France has banned it from all food containers while Belgium has limited the ban to certain containers affecting children under the age of three. The endocrine disruptor (ED) in question is Bisphenol-A (BPA), an agent involved in the composition of plastic containers, cans and other food containers as well as dental cement and thermal papers. In 2015, the European Food Safety Authority (EFSA) set the tolerable daily intake at 4 μg/kg. A study (1) by the University of Liège has shown that two weeks of exposure to a dose which is 160 lower than this threshold is enough to disrupt essential neurotransmission systems in the brains of new-born rats. 

The hypothalamus and the pituitary, situated in the brain, are responsible for the timing of the onset of puberty in both humans and rats. This timing is particularly influenced by various environmental factors, including endocrine disruptors EDs. This issue is at the heart of research carried out by Prof. Bourguignon, Emeritus Professor of Paediatric Endocrinology at GIGA Neurosciences at the University of Liège and Prof. Anne-Simone Parent. She currently leads a team in which Delphine Franssen has been studying the effects of diethylstilbestrol (DES), a carcinogenic ED which has been banned for around 40 years but remains a reference substance. For some fifteen years and to the present days, the scientific community has attributed the early or advanced onset of puberty to EDs.  Against all expectations, it was noted that a dose of 1 μg/kg/day of DES delayed puberty, in contrast to a dose ten times higher which advanced it. These dose-dependent contrasting effects of DES intrigued the team and caused them to study whether similar opposing effects could apply to BPA (Bisphenol-A).

 

Intake level creates opposing effects

More than 95% of us have BPA in our urine. Infants are the most highly exposed to it, with around 1μg/kg/day (micrograms) while average adult exposure is 40 to 60 ng/kg/day (nanograms, i.e. 10^-9 gram). These quantities represent, respectively, 50 times and twice the very low doses of 25 ng.kg/day administered to baby rats in the study which has just been published. The effects of such a small dose had not previously been studied. After exposure to relatively high doses of 5 mg/kg/day, the study confirmed an early onset of puberty. It also demonstrated a new fact: puberty was delayed following exposure to very low doses of BPA. These observations raise the question of knowing which part of the endocrine system is involved in disruptions to the timing of puberty. The onset of puberty is preceded, in the hypothalamus, by changes in intermittent (pulsatile) secretion of the brain hormone (GnRH or gonadoliberin) which controls the ovaries or testicles via the pituitary gland. The study highlights the fact that these changes are accelerated or slowed down depending on the dose of BPA in question. The brain is therefore clearly affected by BPA. But what mechanism is involved?

The onset of puberty, a window into the effects of BPA on the brain 

Delphine Franssen and the research team highlighted that exposure to BPA had an impact upon the expression of messenger RNA of hypothalamic genes involved in GABAergic neurotransmission. GABA is a neurotransmitter which plays an essentially inhibitory role in children and which can contribute to the mechanism which prevents puberty from being triggered in the brain. It is known that GABA activity increases with low doses of BPA and reduces with high doses. This observation led the Liège team to contact Daniel Zalko’s team in Toulouse, which had exposed mice to similar quantities of BPA during the perinatal period. These researchers found, on terms of the brain as a whole, similar effects to those observed in Liège on the hypothalamus. In the foetal brain, GABA plays a stimulating role which is undoubtedly crucial for the child’s development and later functioning

(1) Delayed neuroendocrine sexual maturation in female rats after a very low dose of Bisphenol A through altered GABAergic neurotransmission and opposing effects of a high dose, Franssen Delphine et al. Endocrinology 0013-7227, 2016.