Researchers have provided evidence that complex mixtures of endocrine disrupting chemicals impact children’s brain development and language acquisition. While current risk assessment tackles chemicals one at a time, the current findings show the need to take mixtures of chemicals into account for future risk assessment approaches.
There is increasing evidence that environmental chemicals to which we are continuously exposed can have endocrine disrupting properties and can thus be dangerous to human and animal health and development. While exposure levels for individual chemicals are often below existing limit values, exposure to the same chemicals in complex mixtures can still impact human health. Yet all existing risk assessments, and thus established limit values, are based on chemicals being examined one at a time. There was thus a strong need to test whether an alternative strategy would be possible, in which the actual mixtures measured in real life exposures could be tested as such in both the epidemiological and experimental setting.
The study was conducted in three steps:
• First, a mixture of chemicals in the blood and urine of pregnant women was identified in the Swedish pregnancy cohort SELMA, associated with delayed language development in children at 30 months. This critical mixture included a number of phthalates, bisphenol A, and perfluorinated chemicals.
• Second, experimental studies uncovered the molecular targets through which human-relevant levels of this mixture disrupted the regulation of endocrine circuits and of genes involved in autism and intellectual disability.
• Third, the findings from the experimental studies were used to develop new principles for risk assessment of this mixture.
The SELMA study is conducted at Karlstad University, Sweden, and follows approximately 2,000 mother-child pairs from early pregnancy over childbirth and up to the child reaching school age. The overall aim is to investigate the impact of exposure to suspected or proven endocrine disrupting chemicals during early pregnancy on the child’s health and development later in life. The study has shown a connection between mixtures of different chemicals and the child’s gender development, respiratory problems, cognitive development and growth during childhood.
The researchers were able to show that 54 per cent of children included in the SELMA study were at risk of delayed language development (at age 30 months) as they were prenatally exposed to a mixture of chemicals at levels that were above the levels predicted to impact neurodevelopment. This risk did not become apparent when the current limit values for individual chemicals were used.
“Human brain organoids (advanced in vitro cultures that reproduce salient aspects of human brain development) afforded, for the first time, the opportunity to directly probe the molecular effects of this mixture on human brain tissue at stages matching those measured during pregnancy. Alongside other experimental systems and computational methods, we found that the [chemical] mixture disrupts the regulation of genes linked to autism (one of whose hallmarks is language impairment), hinders the differentiation of neurons and alters thyroid hormone function in neural tissue.”
-Dr. Giuseppe Testa, Principal Investigator of the EDC-MixRisk responsible for the human experimental modelling, Professor of Molecular Biology at the University of Milan, Head of the Neurogenomics Research Centre at Human Technopole and Group Leader at the European Institute of Oncology
“One of the key hormonal pathways affected was thyroid hormone. Optimal levels of maternal thyroid hormone are needed in early pregnancy for brain growth and development, so it’s not surprising that there is an association with language delay as a function of prenatal exposure.”
-Dr. Barbara Demeneix, Professor of Physiology and Endocrinology at the Natural History Museum in Paris and involved in the mechanistic, in vivo, studies
Journal Reference: Nicolò Caporale, Michelle Leemans, Lina Birgersson, Pierre-Luc Germain, Cristina Cheroni, Gábor Borbély, Elin Engdahl, Christian Lindh, Raul Bardini Bressan, Francesca Cavallo, Nadav Even Chorev, Giuseppe Alessandro D’Agostino, Steven M. Pollard, Marco Tullio Rigoli, Erika Tenderini, Alejandro Lopez Tobon, Sebastiano Trattaro, Flavia Troglio, Matteo Zanella, Åke Bergman, Pauliina Damdimopoulou, Maria Jönsson, Wieland Kiess, Efthymia Kitraki, Hannu Kiviranta, Eewa Nånberg, Mattias Öberg, Panu Rantakokko, Christina Rudén, Olle Söder, Carl-Gustaf Bornehag, Barbara Demeneix, Jean-Baptiste Fini, Chris Gennings, Joëlle Rüegg, Joachim Sturve, Giuseppe Testa. From cohorts to molecules: Adverse impacts of endocrine disrupting mixtures. Science, 2022; 375 (6582) DOI: 10.1126/science.abe8244