Introduction: Breast neoplasms with neuroendocrine characteristics form a rare and heterogeneous group that includes both invasive carcinomas showing neuroendocrine differentiation and primary neuroendocrine tumors arising in the breast. Because these lesions are uncommon, their clinicopathological features and biological behavior are still not fully elucidated. Methods: We conducted a retrospective analysis of 22 patients diagnosed with breast tumors showing neuro-endocrine features and treated in 1st Surgical Unit of Regional Institute of Oncology, Iasi. Clinicopathological characteristics, immunohistochemical profile and treatment patterns were analyzed. Results: The median age at diagnosis was 66.1 years (range: 35 83). Most tumors corresponded to invasive carcinoma of no special type with neuroendocrine differentiation, while a smaller subset fulfilled the criteria for primary neuroendocrine neoplasms of the breast. Immunohistochemical analysis revealed a predominantly luminal immunophenotype, characterized by strong estrogen receptor expression and absence of HER2 overexpression. T0he median Ki-67 proliferation index was 40.3%. Lymph node involvement was observed in 45.5% of cases. All patients were treated according to standard breast cancer protocols, including surgery, chemotherapy, endocrine therapy and radiotherapy when indicated. The median follow-up was 26 months. Survival analysis included 20 patients with available follow-up data, while 2 patients were lost to follow-up. During the follow-up period, 9 deaths were recorded, corresponding to an overall mortality rate of approximately 45%. Conclusions: In our study, breast tumors with neuroendocrine features exhibited a luminal immunophenotype and did not demonstrate a clearly distinct clinical behavior compared with conventional hormone receptor positive breast cancer. Neuroendocrine differentiation may therefore represent a morphological feature within the luminal spectrum rather than a distinct biological entity.
The gut microbiota has emerged as a key endocrine modulator that shapes host appetite regulation through its metabolites and their interactions with enteroendocrine and central neuroendocrine pathways. Microbial metabolites-including short-chain fatty acids, bile acid derivatives, indole compounds, and tryptophan-derived serotonin-activate receptors such as G-protein-coupled receptor 41/43, Takeda G protein-coupled receptor 5, and Toll-like receptor 4 on enteroendocrine cells, influence the secretion of appetite-related hormones including ghrelin, leptin, glucagon-like peptide-1, peptide YY, nesfatin-1, and cholecystokinin. These hormones subsequently modulate hypothalamic circuits, particularly the NPY/AgRP and POMC/CART pathways, establishing a mechanistic link between microbial signaling and central appetite control. Ghrelin serves as the primary orexigenic hormone, whereas leptin, glucagon-like peptide-1, peptide YY, nesfatin-1, and cholecystokinin collectively exert anorexigenic effects that promote satiety and energy homeostasis. Dysbiosis disrupts receptor-mediated endocrine signaling, alters hormonal secretion, and contributes to leptin resistance, impaired glucagon-like peptide-1 responsiveness, and dysregulated appetite-key features in obesity, insulin resistance, and metabolic syndrome. This review synthesizes current mechanistic insights into the microbiota-hormone axis and highlights how microbial modulation influences endocrine appetite regulation. Understanding these interactions provides a translational framework for developing microbiota-targeted endocrine therapies aimed at restoring metabolic balance and preventing obesity and related metabolic disorders.
Magnesium deficiency is prevalent and increasingly recognized as an endocrine-relevant condition due to its involvement in hormone secretion, metabolic homeostasis, and cellular signaling. To review current evidence on the role of magnesium in key endocrine systems and evaluate its clinical and therapeutic implications. Magnesium influences glucose metabolism, bone health, thyroid function, reproduction, cardiometabolic regulation, and HPA-axis activity. Clinical evidence shows strong associations between magnesium status and several endocrine diseases. Magnesium plays a multifaceted endocrine role with clinically significant implications. Improved diagnostic approaches and further interventional studies are warranted.
Estrogen receptor-positive (ER+) breast cancers often recur years after endocrine therapy, due to tumor cells escaping a dormant state. Mechanisms underlying dormancy and recurrence are poorly understood. We identify CREB1 as a key regulator of ER+ tumor dormancy and recurrence. Analysis of dormant tumor samples from aromatase inhibitor-treated patients revealed 1,057 dormancy-downregulated genes (DDGs) and 1,142 dormancy-upregulated genes (DUGs). Pathway analyses implicated CREB1, together with ER and E2F1, as central regulators of these gene programs. Similar gene changes were confirmed in ER+ cell and patient-derived xenograft (PDX) tumor models of estrogen deprivation-induced dormancy and reversed upon acquired estrogen independence and tumor recurrence. CREB1 inhibition suppressed DDG expression, induced DUGs, and reduced survival of endocrine- and CDK4/6 inhibitor-resistant ER+ breast cancer cells. Together, the findings establish CREB1 as a key regulator of transcriptional reprogramming during relapse and a promising therapeutic target to overcome endocrine resistance.
Endocrine disrupting chemicals (EDCs) are associated with various adverse health outcomes, thus necessitating high-throughput screening. However, current EDC screening models struggle to achieve high predictive performance and biological interpretability. Considering the predominant contribution of molecular interactions between EDCs and nuclear receptors (NRs) to molecular initiating events associated with adverse health outcomes, it is essential to integrate chemical-NRs interactions profiles into EDCs screening. Herein, we develop mechanism-driven models by integrating chemical-NRs interactions features of 372 434 chemicals with 16 NRs from large-scale molecular docking and chemical structural features, enabling comprehensive molecular representation of binding potential and physicochemical properties. Multiple models are constructed using diverse algorithms (XGBoost, NGBoost, Random Forest, TabPFN, and graph convolutional network), with SHAP analysis identifying key features of endocrine disruption to link predictions to chemical-NRs interactions. The optimal models achieved impressive performance (AUC: 0.815-0.995) and wide applicability with external validation against published EDCs inventory. The models are implemented in an open-access web server named EDC Profiler (http://www.edcprofiler.cn/service/edcprofiler), featuring interactive input interfaces, batch processing capabilities, and intuitive result visualization. The platform facilitates efficient EDCs screening and promotes new approach methods (NAMs) development for EDCs health risk assessment.
While the pain- and stress-reducing effects of music are well investigated, effects of visual art and the combination of both modalities (music and visual art) are much less explored. We tested the (1) pain- and (2) stress-reducing effects of a multimodal (music + visual art) aesthetic experience-expecting stronger effects than single modal aesthetic experiences (music or visual art)-and, in an exploratory manner, (3) investigated underlying mechanisms of aesthetic experience and (4) individual differences. In a repeated-measures design (music, visual art, multimodal aesthetic experience, control), 42 female participants submitted their self-selected movingly beautiful visual artworks and music pieces to the lab, where pain and stress were induced by a cold pressor test. Pain (global pain perception, pain intensity, pain affect, pain tolerance) and stress responses (subjective reports, autonomic [electrocardiography, electrodermal activity, salivary alpha-amylase] and endocrine activity [salivary cortisol]) were measured. Individual differences of the experience, trait empathy and absorption were investigated. Exposure to multimodal art resulted in longer pain tolerance (M = 80.19s; SD = 61.05) compared to visual art (M = 56.63s; SD = 47.86), but not compared to music (M = 81.34s; SD = 64.19; p < .001; η² = .039). Other measures of pain intensity, stress intensity, and pain affect did not differ across the conditions. Exposure to all types of art distracted participants' attention from pain, prompted mind wandering, and elicited greater enjoyment than the control condition. While participants were overall more stressed during the cold pressor test, no differences emerged across the four conditions (p = 0.38; η² = .012). Also, no differences were found regarding cortisol and alpha-amylase. Regarding individual differences, higher trait absorption was associated with longer pain tolerance in the multimodal condition (b = 0.58, SE = 0.29, t(120)=2.02, p = .046) and with lower pain intensity in the music-only condition (b = -0.27, SE = 0.12, t(120)=-2.20, p = .030), compared to the other conditions. In conclusion, exposure to art can influence pain; however, the underlying mechanisms require further research.
Prader-Willi syndrome (PWS) is a rare imprinting disorder characterized by typical dysmorphic features, lack of satiety, infantile hypotonia, and later morbid obesity with complications, short stature, hypogonadotropic hypogonadism, skeletal and psychiatric problems. From the literature, it is well known that patients with PWS have a more favorable metabolic pattern than healthy controls. The aim of the study is to assess the metabolic profile of PWS patients followed at an Expert Center for Rare Endocrine Diseases compared with healthy controls and to look for relations between components of the metabolic syndrome (MetS), adipokines, and the compartments of body composition (BC-lean and fat mass). The current study is a cross-sectional evaluation of 25 patients with Prader-Willi syndrome (mean age 11.3 ± 8.2 years), with a total of 183.6 patient-years of regular follow-up (from the first visit to the center to the data collection cutoff date), compared with 24 age-, sex-, and BMI-matched healthy controls (mean age 11.3 ± 3.9 years). Each participant underwent anthropometric measurements, physical examination, biochemical and hormonal blood sampling, and whole-body DXA scan. Statistical analysis (SPSS 15.0 statistical package, Chicago, IL, USA) was performed to assess the relations between the metrics in the PWS group compared with controls. Patients with PWS showed a better profile of glucose homeostasis with significantly lower serum insulin concentration and calculated HOMA-IR index compared with the controls (p < 0.05). Taking into consideration age, sex, and body mass index (BMI) in the PWS group, the analysis showed strong positive correlations between waist circumference (WC) and systolic blood pressure (SBP) (r = 0.864, p < 0.001), and WC and diastolic blood pressure (DBP) (r = 0.534, p = 0.033). Partial correlation analysis with respect to age, sex, and pubertal development found significant positive WC correlations with insulin (r = 0.796, p = 0.006), HOMA-IR (r = 0.697, p = 0.025), LDL-cholesterol (r = 0.735, p = 0.002), uric acid (r = 0.735, p = 0.002), CRP (r = 0.600, p = 0.023), and leptin (r = 0.730, p = 0.005). Strong negative correlations existed between WC and SHBG (r = -0.772, p = 0.002) and HMW adiponectin (r = -0.998, p = 0.044). Additionally, a negative correlation of HMW adiponectin and SBP was demonstrated. 88% of the patients were treated with recombinant human growth hormone (rhGH). Bone mineral density adjusted for height (BMD/height) was significantly lower in patients with PWS (p < 0.05) compared with healthy controls. The analysis did not reveal significant relationships between BC compartments and metabolic and auxological parameters in the PWS group. Our study confirms that patients with PWS have a favorable metabolic profile compared with healthy controls matched by age, sex, and BMI. Syndromic participants who manifest greater accumulation of abdominal adipose tissue have a higher risk of hemodynamic changes and metabolic disturbances predictive of the development of cardiovascular diseases (CVD) in adulthood. WC could serve as a predictive marker for detecting higher metabolic risk in this syndromic group of patients, and both WC and HMW adiponectin for hypertension. In the future, on this basis, we could possibly implement both of these metrics in clinical practice.
Male infertility is increasing in prevalence due to cancer treatment, environmental exposures, and patient-specific syndromes. Traditional two-dimensional culture systems inadequately recapitulate the complex three-dimensional architecture, microenvironment, and endocrine milieu essential for spermatogenesis. Testicular organoid models aim to circumvent the challenges of two-dimensional culture, mimicking key aspects of the testicular microenvironment, while enabling controlled experimental manipulation and patient-specific disease modeling.
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[This corrects the article DOI: 10.3389/fendo.2026.1837257.].
Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is an uncommon endocrine disorder characterised by the selective reduction or absence of pituitary ACTH secretion, resulting in secondary adrenal insufficiency while other pituitary hormone axes remain functional. The clinical manifestations of this condition are frequently non-specific, and may include symptoms such as fatigue, decreased appetite, weight loss, hypotension, and hyponatremia. These symptoms can be easily confused with those of other diseases, resulting in either missed diagnoses or misdiagnoses. Glucocorticoid replacement therapy is generally considered to provide effective symptom relief and a favourable prognosis. In recent years, the widespread use of immune checkpoint inhibitors (ICIs) in cancer treatment has resulted in a significant increase in immune-related adverse events (irAEs). Isolated ACTH deficiency has been reported as a rare yet severe endocrine-type irAE, potentially arising from immune-mediated pituitary injury. In view of the nonspecific nature of its clinical presentation, early recognition and timely intervention are of critical importance. The present study reports the case of a patient diagnosed with gastric adenocarcinoma who underwent laparoscopic total gastrectomy, followed by combination therapy with oxaliplatin (OXA), nivolumab, and trastuzumab. Approximately eight months into the treatment regimen, the patient exhibited symptoms of isolated ACTH deficiency and hypothyroidism, indicative of a multi-endocrine system adverse reaction. Such multi-system endocrine dysfunction following this combination therapy is relatively uncommon. The present study analyses the patient's clinical presentation, laboratory findings, and imaging data, and discusses the differential diagnosis from post-gastrectomy dumping syndrome. This case demonstrates that in patients with malignant tumours receiving nivolumab and trastuzumab therapy, the presence of unexplained hypoglycaemia, persistent fatigue, anorexia, nausea, or vomiting - non-specific symptoms - should raise high suspicion for immune-related endocrine adverse reactions. It is imperative to emphasise the significance of preliminary testing for serum cortisol, ACTH, and thyroid function levels. Early recognition and prompt initiation of hormone replacement therapy can effectively prevent misdiagnosis, missed diagnosis, and delayed treatment.
Past research on the health impacts of parabens has largely focused on susceptible groups like pregnant women. However, postmenopausal women, due to profound hormonal shifts, are also a sensitive yet underrecognized population. To evaluate paraben exposure patterns, we analyzed pooled urine samples from 6523 Chinese adults. Major paraben congeners (MeP, EtP, PrP, BuP, BzP) were measured to examine paraben exposure of different sexes and age groups. These descriptive data revealed distinctly elevated paraben burdens among women in midlife and older groups. To investigate the endocrine consequences of this heightened exposure, we subsequently evaluated an independent United States cohort comprising 556 premenopausal and 332 postmenopausal women. This integrative approach leverages large-scale exposure characterization from China and individual-level endocrine effect data from NHANES to explore potential susceptibility modifiers. Postmenopausal women exhibited higher sensitivity to paraben-induced disruption, indicating that menopausal status is a critical modifier. Specifically, compared to premenopausal women, postmenopausal women showed a greater increase in paraben mixtures, with an 11.2% rise in sex hormone-binding globulin (SHBG) and a 9.1% increase in the total testosterone/estradiol (TT/E2) ratio, indicating a shift toward relative androgen predominance. Compared with non-obese postmenopausal women (no significant associations), overweight and obese postmenopausal women had elevated TT/E2 ratios with exposure to BuP (52.4%), MeP (27.1%), and EtP (30.1%). These findings strongly suggest a 'two-hit' mechanism in that menopause and obesity jointly magnify paraben-induced endocrine disruption beyond either factor individually. This heightened susceptibility challenges uniform exposure limits, necessitating the integration of menopausal and metabolic status into risk assessments.
Organophosphate flame retardants (OPFRs) are ubiquitous flame-retardant additives with endocrine-disrupting properties. Despite increasing evidence that OPFRs impact neurodevelopment, their effects on the neuroendocrine stress response remain poorly understood. To examine their long-term impact on stress regulation, we treated pregnant C57Bl/6J dams to a mixture of tris(1,3-dichloro-2-propyl) phosphate (TDCPP), triphenyl phosphate (TPP), and tricresyl phosphate (TCP; 1 mg/kg each) from gestational day (GD) 7 through postnatal day (PND) 14. Adult offspring (8-9 weeks of age) were then challenged with acute stressors, including 1 h restraint or a 6-day acute variable stress (AVS) paradigm. Perinatal OPFR exposure produced persistent, sex-specific alterations in the hypothalamic-pituitary-adrenal (HPA) axis and stress-related neurocircuitry. Following 1 h restraint, OPFR-treated females showed heightened serum corticosterone. In addition, gene expression analysis revealed sex-dependent disruptions in key stress-regulatory pathways after OPFR treatment and 1 h restraint in the hypothalamus (Crhr1, Crhr2, Ptpn5) and pituitary (Crhr1, Pomc, Nr3c1). Females demonstrated more differences in adrenal gene expression related to steroidogenesis (Mc2r, Cyp11b2) and catecholamine biosynthesis (Dbh, Pnmt), with OPFR-treated groups having blunted responses. OPFR AVS females displayed reduced corticosterone and Crh mRNA in the hypothalamus, and downregulated Pacap/Pac1r expression in the bed nucleus of the stria terminalis (BNST), accompanied by increased behavioral avoidance and immobility. In males, OPFR exposure led to increased BNST Pacap and Pac1r, expression, along with hyperactivity and avoidance behaviors. Together, these findings demonstrate that early-life OPFR exposure induces lasting, sex-specific dysregulation of the HPA axis and associated stress circuits, highlighting OPFRs as developmental neuroendocrine disruptors with implications for mood and stress-related disorders.
The mammalian pineal gland maintains normal circadian rhythms and homeostasis by secreting melatonin. However, the lack of a single-cell-resolved regulatory map limits our understanding of how these neuroendocrine functions are orchestrated. Here, we constructed a multiomics atlas of the pineal gland from Macaca fascicularis by integrating snRNA-seq, snATAC-seq, and spatial transcriptomics. We identified pinealocytes as the predominant cell type, alongside six glial and vascular lineages. Chromatin accessibility analysis delineated cell-type-specific regions enriched for melatonin synthesis and phototransduction genes. Notably, we resolved a dual-layer regulatory architecture: While melatonin synthesis programs are robustly organized, circadian clock regulators exhibit a distinct, sparse spatial pattern. Coexpression networks further identified core modules and regulatory hubs-including CRX/OTX2, LHX4, and RORA-that integrate these circadian and light-responsive signals. Cell-cell communication analysis identified signaling axes, such as PTN-ALK/SDC2, RA-RORB, and NRG1-ERBB4, that potentially coordinate this spatial functional organization. Integrating genetic traits showed that sleep and neuropsychiatric risk variants preferentially map to these pineal regulatory modules. Specifically, sleep-associated loci converged on MEIS1-linked elements, while bipolar disorder-associated loci highlighted candidate genes of RDH12 and SDK2. Overall, this study reveals the cellular diversity and spatial regulatory logic of the primate pineal gland, providing a physiological foundation for investigating circadian and neuroendocrine regulation in healthy and disease models.
Differentiated thyroid carcinomas (DTC), including papillary thyroid carcinoma (PTC) and follicular carcinoma (FC), account for most thyroid malignancies and are generally associated with excellent prognosis. However, a subset of DTC demonstrate aggressive clinical behavior characterized by increased recurrence, distant metastasis (DM), radioactive iodine (RAI) resistance, and reduced survival. Identification of these tumors is critical for appropriate risk stratification and management. A number of pathologic features have been shown to predict aggressive behavior, including vascular invasion (VI), capsular invasion (CI), and extrathyroidal extension (ETE), as well as high-grade histologic features such as increased mitotic activity and tumor necrosis. In the 2022 World Health Organization (WHO) Classification for Endocrine and Neuroendocrine Tumours, high-grade features are acknowledged as prognostically significant, and DTC meeting these criteria are classified as high grade differentiated thyroid carcinoma (HGDTC), a category with a prognosis similar to PDTC. In addition, certain histologic subtypes of PTC, including the tall cell, hobnail, and columnar cell subtypes, have traditionally been associated with more aggressive clinical outcomes. However, the prognostic significance of histologic subtype alone remains debated, as tumor behavior is often influenced by the presence of invasive features and high-grade morphology. Recent advances in molecular profiling have further refined risk stratification. While the independent prognostic significance of the BRAFV600E mutation remains controversial, TERT promoter mutations have consistently been associated with aggressive tumor biology, including DM, RAI resistance, and decreased survival. Importantly, the coexistence of BRAFV600E and TERT promoter mutations identifies a subset of thyroid carcinomas with particularly poor outcomes. This review summarizes the key pathologic and molecular features associated with aggressive behavior in DTC, highlighting their diagnostic criteria, prognostic significance, and implications for clinical management. Comprehensive pathologic evaluation integrating morphologic and molecular findings remains essential for accurate risk stratification and multidisciplinary care of patients with thyroid carcinoma.
Thyroid hormone (TH) is a key regulator of body temperature; however, its role in the tightly controlled maternal thermoregulatory system that safeguards fetal viability remains unknown. To address this gap, we investigated how maternal hyperthyroidism affects thermoregulation, metabolic tissues, and endocrine signaling in pregnant C57BL/6NCrl mice. Treatment with 3,3',5-Triiodo-L-thyronine (T3) from conception to late gestation initially elevated maternal core temperature, reflecting a hypothalamic pyrexic set-point. However, this effect was gradually attenuated towards term, permitting the normal prepartum drop in core body temperature. Despite elevated TH levels, brown and white adipose tissues showed no thermogenic activation, whereas skeletal muscle exhibited selective metabolic remodeling, including glycogen depletion and increased mitochondrial capacity in glycolytic muscles, without changes in SERCA2 expression. Notably, maternal T3 treatment further boosted the pregnancy-associated increase in FGF21, while adipose tissue remained non-thermogenic, indicating a role of TH-induced FGF21 in sustaining maternal metabolic requirements. Together, these findings reveal a hierarchical adaptation in which central TH effects are overridden, peripheral thermogenic activation is partially suppressed, and endocrine signaling is redirected to maintain maternal-fetal energy balance. In summary, this study identifies a pregnancy-specific mechanism that protects the fetus from hyperthermia while sustaining maternal metabolic demands, with important implications for thyroid dysfunction and fetal programming.
In this prospective longitudinal study, the authors investigated the mechanisms of coupling between energy compensation behaviors and metabolic adaptation in the course of a 48-week training cycle in 120 elite athletes stratified by sport type (endurance versus power/strength). Using energy compensation rate, multi-omics profiling, endocrine biomarkers, and gut microbiota composition in six measurement points from baseline to recovery phases, they found that energy compensation follows a characteristic U-shaped pattern, with nadirs of 79.6% and 82.6% in endurance and power/strength athletes at peak training load, reflecting persistent energy deficits amounting to 624-840 kcal/day. This energy deficit was accompanied by a coordinated suppression of leptin (effect size: - 1.9/- 1.4), an increase in cortisol (+ 1.7/+1.4), upregulation of pathways for fatty acid oxidation, and decreased Firmicutes-to-Bacteroidetes ratios. Systematic correlation analyses point to hierarchical patterns of coupling, according to which endocrine markers most closely related to energy status showed the highest association with compensation rate (leptin: r = 0.55; cortisol: r = - 0.46), whereas downstream phenotypes only express weaker associations. In subgroup analyses, greater metabolic perturbations were observed in athletes experiencing severe energy deficits (effect size: - 1.68 vs. - 0.72). These findings support an integrated "energy behavior-metabolic state" approach for personalized nutritional monitoring and intervention in high-performance sport.
Skeletal muscle's ability to perceive and adapt to physical force is fundamental to tissue homeostasis and systemic health. At the core of this process, mechanosensitive ion channels (MSCs)-notably the Piezo and TRP families-function as primary transducers. This review synthesizes how these channels convert diverse mechanical stimuli into biochemical signals. We delineate how their activation, primarily through Ca2+ influx, engages downstream signaling hubs, including the Hippo-YAP/TAZ, MAPK, and PI3K-Akt-mTOR pathways. These cascades subsequently orchestrate muscle growth, regeneration, and metabolic remodeling. We then bridge these molecular mechanisms to clinical relevance, analyzing how physical therapies like low-intensity pulsed ultrasound and electrical stimulation precisely target these networks to enhance muscle repair. Furthermore, we explore the role of MSCs in driving skeletal muscle's function as an endocrine organ. Mechanical activation triggers myokine release, mediating critical inter-organ communication with bone, adipose, and immune systems. Collectively, this review establishes MSCs as pivotal molecular hubs that integrate external physical energy with local tissue repair and systemic physiological regulation.
Diisononyl phthalate (DINP) is a high molecular weight phthalate and high production volume chemical. DINP's carcinogenic potential has been investigated in four rodent bioassays, with liver tumors observed in three of the studies. Authoritative assessments have hypothesized that DINP acts through the peroxisome proliferator-activated receptor alpha (PPARα) activator-induced mode of action (MOA) for rodent hepatocarcinogenesis. However, these assessments reported disparate conclusions regarding the human relevance of this rodent-specific MOA, and alternative MOAs for DINP-induced rodent liver tumors have been proposed, albeit with limited evidence. Herein, the MOA for DINP-induced rodent liver tumors is assessed according to the MOA framework for PPARα activator-induced rodent hepatocarcinogenicity, which includes four key events (KEs). Findings demonstrate strong evidence that DINP induces KE 1 (PPARα activation) and KE 3 (perturbation of cell growth and survival) in vitro and in vivo in wild-type and PPARα-null rodent models. KE 2 and KE 4 are reasonably inferred, given the strong data for KE 1, KE 3, and the adverse outcome (liver tumors). Alternative MOAs, including genotoxicity, endocrine disruption, other nuclear receptor activation, and cytotoxicity, are not supported by the evidence. The human and nonhuman primate evidence for DINP supports the lack of human relevance of this MOA, as well as the divergent PPARα-mediated pathways between species, with evidence in humans limited to PPARα activation (KE 1). Overall, the weight of evidence strongly supports that DINP acts through the nonhuman-relevant PPARα MOA for rodent hepatocarcinogenesis; therefore, rodent liver tumors and upstream KEs 2-4 should not serve as the basis for human health risk conclusions.