© Springer-Verlag Berlin Heidelberg 2014
Michel Goldberg (ed.)The Dental Pulp10.1007/978-3-642-55160-4_13
13. Effects of Bisphenol A on the Dental Pulp
Department of Oral Biology, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, 45 Rue des Saints Pères, Paris, 75006, France
The xenoestrogen bisphenol A (BPA) is widely used in various food and packaging consumer products, in the manufacture of polycarbonate plastics and epoxy resins. It is released from food and beverage containers, baby’s bottles, children’s toys, and dental restorative materials, including occlusal sealants supposed to prevent the development of carious decays. It produces numerous adverse endocrine and developmental effects in rodents, resulting in general cytotoxic and pathologic outcomes. Some local effects are closely associated with this family of endocrine-disrupting compounds. What is induced is related to the estrogenic properties of BPA and resulting from alterations of synthesis of estradiol and testosterone. These effects are interfering with receptor binding. Irregular cycles, multiple ovarian cysts, reduction in primary follicles, neonatal mortality, sexual dysfunctions, and decreased libido have been reported as undesirable or adverse effects. Epigenetic effects are associated with an increased risk of cancer, namely, breast and prostate malignancies. Low-dose BPA exposure seems to increase adipogenesis in female animals, obesity, non-insulin-dependent diabetes mellitus, allergies, asthma, autism, cognitive decline, memory impairment, depression, and anxiety . In addition to these well-documented general effects, many questions are related to the risks due to release of BPA after the dental restorations after a carious lesion or after the sealing of pits and fissures.
13.2 Cytotoxic Effects and Induced General Pathologies
The lower dose inducing cell damage is determined by the no observed adverse effect level (NOAEL). It was evaluated by the Food and Drug Administration to be as low as 5 mg BPA/kg body weight (bw)/day. However, according to safety authorities and protection agencies, the tolerable daily intake (TDI) considered as a reference would be a dose of 0.05 mg/kg bw/day. The issue of the dose is still a matter of debate, but it is clear that doses below the NOAEL have significant effects. According to Moon et al.  doses of BPA below the NOAEL induce mitochondrial dysfunctions in the liver and are associated with an increase in oxidative stress and inflammation.
Low concentrations of BPA induce lipid accumulation in hepatic cells, mediated by the production of reactive oxygen species in the mitochondria of HepG2 cells. Mitochondrial dysfunctions, including ROS production, lipoperoxidation, and the release of proinflammatory cytokines, are contributing to steatosis. They result from low concentration of BPA .
Traditional classical dogma in toxicology was “the dose makes the poison.” Evolution of the concept suggests that effects may be detected with low doses below that used for traditional toxicological studies. In addition non-monotonic dose-response should also be taken into account. The effects of low doses cannot predict the effects observed at higher doses . This implies that the effects of low doses have to be taken into consideration in terms of undesirable effects and of possible induced pathologies.
Cabaton et al.  have reported the effects of low doses of bisphenol A on the metabolome of perinatally exposed CD-1 mice (a method used for determining the metabolic changes to nutritional, pharmacological, and toxic stimuli). Dose-dependent variations in glucose, pyruvate, some amino acids, and neurotransmitters were identified, supporting that low dose of the endocrine disruptor BPA administered from day 1 up to day 21 interferes and disrupts the global metabolism.
13.2.1 Determination of Blood, Urine, Saliva, and Sweat Parameters of Excretion
Normal values and concentrations found after BPA treatment were reported in body fluids.
Blood: No BPA was found in blood samples prior or after dental treatment.
Saliva: Olea et al.  collected the saliva 1 h before the application of cured sealants. After treatment, all saliva samples contained BPA in amount ranging from 90 to 931 μg. In control patients, BPA was detected in the saliva of all patients prior to the placement of the sealants and ranged between 0.07 and 6.00 ng/ml at baseline. Three hours after treatment, the salivary concentration peaked and returned to the baseline level within 24 h. Low peak levels were 3.98 ng/ml (one sealant application alone), whereas 9.08 ng/ml in the high-dose group (more than four sealants) . Altogether, the different clinical studies available conclude that the highest level of BPA reported in saliva from dental sealants is more than 50,000 lower than the lethal dose 50 (LD50) values reported for BPA. This allows some researchers to conclude that human exposure to BPA from dental resins is minimal and poses no known health risk . This contradicts some findings establishing that some low-dose effects of BPA are at the origin of undesirable effects.
The daily urinary BPA excretion gave a median value of 1.2 μg/day, far below the tolerable daily intake recommended by the European Commission in 2002 .
Human excretion of sweat: Monitoring the bioaccumulation of BPA in blood, urine, and sweat, Genuis et al.  concluded that blood and urine testing might underestimate the total body burden of the potential toxicant. By contrast, they considered that sweat analysis should be considered as an additional method to follow accurately the accumulation of BPA and its elimination.
Therefore, metrologic evaluations should keep attention on the false body fluids and not on what should be considered as significant.
13.2.2 Toxicogenomics and Adverse Health Effects
BPA exhibits toxicogenomics and undesirable effects on human health owning to the 89 common interacting genes/proteins. These genes/proteins may serve as biomarkers to assay the toxicities of the different chemicals leached out from the widely used plastics.
Bisphenol A acting as an endocrine disruptor is implicated in the feminization in various organs and displays various estrogenic effects. Due to a competitive ligand binding, BPA is bound to estrogen receptors α and β. The density of mammary buds was increased in BPA-exposed monkeys, leading to precancerous forms .
13.2.3 Precancerous and Cancerous Effects
Exposure to low doses of BPA resulted in significant alterations in gland morphology, which varied to subtle effects on mammary gland development when the exposure period occurs in adulthood, leading from precancerous to cancerous lesions. Prenatal exposure to relevant doses of BPA increases the number of intraductal hyperplasia and ductal carcinoma. Acevedo et al.  reported that the environmental levels of BPA during gestation and lactation induce mammary gland neoplasms even in the absence of any additional carcinogenic treatment.
13.2.4 Other Adverse Effects
220.127.116.11 Brain Development
Prenatal and lactational exposures to low doses of BPA show effects on brain development in mice.
In the adult mice brains, abnormal neocortical architecture and abnormal corticothalamic projections persisted in the group exposed to the BPA. Epigenetic alterations might trigger some of the effects on brain development after exposure to BPA .
High-dose BPA impairs hippocampal neurogenesis in female mice across generations. This shed lights on another important feature: the transgenerational effect. The evaluation of transgenerational effects of BPA on hippocampal neurogenesis showed that when pregnant female mice were exposed to BPA (F0), the offspring (F2) from F1 generation display a decrease of newly generated cells in the hippocampi of F2 female mice. BPA adversely affects hippocampal neurogenesis of future generation by modulating ERK and BDNF-CREB signaling cascades . The fact that the second or third generation of mice shows epigenetic alterations even without any contact with BPA is important for the potential development of pathologies of BPA-treated patients.
18.104.22.168 Effects on Type 2 Diabetes
Short-term treatment with BPA leads to metabolic abnormalities in insulin-sensitive peripheral tissues. Mice treated with BPA were insulin resistant and had increased glucose-stimulated insulin release. It was concluded that short-term treatment with low dose of BPA slows down whole body energy and disrupts insulin signaling in peripheral tissues. Therefore, BPA can be considered as a risk factor for the development of type 2 diabetes .
Exposure of 3T3-L1 preadipocytes for 14 days to BPA reduced the amount of triglyceride accumulation and suppressed the gene transcription of the lipogenic enzyme lipoprotein lipase. BPA can reduce triglyceride accumulation during adipogenesis .