How endocrine disruptors affect brain development

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. 

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. 

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