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Dental Infection of Porphyromonas gingivalis Induces Preterm Birth in Mice.

Ao M, Miyauchi M, Furusho H, Inubushi T, Kitagawa M, Nagasaki A, Sakamoto S, Kozai K, Takata T - PLoS ONE (2015)

Bottom Line: P.g. infection caused significantly increased numbers of polymorphonuclear leukocytes (PMNLs) and macrophages in placental tissues, associated with increased local expression of pro-inflammatory mediators including TNF-α and COX-2.In vitro, P.g. lipopolysaccharide significantly increased expression of COX-2, IL-8 and TNF-α, in HTR-8 trophoblasts in an NF-κB-dependent fashion.These findings further underscore the importance of local and systemic infections and inflammation during pregnancy and suggest that prevention and/or elimination of dental infections such as marginal or periapical periodontitis before pregnancy may have a beneficial effect on PTB/LBW.

View Article: PubMed Central - PubMed

Affiliation: Department of Oral and Maxillofacial Pathobiology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan; Department of Pediatric Dentistry, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan.

ABSTRACT

Background: Epidemiological studies have revealed a link between dental infection and preterm birth or low birth weight (PTB/LBW), however, the underlying mechanisms remain unclear. Progress in understanding the associated mechanisms has been limited in part by lack of an animal model for chronic infection-induced PTB/LBW, mimicking pregnancy under conditions of periodontitis. We aimed to establish a mouse model of chronic periodontitis in order to investigate the link between periodontitis and PTB/LBW.

Methods: To establish chronic inflammation beginning with dental infection, we surgically opened mouse (female, 8 weeks old) 1st molar pulp chambers and directly infected with w83 strain Porphyromonas gingivalis (P.g.), a keystone periodontal pathogen. Mating was initiated at 6 wks post-infection, by which time dental granuloma tissue had developed and live P.g. was cultured from extracted tooth root, which serves as a persistent source of P.g. The gestational day (gd) and birth weight were recorded during for P.g.-infected and control mice, and serum and placental tissues were collected at gd 15 to evaluate the systemic and local conditions during pregnancy.

Results: Dental infection with P.g. significantly increased circulating TNF-α (2.5-fold), IL-17 (2-fold), IL-6 (2-fold) and IL-1β (2-fold). The P.g.-infected group delivered at gd 18.25 vs. gd 20.45 in the non-infected control (NC) group (p < 0.01), and pups exhibited LBW compared to controls (p < 0.01). P.g. was localized to placental tissues by immunohistochemistry and PCR, and defects in placental tissues of P.g. infected mice included premature rupture of membrane, placental detachment, degenerative changes in trophoblasts and endothelial cells, including necrotic areas. P.g. infection caused significantly increased numbers of polymorphonuclear leukocytes (PMNLs) and macrophages in placental tissues, associated with increased local expression of pro-inflammatory mediators including TNF-α and COX-2. Further placental tissue damage was indicated in P.g. infected mice by decreased CD-31 in endothelial cells, increased expression of 8OHdG, an indicator of oxidative DNA damage, and cleaved caspase-3, a marker of apoptosis. In vitro, P.g. lipopolysaccharide significantly increased expression of COX-2, IL-8 and TNF-α, in HTR-8 trophoblasts in an NF-κB-dependent fashion.

Conclusions: Our novel mouse model supports previous epidemiological studies signifying dental infection as predisposing factor for PTB/LBW. We demonstrate PTB and LBW in infected mice, translocation of P.g to placental tissues, increased circulating and local pro-inflammatory markers, and the capability of P.g. LPS to directly induce cytokine production in trophoblasts, in vitro. These findings further underscore the importance of local and systemic infections and inflammation during pregnancy and suggest that prevention and/or elimination of dental infections such as marginal or periapical periodontitis before pregnancy may have a beneficial effect on PTB/LBW.

No MeSH data available.


Related in: MedlinePlus

Dental Infection of P.g. Increases Pro-inflammatory Cytokines in Serum.ELISA analysis of TNF-α (A), IL-1β (B), IL-6 (C) and IL-17 (D) concentrations in serum (0wk or 6wks post-infection) of non-infected control (NC) and P.g.-infected groups (n = 6 for each). Statistical significance was determined using the Student t-test. **P<0.01.
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pone.0137249.g001: Dental Infection of P.g. Increases Pro-inflammatory Cytokines in Serum.ELISA analysis of TNF-α (A), IL-1β (B), IL-6 (C) and IL-17 (D) concentrations in serum (0wk or 6wks post-infection) of non-infected control (NC) and P.g.-infected groups (n = 6 for each). Statistical significance was determined using the Student t-test. **P<0.01.

Mentions: Statistical differences among experimental groups were evaluated by t-test or chi-square test using GraphPad Prism (version 6.0c, CA, USA) with the level of significance described for p < 0.01 (**) and p < 0.05 (*).


Dental Infection of Porphyromonas gingivalis Induces Preterm Birth in Mice.

Ao M, Miyauchi M, Furusho H, Inubushi T, Kitagawa M, Nagasaki A, Sakamoto S, Kozai K, Takata T - PLoS ONE (2015)

Dental Infection of P.g. Increases Pro-inflammatory Cytokines in Serum.ELISA analysis of TNF-α (A), IL-1β (B), IL-6 (C) and IL-17 (D) concentrations in serum (0wk or 6wks post-infection) of non-infected control (NC) and P.g.-infected groups (n = 6 for each). Statistical significance was determined using the Student t-test. **P<0.01.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556457&req=5

pone.0137249.g001: Dental Infection of P.g. Increases Pro-inflammatory Cytokines in Serum.ELISA analysis of TNF-α (A), IL-1β (B), IL-6 (C) and IL-17 (D) concentrations in serum (0wk or 6wks post-infection) of non-infected control (NC) and P.g.-infected groups (n = 6 for each). Statistical significance was determined using the Student t-test. **P<0.01.
Mentions: Statistical differences among experimental groups were evaluated by t-test or chi-square test using GraphPad Prism (version 6.0c, CA, USA) with the level of significance described for p < 0.01 (**) and p < 0.05 (*).

Bottom Line: P.g. infection caused significantly increased numbers of polymorphonuclear leukocytes (PMNLs) and macrophages in placental tissues, associated with increased local expression of pro-inflammatory mediators including TNF-α and COX-2.In vitro, P.g. lipopolysaccharide significantly increased expression of COX-2, IL-8 and TNF-α, in HTR-8 trophoblasts in an NF-κB-dependent fashion.These findings further underscore the importance of local and systemic infections and inflammation during pregnancy and suggest that prevention and/or elimination of dental infections such as marginal or periapical periodontitis before pregnancy may have a beneficial effect on PTB/LBW.

View Article: PubMed Central - PubMed

Affiliation: Department of Oral and Maxillofacial Pathobiology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan; Department of Pediatric Dentistry, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan.

ABSTRACT

Background: Epidemiological studies have revealed a link between dental infection and preterm birth or low birth weight (PTB/LBW), however, the underlying mechanisms remain unclear. Progress in understanding the associated mechanisms has been limited in part by lack of an animal model for chronic infection-induced PTB/LBW, mimicking pregnancy under conditions of periodontitis. We aimed to establish a mouse model of chronic periodontitis in order to investigate the link between periodontitis and PTB/LBW.

Methods: To establish chronic inflammation beginning with dental infection, we surgically opened mouse (female, 8 weeks old) 1st molar pulp chambers and directly infected with w83 strain Porphyromonas gingivalis (P.g.), a keystone periodontal pathogen. Mating was initiated at 6 wks post-infection, by which time dental granuloma tissue had developed and live P.g. was cultured from extracted tooth root, which serves as a persistent source of P.g. The gestational day (gd) and birth weight were recorded during for P.g.-infected and control mice, and serum and placental tissues were collected at gd 15 to evaluate the systemic and local conditions during pregnancy.

Results: Dental infection with P.g. significantly increased circulating TNF-α (2.5-fold), IL-17 (2-fold), IL-6 (2-fold) and IL-1β (2-fold). The P.g.-infected group delivered at gd 18.25 vs. gd 20.45 in the non-infected control (NC) group (p < 0.01), and pups exhibited LBW compared to controls (p < 0.01). P.g. was localized to placental tissues by immunohistochemistry and PCR, and defects in placental tissues of P.g. infected mice included premature rupture of membrane, placental detachment, degenerative changes in trophoblasts and endothelial cells, including necrotic areas. P.g. infection caused significantly increased numbers of polymorphonuclear leukocytes (PMNLs) and macrophages in placental tissues, associated with increased local expression of pro-inflammatory mediators including TNF-α and COX-2. Further placental tissue damage was indicated in P.g. infected mice by decreased CD-31 in endothelial cells, increased expression of 8OHdG, an indicator of oxidative DNA damage, and cleaved caspase-3, a marker of apoptosis. In vitro, P.g. lipopolysaccharide significantly increased expression of COX-2, IL-8 and TNF-α, in HTR-8 trophoblasts in an NF-κB-dependent fashion.

Conclusions: Our novel mouse model supports previous epidemiological studies signifying dental infection as predisposing factor for PTB/LBW. We demonstrate PTB and LBW in infected mice, translocation of P.g to placental tissues, increased circulating and local pro-inflammatory markers, and the capability of P.g. LPS to directly induce cytokine production in trophoblasts, in vitro. These findings further underscore the importance of local and systemic infections and inflammation during pregnancy and suggest that prevention and/or elimination of dental infections such as marginal or periapical periodontitis before pregnancy may have a beneficial effect on PTB/LBW.

No MeSH data available.


Related in: MedlinePlus