Developmental neurotoxicity evaluation of di(2-ethylhexyl) phthalate (DEHP) and three alternative plasticizers in human neurospheres
Por:
Kühne BA, Klose J, Seeger B, Illa-Armengol M, Muñoz-Torrero D, Koch K, Fritsche E and Barenys M
Publicada:
1 ene 2026
Ahead of Print:
1 ene 2026
Resumen:
Plasticizers like di-(2-ethylhexyl) phthalate (DEHP) are commonly used in medical devices to enhance plastic flexibility. DEHP is classified as a CMR1b substance due to its adverse effects on reproduction and fertility, and it has been linked to neurodevelopmental disorders such as ADHD, autism spectrum disorder, and learning disabilities. While DEHP is scheduled for phase-out by 2030, data on the developmental neurotoxicity (DNT) of alternative plasticizers remain scarce. We evaluated the DNT potential of DEHP and three alternative plasticizers: di-(2-ethylhexyl) terephthalate (DEHT), di-(2-ethylhexyl) adipate (DEHA), and tris-(2-ethylhexyl) trimellitate (TOTM), aiming to identify safer substitutes, particularly for neonates in neonatal intensive care units (NICUs). The human Neurosphere Assay was used to assess plasticizer effects on seven key neurodevelopmental processes: neural progenitor cell (NPC) proliferation, migration of radial glia, neurons, and oligodendrocytes, neurite outgrowth, and differentiation of neurons and oligodendrocytes. Concentration-response analyses provided benchmark concentrations (BMCs) and lowest observed adverse effect concentrations (LOAECs). Gene expression profiling provided mechanistic insights, and toxicity was ranked using the most sensitive endpoint (MSE) and ToxPi Tool. DEHP and TOTM showed the highest DNT potential, with NPC proliferation as the MSE. DEHT impacted oligodendrocyte differentiation, while no BMC was determined for DEHA within the tested concentrations. Considering an exposure scenario in NICUs, the estimated neonatal DEHP plasma levels exceeded the LOAEC for NPC proliferation, raising concerns for DNT. Overall, DEHA emerged as the least hazardous alternative for neurodevelopment, highlighting the value of combined human-relevant in vitro phenomics and human biomonitoring for DNT hazard evaluation.
Filiaciones:
:
GRET and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
IUF - Leibniz Research Institute for Environmental Medicine, Duesseldorf, Germany
German Federal Institute for Risk Assessment (BfR), German Centre for the Protection of Laboratory Animals (Bf3R), Berlin, Germany
BCNatal | Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), University of Barcelona, Barcelona, Spain
University of Veterinary Medicine Hannover, Foundation, Institute for Food Quality and Food Safety, Research Group Food Toxicoloy, Alternatives/Complementary Methods to Animal Experiments, Hannover, Germany
Klose J:
IUF - Leibniz Research Institute for Environmental Medicine, Duesseldorf, Germany
DNTOX GmbH, Duesseldorf, Germany
Seeger B:
University of Veterinary Medicine Hannover, Foundation, Institute for Food Quality and Food Safety, Research Group Food Toxicoloy, Alternatives/Complementary Methods to Animal Experiments, Hannover, Germany
Illa-Armengol M:
BCNatal | Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), University of Barcelona, Barcelona, Spain
Institut de Recerca Sant Joan de Déu, Fundació Sant Joan de Déu, Barcelona, Spain
Spanish Network in Maternal, Neonatal, Child and Developmental Health Research (RICORS-SAMID, RD24/0013/0004), Instituto de Salud Carlos III, 28040 Madrid, Spain
Muñoz-Torrero D:
Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain
Koch K:
IUF - Leibniz Research Institute for Environmental Medicine, Duesseldorf, Germany
DNTOX GmbH, Duesseldorf, Germany
Fritsche E:
IUF - Leibniz Research Institute for Environmental Medicine, Duesseldorf, Germany
DNTOX GmbH, Duesseldorf, Germany
Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany
SCAHT - Swiss Centre for Applied Human Toxicology, Basel, Switzerland
Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
Barenys M:
GRET and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
German Federal Institute for Risk Assessment (BfR), German Centre for the Protection of Laboratory Animals (Bf3R), Berlin, Germany
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