosis and fibrosis (q&amp;lt;0.05) in undifferentiated hepatocytes. Differentiated hepatocytes showed decreased expression of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), peroxisome proliferator-activated receptor γ (PPARγ), forkhead box protein O1 (FOXO1) and increased expression of pyruvate dehydrogenase kinase isozyme 4 (PDK4), genes linked to regulation of lipid metabolism and insulin signaling (q &amp;lt;0.05). MethylSeq analysis identified changes in DMRs located in exons, introns, and intergenic regions, with 57 DMRs in undifferentiated hepatocytes (46 with gains; 11 with losses; q &amp;lt;0.05) and 75 DMRs in differentiated hepatocytes (32 with gains; 41 with losses; q&amp;lt;0.05). HOMER identified 29 known transcription factor binding motifs with changes in methylation in undifferentiated hepatocytes (p&amp;lt;0.05) and 19 in differentiated hepatocytes after PFOA treatment (p&amp;lt;0.05), with significant changes in the EGR1 consensus sequence identified in both comparisons. Conclusions We conclude hepatocyte progenitor cells exposed to low dose PFOA results in changes in DNA methylation and expression of key metabolic genes linked to NAFLD, notably EGR1, a gene previously linked to NAFLD, suggesting PFOA exposure in utero has lasting effects. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:48 p.m. - 12:53 p.m.

  PublisherOA PDFDOI

• Diagnostic and management considerations in pseudohypoaldosteronism type 1b

  BMJ Case Reports · 2022-01-01 · 1 citations

  articleOpen access

  Pseudohypoaldosteronism type 1B is a rare autosomal recessive disorder caused by dysfunction of amiloride-sensitive epithelial sodium channels (ENaCs). We present the case of a neonate with cardiogenic shock after cardiac arrest due to profound hyperkalaemia. Genetic testing revealed a novel homozygous variant in SCNNIA . We review diagnostic considerations including the molecular mechanisms of disease, discuss treatment approaches and highlight the possible significance of the diversity of pulmonary ENaCs.

  PublisherOA PDFDOI

• PFOA Exposure Prior to Hepatocyte Differentiation Leads to Gene Expression Changes Implicated in Non-Alcoholic Fatty Liver Disease

  Journal of the Endocrine Society · 2021-05-01

  articleOpen accessSenior author

  Abstract Background: Perfluorooctanoic acid (PFOA), is a persistent fluorinated compound with oil and water repelling properties found in cookware, food packaging and municipal water systems. Adult animals exposed to PFOA develop hepatomegaly, fatty liver, peroxisome proliferation, and immunotoxicity. Rodents exposed to PFCs in utero have altered hepatic lipid metabolism, increased hepatic de novo lipogenesis and susceptibility to non-alcoholic fatty liver disease (NAFLD), but underlying molecular mechanisms remain unknown. With increasing rates of obesity, diabetes, and NAFLD it is critical to examine the mechanisms by which in utero exposure to PFOA contributes to the development of metabolic syndrome in offspring. Objective: To determine mechanism by which PFOA alters gene expression in undifferentiated hepatic progenitor cells. Design/methods: HepaRG cells, a human derived hepatocyte progenitor cell line, was treated with 0.5uM PFOA or vehicle for 48 hours followed by differentiation into hepatocytes. Total RNA was extracted using the RNeasy (Qiagen) [total RNA A260/280&amp;gt;2 and RNA integrity number &amp;gt;7 (Agilent Bioanalyzer)] to generate libraries with the Illumina TruSeq stranded total RNA kit. RNA-Seq was performed using 85 bp single-end read sequencing to generate &amp;gt;20 million reads per sample. RNAseq data was aligned to hg38 using STAR v2.6.1a and then quantified with featureCounts v1.6.2. DESeq2 identified differentially expressed genes via FDR (false discovery rate) after Bonferroni correction. Differentially expressed gene lists were used for Ingenuity Pathway Analysis (IPA) to identify pathways of biological significance. Results: PFOA treatment resulted in increased expression of transcription factors EGR1 (early growth response protein 1), NR4A1 (nuclear receptor Nur77), EGR2 (early growth response protein 2), KLF10 (Krueppel-like factor 10) and FOSL1 (Fos-related antigen 1), key genes linked to impaired hepatic insulin signaling, hepatic lipid metabolism, steatosis and fibrosis (fold change &amp;gt; 1.5; q &amp;lt;0.05). IPA identified enrichment of canonical pathways with biological relevance including hepatic fibrosis signaling, stellate cell activation, VDR/RXR/TR activation, and Type 2 diabetes mellitus signaling (p&amp;lt;0.01). Conclusion: Hepatocyte progenitor cells exposed to low dose PFOA for 48 hours prior to differentiation results in changes in expression of key metabolic genes linked to the development of NAFLD and enrichment of biologically relevant pathways associated with hepatic fibrosis and hepatocellular carcinoma. These results suggest that PFOA exposure in utero may have lasting effects on hepatic glucose and lipid metabolism after differentiation. Further studies are needed to characterize the longstanding metabolic effects of in utero PFOA exposure in offspring and the mechanisms driving the persistence of these changes.

  PublisherOA PDFDOI

• Identification of Novel Regulatory Regions Induced by Intrauterine Growth Restriction in Rat Islets

  Figshare · 2021-01-01

  datasetOpen access

  Supplemental Tables and Figure

  PublisherDOI

• Identification of Novel Regulatory Regions Induced by Intrauterine Growth Restriction in Rat Islets

  Endocrinology · 2021-12-11 · 6 citations

  articleOpen access

  Intrauterine growth restriction (IUGR) leads to the development of type 2 diabetes in adulthood, and the permanent alterations in gene expression implicate an epigenetic mechanism. Using a rat model of IUGR, we performed TrueSeq-HELP Tagging to assess the association of DNA methylation changes and gene dysregulation in islets. We identified 511 differentially methylated regions (DMRs) and 4377 significantly altered single CpG sites. Integrating the methylome and our published transcriptome data sets resulted in the identification of pathways critical for islet function. The identified DMRs were enriched with transcription factor binding motifs, such as Elk1, Etv1, Foxa1, Foxa2, Pax7, Stat3, Hnf1, and AR. In silico analysis of 3-dimensional chromosomal interactions using human pancreas and islet Hi-C data sets identified interactions between 14 highly conserved DMRs and 35 genes with significant expression changes at an early age, many of which persisted in adult islets. In adult islets, there were far more interactions between DMRs and genes with significant expression changes identified with Hi-C, and most of them were critical to islet metabolism and insulin secretion. The methylome was integrated with our published genome-wide histone modification data sets from IUGR islets, resulting in further characterization of important regulatory regions of the genome altered by IUGR containing both significant changes in DNA methylation and specific histone marks. We identified novel regulatory regions in islets after exposure to IUGR, suggesting that epigenetic changes at key transcription factor binding motifs and other gene regulatory regions may contribute to gene dysregulation and an abnormal islet phenotype in IUGR rats.

  PublisherOA PDFDOI

• Identification of Novel Regulatory Regions Induced by Intrauterine Growth Restriction in Rat Islets

  Figshare · 2021-01-01

  datasetOpen access

  Supplemental Tables and Figure

  PublisherDOI

• Exposure to high fructose corn syrup during adolescence in the mouse alters hepatic metabolism and the microbiome in a sex‐specific manner

  The Journal of Physiology · 2021-01-16 · 36 citations

  articleOpen access

  KEY POINTS: The prevalence of obesity and non-alcoholic fatty liver disease in children is dramatically increasing at the same time as consumption of foods with a high sugar content. Intake of high fructose corn syrup (HFCS) is a possible aetiology as it is thought to be more lipogenic than glucose. In a mouse model, HFCS intake during adolescence increased fat mass and hepatic lipid levels in male and female mice. However, only males showed impaired glucose tolerance. Multiple metabolites including lipids, bile acids, carbohydrates and amino acids were altered in liver in a sex-specific manner at 6 weeks of age. Some of these changes were also present in adulthood even though HFCS exposure ended at 6 weeks. HFCS significantly altered the gut microbiome, which was associated with changes in key microbial metabolites. These results suggest that HFCS intake during adolescence has profound metabolic changes that are linked to changes in the microbiome and these changes are sex-specific. ABSTRACT: The rapid increase in obesity, diabetes and fatty liver disease in children over the past 20 years has been linked to increased consumption of high fructose corn syrup (HFCS), making it essential to determine the short- and long-term effects of HFCS during this vulnerable developmental window. We hypothesized that HFCS exposure during adolescence significantly impairs hepatic metabolic signalling pathways and alters gut microbial composition, contributing to changes in energy metabolism with sex-specific effects. C57bl/6J mice with free access to HFCS during adolescence (3-6 weeks of age) underwent glucose tolerance and body composition testing and hepatic metabolomics, gene expression and triglyceride content analysis at 6 and 30 weeks of age (n = 6-8 per sex). At 6 weeks HFCS-exposed mice had significant increases in fat mass, glucose intolerance, hepatic triglycerides (females) and de novo lipogenesis gene expression (ACC, DGAT, FAS, ChREBP, SCD, SREBP, CPT and PPARα) with sex-specific effects. At 30 weeks, HFCS-exposed mice also had abnormalities in glucose tolerance (males) and fat mass (females). HFCS exposure enriched carbohydrate, amino acid, long chain fatty acid and secondary bile acid metabolism at 6 weeks with changes in secondary bile metabolism at 6 and 30 weeks. Microbiome studies performed immediately before and after HFCS exposure identified profound shifts of microbial species in male mice only. In summary, short-term HFCS exposure during adolescence induces fatty liver, alters important metabolic pathways, some of which continue to be altered in adulthood, and changes the microbiome in a sex-specific manner.

  PublisherOA PDFDOI

• A Novel Graph Based Semi-Supervised Learning Approach to Identify Pathways Contributing to the Development of Diabetes and Obesity

  Journal of the Endocrine Society · 2021-05-01

  articleOpen accessSenior author

  Abstract Background: Gestational diabetes (GDM) has profound effects on the intrauterine metabolic milieu, induces marked abnormalities in fetal glucose and insulin secretion and is linked to obesity and diabetes in the offspring, but the mechanisms remain largely unknown. Epigenetic modifications in stems cells may be one mechanism by which an in utero exposure can lead to the development of diabetes and obesity later in life. Objective: To identify novel pathways contributing to the development of diabetes and obesity in offspring exposed to GDM in utero by integrating data generated from transcriptome and methylome analysis from second trimester human amniocytes exposed to GDM in utero. Methods: We analyzed RNAseq and genome wide DNA methylation data (ERRBS) generated from second trimester amniocytes obtained from women with GDM (n=14). Amniocytes have stem cells-like characteristics and are derived from the fetus. Expression data of 22,271 genes were retrieved from RNAseq data. CpGs with significant changes in DNA methylation were mapped into 20,028 genes by collapsing methylation probes into promoter and gene regions. To better understand the associations among diverse gene sets or among gene sets and GDM,we first constructed two weighted co-expression networks from RNAseq and DNA methylation data, respectively. Then, two co-expression networks were integrated using a linear combination. With the integrated co-expression network, graph-based label propagation algorithm was employed to prioritize GDM-associated genes. Results: From the differential expression analysis between GDM and control, the top 20 query genes, including 11 genes and 9 methylated genes, were selected for label propagation. Finally, the top 100 genes were picked up for the pathway enrichment testusing an over-representation analysis approach. Significantly enriched pathways included: Interferon Signaling, N-glycan Antennae Elongation, Sphingolipid Pathway and Metabolism, Classical Complement Pathway, Complement and Coagulation Cascades, Tryptophan Metabolism, Peroxisomal Protein Import, Unsaturated Fatty Acid Metabolism, Complement Activation, Human Innate Immune Response, Ceramide Metabolism, Fertilization Pathway, Keratan Sulfate Biosynthesis Pathway, Transport to the Golgi and Modification Pathway (FDR q&amp;lt;0.05 for all pathways). Conclusion: Using a novel bioinformatic approach to synthesize transcriptome and methylome data derived from human amniocytes exposed to GDM in utero, we identified potential pathways involved in programming of diabetes and obesity in offspring including pathways involving the immune response, complex lipid metabolism, the complement pathway, and protein transport and processing. Further investigation of these pathways may yield new mechanisms contributing to diabetes and obesity.

  PublisherDOI

Recent grants

• NIH Grant K08DK090302

  NIH · $581k · 2017

• Longitudinal study of endocrine disrupting chemical exposure and the early hormonal milieu of girls around the time of thelarche

  NIH · $861k · 2018–2023

• Community Engagement Core

  NIH · $31.3M · 1997–2025

Frequent coauthors

• Rebecca A. Simmons

  48 shared

• Apoorva Joshi

  All India Institute of Medical Sciences, Nagpur

  11 shared

• Lane J. Jaeckle Santos

  University of Pennsylvania

  9 shared

• Yilong Han

  University of Pennsylvania

  9 shared

• Clementina Mesaros

  8 shared

• Amita Bansal

  Novartis (Switzerland)

  8 shared

• Nathaniel W. Snyder

  8 shared

• Ian A. Blair

  University of Pennsylvania

  8 shared

Labs

• Sara Elizabeth Pinney LabPI