Bisphenol-A, is very little still too much?

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

A closer look at the damaging effects of BPA on the foetal brain was required, with a view to determining the possible consequences for neuro-developmental difficulties such as autism, which is on the rise. Once again, science turns to regulatory provisions. In France, BPA has been banned in all food containers, regardless of the age of the consumer. In Belgium, this provision only applies to children under the age of three, and thus does not reply to pregnant women and their unborn children. Does the research mentioned above, alongside other publications, justify extending the precautionary principle which has been applied to young children to pregnant women and unborn children? Can we extrapolate the data from rats to issues affecting human health? 

Are humans really at risk?

We know that BPA is detectable in the urine of the majority of the population. Some studies in humans suggest a link with changes in the onset of puberty. Moreover, the ‘mixture’ effect with other chemical substances in our environment should not be overlooked. We are exposed to hundreds of chemical compounds. The mixture effect refers to the combination of low or very low doses of several substances which do not lead to the effect individually, but which results from the combination of these substances. Moreover, the environmental factors which humans face are not limited to endocrine disruptors. Thus, quantitative and qualitative variations in the supply of nutrients may have consequences which are just as severe when they are combined as exposure to endocrine disruptors. In this context, Delphine Franssen has shown that the combination of a prenatal nutritional deficit and post-natal early exposure to DES leads to combined effects, with a total loss of the receptiveness of the GnRH system to leptin. Concerns around the combined effects of different ‘stress factors’ are greatest for the foetus and new-born, and can have life-long consequences. Both in rats and humans, foetal life and the peri-natal period are key moments when the body establishes mechanisms to adapt to the environment. If these mechanisms are disrupted within the body during development, the impact may be felt throughout life. 

Are issues restricted to puberty?

Beyond the effects of BPA on the development of puberty, several studies suggest that early exposure to BPA may be associated with an increased risk of obesity, neurodevelopmental anomalies and behavioural difficulties. These pathologies present a high cost in terms of treatment. It has been shown that exposure to endocrine disruptors in Europe contributes substantially to the increase in illnesses affecting the reproductive system, metabolism and neurodevelopment, with costs estimated at close to 160 billion euros per year. 

Moreover, it appears that products which are marketed as replacing BPA may also have endocrine disruptive effects. In April, the European Food Safety Authority (EFSA) announced that the BPA case would be reopened. The conclusions are eagerly awaited, as well as proposals which the European Commission has been working on since December 2013 for the criteria to identify endocrine disruptors. It is to be hoped that ‘strength’ is not one of the criteria selected. In line with other studies, the work carried out in the Liège lab stresses the inadequacy and potential incongruousness of trying to identify a ‘threshold’ dose depending on the strength of a chemical agent such as BPA.

(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.