The STRAT-PARK cohort: A personalized initiative to stratify Parkinson's disease.

The STRAT-PARK initiative aims to provide a platform for stratifying Parkinson's disease (PD) into biological subtypes, using a bottom-up, multidisciplinary biomarker-based and data-driven approach. PD is a heterogeneous entity, exhibiting high interindividual clinicopathological variability. This diversity suggests that PD may encompass multiple distinct biological entities, each driven by different molecular mechanisms. Molecular stratification and identification of disease subtypes is therefore a key priority for understanding and treating PD. STRAT-PARK is a multi-center longitudinal cohort aiming to recruit a total of 2000 individuals with PD and neurologically healthy controls from Norway and Canada, for the purpose of identifying molecular disease subtypes. Clinical assessment is performed annually, whereas biosampling, imaging, and digital and neurophysiological phenotyping occur every second year. The unique feature of STRAT-PARK is the diversity of collected biological material, including muscle biopsies and platelets, tissues particularly useful for mitochondrial biomarker research. Recruitment rate is ∼150 participants per year. By March 2023, 252 participants were included, comprising 204 cases and 48 controls. STRAT-PARK is a powerful stratification initiative anticipated to become a global research resource, contributing to personalized care in PD.

Making ties and social identities: Drawing connections between PPNB communities as based on shell bead typology.

People tend to belong to multiple social circles, which construct and reflect a person's social identity. Group affiliation is embodied and may be expressed by personal adornment. Personal adornment in general has multiple functions in human societies, among them the assimilation and transmission of different aspects of personal and collective, social and cultural identity. Beads in general, including shell beads, often constitute parcels of composite adornment, and as such are used in different configurations to portray these messages. The shared use of similar bead types by different individuals and communities indicates the mutual affiliation of the sharing parties to the same cultural circles and reflects social ties and relationships. The Pre-Pottery Neolithic B (PPNB) period in the Levant is a time of pivotal changes to human lifeways necessitating profound adjustments in all aspects of life, including social relations and networks. Here we use the shell bead assemblage from the cultic-mortuary aggregation site of Kfar HaHoresh, in comparison to shell bead assemblages from multiple other sites in the Levant, as a proxy for the exploration of local and regional networks and connections between PPNB communities. Multivariate analyses of shell bead type distribution patterns across the Levant demonstrate that some types were widely shared among different communities, characterising different geographic regions, while others were rare or unique, highlighting relationships between sites and regions, which are occasionally independent of geographic proximity. Specific occurrences of shared shell bead types between Kfar HaHoresh and compared sites further illuminate the web of connections between PPNB communities in the Levant and the varying breadths of sharing-patterns reflect the hierarchical nature of the underlying social circles. Outlining these widening social affiliations sheds light on the complex structure of Neolithic social identity.

Fungal Rhinosinusitis Caused by a Curvularia sp. Infection in a Female Sumatran Orangutan: A Case Report.

Mycotic nasal cavity and paranasal sinus infections in non-human primates (NHPs) are relatively uncommon diseases of the upper respiratory tract. This case study describes the clinical and pathological features as well as the diagnostic techniques and interventions applied to treat the associated disease. A 23-year-old primiparous female Sumatran orangutan residing at Perth Zoo in Western Australia developed intermittent episodes of right-sided epistaxis. An ulcerative nasal mass was identified from a diagnostic endoscopy. The mass was initially biopsied and showed the morphological characteristics of a dematiaceous fungal organism upon a histological examination. There were prominent mucosal and submucosal granulomatous infiltrates containing histocytes, giant cells, and lymphocytes admixed with fewer numbers of neutrophils and eosinophils surrounding the fungal organism. The organism was identified as Curvularia sp. by the fungal characteristics associated with the histopathology, culture growth, and PCR analysis. The mass was subsequently removed with endoscopic sinus surgery (ESS) and the orangutan was medically treated with itraconazole for several months. The recovery was uneventful and the orangutan returned to full health.

Brain iron deposition and movement disorders in hereditary haemochromatosis without liver failure: A cross-sectional study.

BACKGROUND AND PURPOSE: Hereditary haemochromatosis (HH) is the most common inherited disorder of systemic iron excess in Northern Europeans. Emerging evidence indicates that brain iron overload occurs in HH. Despite this observation, there is a paucity of literature regarding central neurological manifestations, in particular movement disorders, in HH. The current study documents deep gray matter (DGM) nuclei iron deposition, movement disorders, and clinicoradiological correlations in HH without liver failure. METHODS: This is a cross-sectional study. Consecutive subjects with HFE-haemochromatosis without liver disease were recruited from an outpatient gastroenterology clinic. Age- and sex-matched healthy controls (HCs) were enrolled. Iron content in individual DGM nuclei was measured as mean susceptibility on magnetic resonance imaging using quantitative susceptibility mapping-based regions of interest analysis. Occurrence and phenotype of movement disorders were documented and correlated with patterns of DGM nuclei iron deposition in subjects with HH. RESULTS: Fifty-two subjects with HH and 47 HCs were recruited. High magnetic susceptibility was demonstrated in several DGM nuclei in all HH subjects compared to HCs. Thirty-five subjects with HH had movement disorders. Magnetic susceptibility in specific DGM nuclei correlated with individual movement disorder phenotypes. Serum ferritin, phlebotomy frequency, and duration were poor predictors of brain iron deposition. CONCLUSIONS: Abnormal brain iron deposition can be demonstrated on imaging in all subjects with HH without liver failure. A significant proportion of these subjects manifest movement disorders. Peripheral iron measurements appear not to correlate with brain iron deposition. Therefore, routine neurological examination and quantitative brain iron imaging are recommended in all subjects with HH.

Clinical, surgical, and pathological findings in client-owned rabbits with histologically confirmed appendicitis: 19 cases (2015-2019).

OBJECTIVE: To report clinical, surgical, and pathological findings in client-owned rabbits with histologically confirmed appendicitis. ANIMALS: 19 rabbits. PROCEDURES: Medical records for client-owned rabbits that had a histologic diagnosis of appendicitis were reviewed. RESULTS: Median age of the rabbits at presentation was 24.0 months (range, 4 to 84 months). Seventeen cases occurred during the summer and fall seasons. Decreased appetite (17/19 rabbits), abnormal rectal temperature (hyperthermia, 9/16 rabbits; hypothermia, 4/16 rabbits), hypocalcemia (8/11 rabbits), and hypoglycemia (7/15 rabbits) were common signs. Abdominal ultrasonography and CT findings were suggestive of appendicitis in 6 of 8 rabbits and in 1 of 2 rabbits, respectively. Of the 6 rabbits that received medical treatment, 3 died at 48 hours, 1 died at 24 hours after hospitalization, and 1 died at 10 days after presentation; 1 rabbit was alive at 1,030 days after presentation. Of the 8 rabbits that underwent appendectomy, 3 died before discharge from the hospital and 1 died 113 days after surgery; 4 rabbits were alive at 315, 334, 1,433, and 1,473 days after presentation. The remaining 5 rabbits either died or were euthanized before treatment could be instituted. In each of the 19 rabbits, the appendix had evidence of severe inflammation with mucosal ulceration, heterophilic inflammation, and necrotic debris. CLINICAL RELEVANCE: For rabbits with decreased appetite and an apparently painful abdomen, hyperthermia, hypocalcemia, or hypoglycemia, appendicitis should be considered as a differential diagnosis. Further comparisons of medical and surgical treatments are required to establish treatment recommendations for rabbits with appendicitis.

Computed tomographic assessment of lung aeration at different positive end-expiratory pressures in a porcine model of intra-abdominal hypertension and lung injury.

BACKGROUND: Intra-abdominal hypertension (IAH) is common in critically ill patients and is associated with increased morbidity and mortality. High positive end-expiratory pressures (PEEP) can reverse lung volume and oxygenation decline caused by IAH, but its impact on alveolar overdistension is less clear. We aimed to find a PEEP range that would be high enough to reduce atelectasis, while low enough to minimize alveolar overdistention in the presence of IAH and lung injury. METHODS: Five anesthetized pigs received standardized anesthesia and mechanical ventilation. Peritoneal insufflation of air was used to generate intra-abdominal pressure of 27 cmH2O. Lung injury was created by intravenous oleic acid. PEEP levels of 5, 12, 17, 22, and 27 cmH2O were applied. We performed computed tomography and measured arterial oxygen levels, respiratory mechanics, and cardiac output 5 min after each new PEEP level. The proportion of overdistended, normally aerated, poorly aerated, and non-aerated atelectatic lung tissue was calculated based on Hounsfield units. RESULTS: PEEP decreased the proportion of poorly aerated and atelectatic lung, while increasing normally aerated lung. Overdistension increased with each incremental increase in applied PEEP. "Best PEEP" (respiratory mechanics or oxygenation) was higher than the "optimal CT inflation PEEP range" (difference between lower inflection points of atelectatic and overdistended lung) in healthy and injured lungs. CONCLUSIONS: Our findings in a large animal model suggest that titrating a PEEP to respiratory mechanics or oxygenation in the presence of IAH is associated with increased alveolar overdistension.

Osseous Migration of a Perforating Gastrointestinal Foreign Body in an Indian Runner Duck (Anas platyrhynchos domesticus).

An Indian runner duck (Anas platyrhynchos domesticus) was presented for a second opinion after a linear, metallic foreign body was identified on radiographic images. The primary veterinarian performed diagnostic imaging while investigating the presenting complaint of the duck's left pelvic limb lameness. The images obtained from a computed tomography scan performed during the second-opinion visit revealed a linear, metallic foreign body with an associated migration tract originating from the ventriculus and terminating in the proximal left femur. Significant osteomyelitis was noted at the proximal left femur associated with the presence of the linear, metallic object. The foreign body and the adhesions associated with its migration were removed in 2, staged, surgical procedures. Although penetrating ventricular foreign bodies have been previously reported, migration through the cortex of a long bone is an unusual presentation. This case demonstrates that perforating, migrating, gastrointestinal foreign bodies can result in lameness refractory to analgesia and ancillary supportive care.

Surgical treatment and outcome of complete unilateral urinary tract duplication in a dog.

OBJECTIVE: To report the surgical technique and outcome for correction of complete unilateral duplication of the left urinary tract in a dog. ANIMALS: One 7-month-old entire male Jack Russell terrier. STUDY DESIGN: Case report METHODS: A dog was referred for investigation because of urinary incontinence (UI), preputial irritation (pruritus), diphallia, and cryptorchidism. Computed tomography including urethrographic studies revealed a left duplex kidney, double ectopic left ureters, and a duplex urinary bladder comprising two halves separated by a median septum, each of which emptied into a separate urethra which coursed through separate penises. The left testis was abdominally retained. The right upper urinary tract was considered normal, and the right testis was within the scrotum. Left sided ureteronephrectomy was performed, the median bladder septum was ablated, and the left urethra was ligated. The left penis was partially amputated, and the dog was castrated. RESULTS: Urinary incontinence was improved but persisted after surgery. After repeat imaging, revision surgery was performed 3 months later in which the distal stumps of the (left) ectopic ureters were found to be filling with urine from the right urethra. Urinary incontinence resolved after resection of these ureteric stumps from the prostate and complete transection of the left urethra. CONCLUSION: Extensive surgery with resection and correction of urinary tract duplication was successful in resolving UI in this case. Urogenital duplication should be considered a rare cause of UI. The presence of external congenital deformity (eg, diphallia) should alert clinicians to the possibility of significant concurrent internal abnormalities.

A Noninvasive Blood-based Combinatorial Proteomic Biomarker Assay to Detect Breast Cancer in Women over age 50 with BI-RADS 3, 4, or 5 Assessment.

PURPOSE: With improvements in breast cancer imaging, there has been a corresponding increase in false-positives and avoidable biopsies. There is a need to better differentiate when a breast biopsy is warranted and determine appropriate follow-up. This study describes the design and clinical performance of a combinatorial proteomic biomarker assay (CPBA), Videssa Breast, in women over age 50 years. EXPERIMENTAL DESIGN: A BI-RADS 3, 4, or 5 assessment was required for clinical trial enrollment. Serum was collected prior to breast biopsy and subjects were followed for 6-12 months and clinically relevant outcomes were recorded. Samples were split into training (70%) and validation (30%) cohorts with an approximate 1:4 case:control ratio in both arms. RESULTS: A CPBA that combines biomarker data with patient clinical data was developed using a training cohort (469 women, cancer incidence: 18.5%), resulting in 94% sensitivity and 97% negative predictive value (NPV). Independent validation of the final algorithm in 194 subjects (breast cancer incidence: 19.6%) demonstrated a sensitivity of 95% and a NPV of 97%. When combined with previously published data for women under age 50, Videssa Breast achieves a comprehensive 93% sensitivity and 98% NPV in a population of women ages 25-75. Had Videssa Breast results been incorporated into the clinical workflow, approximately 45% of biopsies might have been avoided. CONCLUSIONS: Videssa Breast combines serum biomarkers with clinical patient characteristics to provide clinicians with additional information for patients with indeterminate breast imaging results, potentially reducing false-positive breast biopsies.

Bilateral bronchial stent deployment for palliative treatment of a compressive intrathoracic mass in a cat.

CASE SUMMARY: Bronchial stents may be useful to relieve clinical signs of extraluminal compression. Herein we describe a case which, to our knowledge, is the first cat where bilateral bronchial stents have been used clinically. Respiratory signs of principal bronchial compression were alleviated after the stent procedure. Minor complications occurred, specifically: severe hypoxia during stent deployment; a transient, self-limiting postoperative pneumothorax possibly associated with ventilation-induced lung injury; bronchopneumonia (possibly pre-existing); and transient worsening of cough postoperatively. Stents were well- tolerated long- term. The cat was euthanased at 44 weeks post-stent procedure, owing to clinical signs of regurgitation, seemingly related to oesophageal dysfunction associated with tumour invasion. RELEVANCE AND NOVEL INFORMATION: In this case, it appeared that bronchial stents were feasible and the procedure was associated with long-term improvement in respiratory signs related to extraluminal bronchial compression.

A Combinatorial Proteomic Biomarker Assay to Detect Ovarian Cancer in Women.

Ovarian cancer is often fatal and incidence in the general population is low, underscoring the necessity (and the challenges) for advancements in screening and early detection. The goal of this study was to design a serum-based biomarker panel and corresponding multivariate algorithm that can be used to accurately detect ovarian cancer. A combinatorial protein biomarker assay (CPBA) that uses CA125, HE4, and 3 tumor-associated autoantibodies resulted in an area under the curve of 0.98. The CPBA Ov algorithm was trained using subjects who were suspected to have gynecological cancer and were scheduled for surgery. As a surgical rule-out test, the clinical performance achieves 100% sensitivity and 83.7% specificity. Although sample size (n = 60) is a limiting factor, the CPBA Ov algorithm performed better than either CA-125 alone or the Risk of Ovarian Malignancy Algorithm.

Breast density does not impact the ability of Videssa® Breast to detect breast cancer in women under age 50.

Breast density is associated with reduced imaging resolution in the detection of breast cancer. A biochemical approach that is not affected by density would provide an important tool to healthcare professionals who are managing women with dense breasts and suspicious imaging findings. Videssa® Breast is a combinatorial proteomic biomarker assay (CPBA), comprised of Serum Protein Biomarkers (SPB) and Tumor Associated Autoantibodies (TAAb) integrated with patient-specific clinical data to produce a diagnostic score that reliably detects breast cancer (BC) as an adjunctive tool to imaging. The performance of Videssa® Breast was evaluated in the dense (a and b) and non-dense (c and d) groups in a population of n = 545 women under age 50. The sensitivity and specificity in the dense breast group were calculated to be 88.9% and 81.2%, respectively, and 92.3% and 86.6%, respectively, for the non-dense group. No significant differences were observed in the sensitivity (p = 1.0) or specificity (p = 0.18) between these groups. The NPV was 99.3% and 99.1% in non-dense and dense groups, respectively. Unlike imaging, Videssa® Breast does not appear to be impacted by breast density; it can effectively detect breast cancer in women with dense and non-dense breasts alike. Thus, Videssa® Breast provides a powerful tool for healthcare providers when women with dense breasts present with challenging imaging findings. In addition, Videssa® Breast provides assurance to women with dense breasts that they do not have breast cancer, reducing further anxiety in this higher risk patient population.

A Noninvasive Blood-based Combinatorial Proteomic Biomarker Assay to Detect Breast Cancer in Women Under the Age of 50 Years.

BACKGROUND: Despite significant advances in breast imaging, the ability to detect breast cancer (BC) remains a challenge. To address the unmet needs of the current BC detection paradigm, 2 prospective clinical trials were conducted to develop a blood-based combinatorial proteomic biomarker assay (Videssa Breast) to accurately detect BC and reduce false positives (FPs) from suspicious imaging findings. PATIENTS AND METHODS: Provista-001 and Provista-002 (cohort one) enrolled Breast Imaging Reporting and Data System 3 or 4 women aged under 50 years. Serum was evaluated for 11 serum protein biomarkers and 33 tumor-associated autoantibodies. Individual biomarker expression, demographics, and clinical characteristics data from Provista-001 were combined to develop a logistic regression model to detect BC. The performance was tested using Provista-002 cohort one (validation set). RESULTS: The training model had a sensitivity and specificity of 92.3% and 85.3% (BC prevalence, 7.7%), respectively. In the validation set (BC prevalence, 2.9%), the sensitivity and specificity were 66.7% and 81.5%, respectively. The negative predictive value was high in both sets (99.3% and 98.8%, respectively). Videssa Breast performance in the combined training and validation set was 99.1% negative predictive value, 87.5% sensitivity, 83.8% specificity, and 25.2% positive predictive value (BC prevalence, 5.87%). Overall, imaging resulted in 341 participants receiving follow-up procedures to detect 30 cancers (90.6% FP rate). Videssa Breast would have recommended 111 participants for follow-up, a 67% reduction in FPs (P < .00001). CONCLUSIONS: Videssa Breast can effectively detect BC when used in conjunction with imaging and can substantially reduce unnecessary medical procedures, as well as provide assurance to women that they likely do not have BC.

Identifying Community Perspectives for a Lung Cancer Screening Awareness Campaign in Appalachia Kentucky: The Terminate Lung Cancer (TLC) Study.

Lung cancer screening with low-dose computed tomography (LDCT) scan is now covered by Centers for Medicare & Medicaid Services following an evidence-based recommendation, but a shared decision making process should inform patients of risks and limitations. An awareness campaign promoting LDCT screenings is an opportunity to elicit patient engagement with health providers about the risks and benefits. Focus groups representing three regions of Appalachian Kentucky known for high lung cancer rates discussed development of a lung cancer screening campaign. Recommendations included messaging content, appeals or design, campaign implementation, and trusted information or communication sources. Community health workers (CHWs) from three Eastern Kentucky regions recruited individuals from their local communities using established client files. CHWs hosted six total focus groups (7-11 participants each) using questions guided by the Communication-Persuasion Matrix framework. All sessions were recorded and transcribed for independent content analysis. A total of 54 individuals (61.1 % female; >55 pack year history) were participated. Prior to discussion, most participants had not heard of lung cancer screening. Cited needs for content of a campaign included benefits of early detection and payment information. Messages considered most persuasive were those that include personal testimony, messages of hope, prolonged life, and an emphasis on family and the ambition to survive. Having information come from one's family doctor or specialty provider was considered important to message communication. Messages about survivorship, family, and prolonged life should be considered in lung cancer screening awareness campaigns. Our results provide community input about messages regarding screening options.

Terminate lung cancer (TLC) study-A mixed-methods population approach to increase lung cancer screening awareness and low-dose computed tomography in Eastern Kentucky.

For low dose CT lung cancer screening to be effective in curbing disease mortality, efforts are needed to overcome barriers to awareness and facilitate uptake of the current evidence-based screening guidelines. A sequential mixed-methods approach was employed to design a screening campaign utilizing messages developed from community focus groups, followed by implementation of the outreach campaign intervention in two high-risk Kentucky regions. This study reports on rates of awareness and screening in intervention regions, as compared to a control region.

Corexit-EC9527A Disrupts Retinol Signaling and Neuronal Differentiation in P19 Embryonal Pluripotent Cells.

Corexit-EC9500A and Corexit-EC9527A are two chemical dispersants that have been used to remediate the impact of the 2010 Deepwater Horizon oil spill. Both dispersants are composed primarily of organic solvents and surfactants and act by emulsifying the crude oil to facilitate biodegradation. The potential adverse effect of the Corexit chemicals on mammalian embryonic development remains largely unknown. Retinol (vitamin A) signaling, mediated by all-trans retinoic acid (RA), is essential for neural tube formation and the development of many organs in the embryo. The physiological levels of RA in cells and tissues are maintained by the retinol signaling pathway (RSP), which controls the biosynthesis of RA from dietary retinol and the catabolism of RA to polar metabolites for removal. RA is a potent activating ligand for the RAR/RXR nuclear receptors. Through RA and the receptors, the RSP modulates the expression of many developmental genes; interference with the RSP is potentially teratogenic. In this study the mouse P19 embryonal pluripotent cell, which contains a functional RSP, was used to evaluate the effects of the Corexit dispersants on retinol signaling and associated neuronal differentiation. The results showed that Corexit-EC9500A was more cytotoxic than Corexit-EC9527A to P19 cells. At non-cytotoxic doses, Corexit-EC9527A inhibited retinol-induced expression of the Hoxa1 gene, which encodes a transcription factor for the regulation of body patterning in the embryo. Such inhibition was seen in the retinol- and retinal- induced, but not RA-induced, Hoxa1 up-regulation, indicating that the Corexit chemicals primarily inhibit RA biosynthesis from retinal. In addition, Corexit-EC9527A suppressed retinol-induced P19 cell differentiation into neuronal cells, indicating potential neurotoxic effect of the chemicals under the tested conditions. The surfactant ingredient, dioctyl sodium sulfosuccinate (DOSS), may be a major contributor to the observed effect of Corexit-EC9527A in the cell.

Integration of Serum Protein Biomarker and Tumor Associated Autoantibody Expression Data Increases the Ability of a Blood-Based Proteomic Assay to Identify Breast Cancer.

Despite significant advances in breast imaging, the ability to accurately detect Breast Cancer (BC) remains a challenge. With the discovery of key biomarkers and protein signatures for BC, proteomic technologies are currently poised to serve as an ideal diagnostic adjunct to imaging. Research studies have shown that breast tumors are associated with systemic changes in levels of both serum protein biomarkers (SPB) and tumor associated autoantibodies (TAAb). However, the independent contribution of SPB and TAAb expression data for identifying BC relative to a combinatorial SPB and TAAb approach has not been fully investigated. This study evaluates these contributions using a retrospective cohort of pre-biopsy serum samples with known clinical outcomes collected from a single site, thus minimizing potential site-to-site variation and enabling direct assessment of SPB and TAAb contributions to identify BC. All serum samples (n = 210) were collected prior to biopsy. These specimens were obtained from 18 participants with no evidence of breast disease (ND), 92 participants diagnosed with Benign Breast Disease (BBD) and 100 participants diagnosed with BC, including DCIS. All BBD and BC diagnoses were based on pathology results from biopsy. Statistical models were developed to differentiate BC from non-BC (i.e., BBD and ND) using expression data from SPB alone, TAAb alone, and a combination of SPB and TAAb. When SPB data was independently used for modeling, clinical sensitivity and specificity for detection of BC were 74.7% and 77.0%, respectively. When TAAb data was independently used, clinical sensitivity and specificity for detection of BC were 72.2% and 70.8%, respectively. When modeling integrated data from both SPB and TAAb, the clinical sensitivity and specificity for detection of BC improved to 81.0% and 78.8%, respectively. These data demonstrate the benefit of the integration of SPB and TAAb data and strongly support the further development of combinatorial proteomic approaches for detecting BC.

Disruption of Retinol (Vitamin A) Signaling by Phthalate Esters: SAR and Mechanism Studies.

A spectrum of reproductive system anomalies (cryptorchidism, hypospadias, dysgenesis of Wolffian duct-derived tissues and prostate, and reduced sperm production) in male rats exposed in utero to phthalate esters (PEs) are thought to be caused by PE inhibition of fetal testosterone production. Recently, dibutyl and dipentyl phthalate (DBuP, DPnP) were shown to disrupt the retinol signaling pathway (RSP) in mouse pluripotent P19 embryonal carcinoma cells in vitro. The RSP regulates the synthesis and cellular levels of retinoic acid (RA), the active metabolite of retinol (vitamin A). In this new study, a total of 26 di- and mono-esters were screened to identify additional phthalate structures that disrupt the RSP and explore their mechanisms of action. The most potent PEs, those causing > 50% inhibition, contained aryl and cycloalkane groups or C4-C6 alkyl ester chains and were the same PEs reported to cause malformations in utero. They shared similar lipid solubility; logP values were between 4 and 6 and, except for PEs with butyl and phenyl groups, were stable for prolonged periods in culture. Mono- and cognate di-esters varied in ability to disrupt the RSP; e.g., DEHP was inactive but its monoester was active while DBuP was active yet its monoester was inactive. DBuP and dibenzyl phthalate both disrupted the synthesis of RA from retinol but not the ability of RA to activate gene transcription. Both PEs also disrupted the RSP in C3H10T1/2 multipotent mesenchymal stem cells. Based on this in vitro study showing that some PEs disrupt retinol signaling and previous in vivo studies that vitamin A/RA deficiency and PEs both cause strikingly similar anomalies in the male rat reproductive system, we propose that PE-mediated inhibition of testosterone and RA synthesis in utero are both causes of malformations in male rat offspring.