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