More chemicals, fewer words: Exposure to chemical mixtures during
pregnancy alters brain development

Date:
February 17, 2022
Source:
Uppsala University
Summary:
By linking human population studies with experiments in cell and
animal models, researchers have provided evidence that complex
mixtures of endocrine disrupting chemicals impact children's brain
development and language acquisition. With their novel approach,
the scientists show that up to 54 per cent of pregnant women
were exposed to experimentally defined levels of concern. While
current risk assessment tackles chemicals one at a time, these
findings show the need to take mixtures into account for future
risk assessment approaches.



FULL STORY ==========================================================================
By linking human population studies with experiments in cell and animal
models, researchers have provided evidence that complex mixtures of
endocrine disrupting chemicals impact children's brain development and
language acquisition. With their novel approach, the scientists show that
up to 54 per cent of pregnant women were exposed to experimentally defined levels of concern. While current risk assessment tackles chemicals one
at a time, these findings show the need to take mixtures 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. Every
year sees the release of a huge number of new compounds as part of the
market authorisation and production processes of a vast range of goods,
chiefly but not only plastic derivatives, that enter the human body
from several sources, including water, food and air. 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 EU- funded EDC-MixRisk project set out to
tackle this unmet need.

"The uniqueness of this comprehensive project is that we have linked
population data with experimental studies, and then used this information
to develop new methods for risk assessment of chemical mixtures,"
says Carl-Gustaf Bornehag, Professor at Karlstad University, Project
Manager of the SELMA study and responsible for the epidemiological part
of EDC-MixRisk.

The study was conducted in three steps: o 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.

o 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.

o Third, the findings from the experimental studies were used to develop
new principles for risk assessment of this mixture.



==========================================================================
"It is striking that the findings in the experimental systems well
reflected what we found in the epidemiological part, and that the
effects could be demonstrated at normal exposure levels for humans,"
says Joe"lle Ru"egg, Professor of Environmental Toxicology at Uppsala University and Vice Coordinator of EDC-MixRisk.

"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 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," says 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," says Barbara Demeneix, Professor of Physiology and Endocrinology at the Natural History Museum in Paris and involved in the mechanistic, in vivo, studies.

By linking different scientific methods in this way, 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.

The study was conducted in a collaboration among universities and
research centres from Sweden (Uppsala University, Karlstad University, University of Gothenburg, Karolinska Institutet, Lund University,
Stockholm University, O"rebro University), Italy (University of Milan,
European Institute of Oncology and Human Technopole), France (CNRS/Muse'um d'histoire naturelle), Finland (Finnish Institute for Health and Welfare (THL)), Germany (University of Leipzig), Greece (National and Kapodistrian University of Athens), and the US (Icahn School of Medicine at Mount
Sinai, New York).

More about the SELMA-study: 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.

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========================================================================== Journal Reference:
1. Nicolo` Caporale, Michelle Leemans, Lina Birgersson, Pierre-Luc
Germain,
Cristina Cheroni, Ga'bor Borbe'ly, 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, AAke Bergman, Pauliina Damdimopoulou, Maria
Jo"nsson, Wieland Kiess, Efthymia Kitraki, Hannu Kiviranta, Eewa
Naanberg, Mattias O"berg, Panu Rantakokko, Christina Rude'n, Olle
So"der, Carl-Gustaf Bornehag, Barbara Demeneix, Jean-Baptiste Fini,
Chris Gennings, Joe"lle Ru"egg, Joachim Sturve, Giuseppe Testa. From
cohorts to molecules: Adverse impacts of endocrine disrupting
mixtures. Science, 2022; 375 (6582) DOI: 10.1126/science.abe8244 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220217141304.htm

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