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