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How endocrine disruptors affect brain development

Vincent Prevot
Vincent Prevot
Research Director at Inserm within the Lille Neuroscience & Cognition Research Centre, Université de Lille
Key takeaways
  • In the second week after birth, a peak of hormones is secreted from GnRH neurons in a phenomenon known as "mini puberty". It seems to signal to the body that the birth has gone well and that it can continue to grow reproductive organs and a brain.
  • Endocrine disruptors – compounds very often found in plastics that resemble molecules of the hormonal system – can affect this process. We are all exposed to these molecules, in varying doses.
  • Low concentrations of endocrine disruptors at key moments like "mini puberty" can affect these natural processes, stunting childhood development of the reproductive system and brain.
  • Vincent Prevot aims to study the exposure of children during the first 1,000 days of their life and to support families in limiting the presence of toxic substances in their environment.

By dis­rupt­ing the inter­ac­tion between neu­rons and their astro­cytes, petro­chem­i­cal-derived mol­e­cules with endocrine activ­i­ty dis­rupt both repro­duc­tive func­tion and brain development.

The brain is com­posed of two main fam­i­lies of cells: neu­rons, which car­ry out the actu­al brain activ­i­ty, and glial cells (notably astro­cytes), which mod­u­lates how neu­rones work. This reg­u­la­tion is essen­tial dur­ing devel­op­ment of a baby but can be altered by pol­lu­tants, such as endocrine dis­rup­tors (such as bisphe­nol A) that have invad­ed our environment. 

It all takes place in the hypo­thal­a­mus. This struc­ture, locat­ed at the heart of the brain, at the inter­face between the cor­tex and the spinal cord, con­trols the secre­tion of the gonadotrop­ic hor­mones, LH and FSH. Their role is to ensure the growth of the gonads in chil­dren – in oth­er words, the organs des­tined to pro­duce sex­u­al hormones.

Once formed, the gonads secrete steroid hor­mones, which are in turn detect­ed by the hypo­thal­a­mus. Through this loop, the brain is thus informed about the matu­ri­ty of the repro­duc­tive sys­tem. Lat­er in life, after puber­ty, it is this loop that reg­u­lates the men­stru­al cycle in women and sperm pro­duc­tion in men. 

Special neurons

The sys­tem we are refer­ring to is based on only a hand­ful of neu­rons in the brain – 2 000 in humans and 800 in mice – that release Gonadotrophin Releas­ing Hor­mone (GnRH). They are spe­cial from birth: as they are not formed in the brain but in the nose. They migrate dur­ing foetal life to the hypo­thal­a­mus. They are also spe­cial because of their organ­i­sa­tion: unlike most spe­cialised neu­rons, they do not form nuclei. They are scat­tered between the olfac­to­ry bulb and the hypo­thal­a­mus. Spe­cial because, despite this uncon­ven­tion­al organ­i­sa­tion, they coor­di­nate and con­trol the secre­tion of gonadotrop­ic hormones. 

GnRH neu­rons do not work alone. They work togeth­er with oth­er neu­rons, which receive infor­ma­tion from the rest of the body and the out­side world. In this way, they can put the repro­duc­tive func­tion on stand­by if nec­es­sary, so that valu­able resources are not wast­ed at a time that is unfavourable for reproduction.

Glial cells ensure the cre­ation and main­te­nance of synap­tic con­nec­tions between neu­rons. This is a cru­cial but frag­ile role that plays a crit­i­cal role in the sec­ond week after birth, when GnRH neu­rons secrete a peak of hor­mones. This phe­nom­e­non is called « mini puber­ty ». It seems to sig­nal that the birth has gone well and that the body can con­tin­ue to grow repro­duc­tive organs and a brain in gen­er­al. In the hypo­thal­a­mus, this is the time when astro­cytes stick to GnRH neu­rons and remain there for life. 

A crucial association

This « mini puber­ty » can be dis­rupt­ed by pre­ma­ture birth, per­haps explain­ing the vul­ner­a­bil­i­ty of chil­dren born too ear­ly to non-com­mu­ni­ca­ble dis­eases, such as learn­ing or meta­bol­ic dis­or­ders. It is also sen­si­tive to the chem­i­cal envi­ron­ment. One fam­i­ly of chem­i­cal mol­e­cules is of par­tic­u­lar con­cern: endocrine dis­rup­tors. These are com­pounds very often found in plas­tics that resem­ble mol­e­cules of the hor­mon­al sys­tem. They alter the com­mu­ni­ca­tion between organs, for exam­ple by mas­querad­ing as a sex hor­mone or by block­ing it bind­ing to its receptor.

In rats, stud­ies have shown that expo­sure to endocrine dis­rup­tors pre­vents the asso­ci­a­tion between astro­cytes and GnRH neu­rons. This results in delayed puber­ty and fer­til­i­ty prob­lems in adults, but the func­tion of GnRH neu­rons alone does not appear to be impaired. 

What about in humans? This is a ques­tion that we are try­ing to answer thanks to the hos­pi­tal-uni­ver­si­ty fed­er­a­tion project « 1,000 days for health: care before treat­ment », led by the uni­ver­si­ties of Lille and Amiens, Inserm, the Jeanne de Flan­dre Hos­pi­tal of the Lille Uni­ver­si­ty Hos­pi­tal and coor­di­nat­ed by Lau­rent Storme. The aim is to study the expo­sure of chil­dren dur­ing the first 1,000 days of life and to sup­port fam­i­lies in lim­it­ing the pres­ence of tox­ic sub­stances in their environment. 

Oth­er stud­ies have already revealed the impor­tance of the chem­i­cal envi­ron­ment on chil­dren, in par­tic­u­lar those of Anne-Simone Par­ent in Bel­gium. With her team, she showed that migrant chil­dren, whether adopt­ed or accom­pa­ny­ing their par­ents, trig­gered ear­ly puber­ty when they moved to Bel­gium at the age of 5 or 6. It seems that the change in expo­sure to endocrine dis­rup­tors, very present in Africa and Asia (main­ly in pes­ti­cides), explains this phe­nom­e­non. Dis­rup­tors block repro­duc­tive mat­u­ra­tion. When their con­cen­tra­tion decreas­es in the envi­ron­ment of chil­dren, this inhi­bi­tion is lift­ed, and the brain ini­ti­ates full puberty. 

In con­trast, in chil­dren born and liv­ing in Europe, these prod­ucts seem to delay puber­ty. Their action is com­plex for sev­er­al rea­sons. On the one hand, we are all exposed to dif­fer­ent mol­e­cules, in vary­ing dos­es. It’s a chem­i­cal cock­tail that needs to be under­stood. Sec­ond­ly, because of their inter­ac­tion with the hor­mon­al sys­tem, they do not act in a lin­ear way. Their activ­i­ty is described by a U‑shaped or invert­ed U curve. The effect seems to be max­i­mal for low con­cen­tra­tions, espe­cial­ly dur­ing win­dows of vul­ner­a­bil­i­ty, such as « mini puberty ». 

Like ours, stud­ies are under­way that are dif­fi­cult to con­duct in a con­text where expo­sure is unavoid­able, and to inter­pret because of the vari­able effects over time accord­ing to the cock­tail. But we are are not lim­it­ed to analysing the effects of this type of pol­lu­tion on repro­duc­tive func­tions. As we have explained, brain mat­u­ra­tion is close­ly linked to gonadal matu­ri­ty. Endocrine dis­rup­tors are thus the main sus­pects in the autism epi­dem­ic observed in the Unit­ed States. We hope that elu­ci­dat­ing the mech­a­nisms of action of these pol­lu­tants on the brain and devel­op­ment in gen­er­al will help soci­ety to pro­tect itself bet­ter.

Interview by Agnès Vernet

For more information:

  • GnRH neu­rons recruit astro­cytes in infan­cy to facil­i­tate net­work inte­gra­tion and sex­u­al mat­u­ra­tion. Pel­le­gri­no et al., Nature Neu­ro­science 2021. doi: 10.1038/s41593-021–00960‑z
  • Cel­lu­lar and mol­e­c­u­lar fea­tures of EDC expo­sure: con­se­quences for the GnRH net­work. Lopez-Rodriguez et al. Nature Rewiews 2021. doi: 10.1038/s41574-020–00436‑3

Contributors

Vincent Prevot

Vincent Prevot

Research Director at Inserm within the Lille Neuroscience & Cognition Research Centre, Université de Lille

Vincent Prevot's research focuses on systems neuroscience and neuroendocrinology, in particular the study of brain circuits that control reproduction and metabolism and the neural pathways by which they respond to peripheral information. He is a member of the executive committees of several learned societies, and is currently President of the International Federation of Neuroendocrinology (INF), Treasurer of the French Brain Council, Past President of the French Society of Neuroendocrinology (SNE), and Treasurer of the Federation of European Neuroscience Societies (FENS)