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How to limit the effects of endocrine disruptors on the brains of children

Jean-Baptiste Fini
Jean-Baptiste Fini
Professor at the French National Museum of Natural History (MNHN)
Key takeaways
  • Last April, the European Commission published a roadmap for banning thousands of dangerous substances in consumer products by 2030 – including endocrine disruptors.
  • Contrary to most toxicological measures, their dose does not predict the toxicity of exposure – a tiny amount can lead to long-term damage to health and there is there is a “cocktail” effect of different molecules.
  • Using the EDC-MixRisk project which studies children's health in relation to mothers’ exposure to endocrine disruptors, researchers identified a realistic “cocktail” that was potentially damaging to brain development.
  • Eleven molecules were identified as being at risk for a delay in cognitive development including phthalates, perfluorinated compounds and phenols.
  • The study suggests that if they had used these doses to control chemicals in everyday products, they could have prevented 57% of women from being exposed to dangerous doses.

As the Euro­pean Com­mis­sion pre­pares a black­list of tox­ic sub­stances to be banned from con­sumer prod­ucts cir­cu­lat­ing in the EU, the ques­tion that has haunt­ed tox­i­col­o­gists for the past 20 years becomes inescapable: how do we assess endocrine dis­rup­tors? Present in plas­tics, cos­met­ics, paints and even fruit and veg­eta­bles because of pes­ti­cides, this fam­i­ly of chem­i­cal mol­e­cules is not defined by its chem­i­cal struc­ture nor the nature of its appli­ca­tions. Rather, it is defined but by the type of unde­sir­able effects it induces in liv­ing organ­isms – effects involv­ing dis­rup­tion of hormones. 

The fam­i­ly of endocrine dis­rup­tors includes var­i­ous types of mol­e­cules: phtha­lates, per­flu­o­ri­nat­ed com­pounds, parabens, etc. And their cumu­la­tive action with­in a bio­log­i­cal sys­tem is dif­fi­cult to pre­dict. Yet, this is what we expect from reg­u­la­tions, in the form of thresh­olds below which con­sumers, pro­fes­sion­als using these prod­ucts or users of the spaces where they are present are pro­tect­ed from their harm­ful effects. A seem­ing­ly sim­ple problem.

Changing the regulatory paradigm

But “the dose makes the poi­son” is the par­a­digm of tox­i­col­o­gy, not endocrinol­o­gy. Indeed, expo­sure to infin­i­tes­i­mal dos­es of cyanide, for exam­ple, is not very risky. It is even found nat­u­ral­ly in hydrangea leaves, apple seeds and cher­ry pits; yet this does not mean that apple trees should be banned.

How­ev­er, if cyanide were an endocrine dis­rup­tor, we would have to think dif­fer­ent­ly. Because of their mode of action, the dose does not pre­dict the tox­i­c­i­ty of expo­sure to endocrine dis­rup­tors. An infin­i­tes­i­mal amount admin­is­tered at a key moment dur­ing a cru­cial process such as brain devel­op­ment in chil­dren can lead to long-term dam­age to health. 

An infin­i­tes­i­mal amount admin­is­tered at a key moment dur­ing brain devel­op­ment can lead to long-term dam­age to health.

Sim­i­lar­ly, the sum of small dos­es accu­mu­lat­ed on the same tar­get can pro­duce con­se­quences lat­er in life. This is the “cock­tail” effect. Hence, assess­ing action of endocrine dis­rup­tors is a chal­lenge for reg­u­la­to­ry sci­ence. And research by sev­er­al Euro­pean lab­o­ra­to­ries, in col­lab­o­ra­tion with the Icahn School of Med­i­cine at Mount Sinai, with­in the H2020 EDC-MixRisk project (2015–2019), is seek­ing a solu­tion to this prob­lem. They pre­sent­ed a very ambi­tious approach last Feb­ru­ary1.

Jean Bap­tiste Fini, a biol­o­gist spe­cial­is­ing in endocrine dis­rup­tors and one of the authors of the arti­cle, explains, “our idea was to study the effects of mix­tures instead of test­ing them mol­e­cule by mol­e­cule. This approach bet­ter rep­re­sents the expo­sure of indi­vid­u­als in real life because the risk of devel­op­ing a dis­ease depends on a mul­ti­tude of expo­sures to mol­e­cules, the dos­es of which are often low and below cur­rent reg­u­la­to­ry thresh­olds.

The aim is to increase the num­ber of tests to bet­ter account for the risks. Their work takes advan­tage of the Swedish Sel­ma cohort, which fol­lows more than 2000 moth­er-child pairs since the 10th week of preg­nan­cy2. The EDC-MixRisk project has set out to study chil­dren’s health in rela­tion to moth­ers’ expo­sure to endocrine disruptors.

Endocrine disruptors affect the brain

“We stud­ied the health of the sub­jects from sev­er­al angles. The first study we pub­lished con­cerned the cog­ni­tive aspect,” explains Jean-Bap­tiste Fini. The sci­en­tists researched which chem­i­cal mol­e­cules were asso­ci­at­ed with lan­guage delay in chil­dren whose moth­ers were exposed to these prod­ucts. Eleven mol­e­cules were iden­ti­fied as being at risk for this cog­ni­tive-delay cri­te­ri­on. The pan­el of chem­i­cals cho­sen will not sur­prise any tox­i­col­o­gist: phtha­lates, per­flu­o­ri­nat­ed com­pounds, phe­nols… these mol­e­cules are known to spe­cial­ists, and some are already sub­ject to reg­u­la­to­ry restrictions. 

“Once we had estab­lished the mix of chem­i­cals, it was sent to all the lab­o­ra­to­ries par­tic­i­pat­ing in this study,” says the French spe­cial­ist. The cock­tail was sub­ject­ed to a bat­tery of tests, on human cells in cul­ture and on recog­nised ani­mal mod­els such as zebrafish and xeno­pus.  The strength of this study is that it links epi­demi­o­log­i­cal data with con­trolled lab­o­ra­to­ry tests.

On human brain cells in cul­ture, the researchers from the Uni­ver­si­ty of Milan demon­strat­ed that the cock­tail caus­es cel­lu­lar repro­gram­ming. As such, gene acti­va­tion was mod­i­fied, in par­tic­u­lar genes involved in learn­ing disorders.

In ani­mal research, sci­en­tists from the Muse­um Nation­al d’Histoire Naturelle in France and the Uni­ver­si­ty of Gothen­burg in Swe­den observed thy­roid effects on amphib­ian and zebrafish lar­vae. The mol­e­c­u­lar mech­a­nisms involved do not, how­ev­er, involve exact­ly the same genes as those in human cells. “This high­lights the fact that, even if phys­i­o­log­i­cal traits, in par­tic­u­lar dis­rup­tion of the ner­vous sys­tem, are con­served among ver­te­brates, the genes involved may be dif­fer­ent between aquat­ic mod­els and mam­mals,” explains Jean-Bap­tiste Fini.

Risk calculation

Togeth­er, these data con­tribute to a body of sci­en­tif­ic evi­dence demon­strat­ing the risk of expo­sure to these endocrine dis­rup­tors dur­ing the pre­na­tal phase – even at dos­es accept­ed by cur­rent regulations.

But the great pow­er of this study lies in the risk analy­sis of the cock­tail of mol­e­cules. “This is a very inno­v­a­tive and com­plex approach devel­oped by Chris Gen­nings, a sta­tis­ti­cian from Mount Sinai,” he explains. Using the exper­i­men­tal data, she was able to cal­cu­late the risk of the mix­ture and pre­dict a thresh­old above which the chil­dren would have been pro­tect­ed from cog­ni­tive impairment. 

“If we had used these dos­es to con­trol chem­i­cals in every­day prod­ucts, we would have pre­vent­ed 57% of women from being exposed to dan­ger­ous dos­es,” sum­maris­es the French specialist.

This research comes at a time of reg­u­la­to­ry change in Europe. Last April, the Euro­pean Com­mis­sion pub­lished a roadmap for ban­ning thou­sands of dan­ger­ous sub­stances in con­sumer prod­ucts by 20303. The inclu­sion of prod­ucts on this future black­list is a cru­cial issue for reg­u­la­to­ry sci­ence, and the con­sid­er­a­tion of endocrine dis­rup­tors will be cen­tral to it. The approach devised by the Euro­pean con­sor­tium could con­tribute to this.

“We hope that our work will help reg­u­la­to­ry sci­ence to address the prob­lem in order to bet­ter pro­tect the pub­lic,” says Jean-Bap­tiste Fini.

Agnès Vernet
1N. Capo­rale et al., Sci­ence  (2022), 375, 6582 doi: 10.1126/science.abe8244
2C‑G Borne­hag et al., Pae­di­a­tr Peri­nat Epi­demi­ol. (2012) 26:456–67. doi: 10.1111/j.1365–3016.2012.01314.x

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