Saliva is a fluid secreted primarily by the three major salivary glands, i.e. parotid, submandibular and sublingual glands. Human salivary glands typically secrete 0.5–1 liter of saliva per day in response to sympathetic and parasympathetic stimulation 
. Fluid and electrolyte secretion involves two stages: the secretory endpiece secretes an isotonic NaCl-rich, plasma-like fluid (stage 1) which is subsequently modified as it passes through the ductal network (stage 2). Most of the NaCl is reabsorbed in the ducts, and importantly, KHCO3
is secreted. HCO3−
ions play a major role in buffering the pH of saliva.
Salivary glands express CFTR, an anion channel gated by an increase in intracellular cAMP. CFTR channels have been postulated to be involved in both acinar (stage 1) and ductal (stage 2) functions 
. Using the ΔF508 mouse model of cystic fibrosis, we found that the CFTR channel mediates Cl−
reabsorption by salivary gland ducts but fluid secretion was normal 
. We also noted that the submandibular saliva pH in ΔF508 mice was decreased compared to their wildtype littermates. In the present study, the pH of whole saliva, which is most relevant to caries formation and progress, was also significantly reduced in the ΔF508 mouse. However, the pH of whole saliva was higher than observed previously in submandibular saliva 
. The difference in the saliva pH between the two studies is likely the consequence of the different stimulation protocol (carbachol/isopreterenol-stimulated vs. pilocarpine-stimulated), different type of saliva collected (submandibular ductal saliva vs. whole saliva), and/or the difference in flow rate between ex vivo
and in vivo
approaches. Related to this last point, HCO3−
secretion is flow rate dependent.
The lower saliva pH observed in the ΔF508 mouse suggests that the ΔF508 CFTR mutation compromises the HCO3−
secretion mechanism. Consistent with this prediction, we found that the bicarbonate concentration of pilocarpine-stimulated whole saliva was severely reduced in the ΔF508 mice. HCO3−
is the most important pH buffering system in saliva, while adherence and survival of many oral bacteria are dependent on pH. Consequently, we hypothesized that S. mutans
colonization and prevalence of carious lesions may be enhanced in the ΔF508 mouse model of cystic fibrosis. We found that the incidence of both smooth and sulcal surface caries of mandibular and maxillary molars was significantly elevated in the ΔF508 mouse. The severity of carious lesions was also dramatically elevated, increasing in most cases by an order of magnitude for both smooth and sulcal surfaces. This remarkable increase in the severity of carious lesions in the ΔF508 mouse in just five weeks exposure to a cariogenic diet is noteworthy in that it is comparable to that seen in mice that had been desalivated 
. Nevertheless, the elevated incidence and severity of dental caries was not related to a decrease in saliva by itself because the fluid secretion volume was essentially unchanged in the ΔF508 mouse 
. Thus, the ΔF508 CFTR mutation appears to decrease HCO3−
secretion in salivary glands, reducing the buffering capacity and pH of saliva. These phenomena would greatly affect the ability of saliva to reduce the adverse effects of acid production by S. mutans
and other acidogenic bacteria, and thereby increase the extent of acidification within the dental plaque on the tooth surface. The persistence of this aciduric environment in the plaque's matrix leads to selection and establishment of highly acid-tolerant (and acidogenic) organisms such as S. mutans
, and the acidic pH at plaque-tooth interface results in dissolution of enamel 
Another possible mechanism for the elevated incidence and severity of lesions in the CF mouse is that the ΔF508 mutation might alter the composition of the tooth enamel. However, Bronckers et al.
found that the ameloblasts of molars were not structurally affected in mice lacking Cftr 
. Indeed, Gawenis et al.
failed to detect changes in the ion composition of the molars of these mice 
. No lesions were detected in the mouse incisors probably because they erupt continuously. Consequently, considering that HCO3−
is the most important pH buffering system in saliva, and tight adherence and survival of aciduric bacteria such as S. mutans
are enhanced at low pH values, the decrease in the HCO3−
content and pH buffering of the saliva is most likely to be at least partially responsible for the severity of lesions observed in the CF mouse. Importantly, this is the first genetic model to demonstrate a clear relationship between saliva composition and the incidence of carious lesions. Accordingly, the ΔF508 CF mouse paves the way for future studies to evaluate the complex, multifactorial relationship between host genetic factors and the pathogenesis of dental caries. The insight gained from such studies may ultimately lead to the generation of cost effective preventive agents for dental caries, the most common and costly oral infectious disease worldwide.