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Title: Listeria monocytogenes infection in pregnant guinea pigs is associated with maternal liver necrosis, a decrease in maternal serum TNF-alpha concentrations, and an increase in placental apoptosis

Author
item IRVIN, ELIZABETH - TOX.PROG.,UGEORGIA,ATHENS
item WILLIAMS, DENITA - TOX.PROG.,UGEORGIA,ATHENS
item Voss, Kenneth
item SMITH, MARY - ENV.HLTH.SCI.,UGEORGIA

Submitted to: Toxicology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/18/2008
Publication Date: 11/1/2008
Citation: Irvin, E.A., Williams, D., Voss, K.A., Smith, M.A. 2008. Listeria monocytogenes infection in pregnant guinea pigs is associated with maternal liver necrosis, a decrease in maternal serum TNF-alpha concentrations, and an increase in placental apoptosis. Reproductive Toxicology. 26:123-129.

Interpretive Summary: Listeriosis results from infection with Listeria monocytogenes, a bacteria found in foods. Listeriosis most commonly affects the elderly, immunocompromised individuals and pregnant women. The effects of listeriosis in pregnant women, who make up about one-third of the annual cases, include miscarriage, stillbirth and death of infected infants shortly after birth. Pregnant women exposed to this food borne pathogen have a 20 to 30 percent risk of having a stillbirth. Due to similarities in placental anatomy and commonalities in the chemical structure of E-cadherin, a protein that provides a critical binding site for the bacteria in the gastrointestinal tract, the guinea pig shows promise as a useful small animal model for studying the effects of listeriosis on pregnancy. We collaborated with University of Georgia scientists to further characterize the effects of Listeria monocytogenes in guinea pigs. Groups of pregnant animals were given single oral doses of the bacteria ranging from 10E4 to 10E8 CFUs (doses of bacteria are measured in Colony Forming Units). The bacteria caused liver injury and altered the animals' concentrations of serum tumor necrosis factor alpha, an important signaling molecule involved in inflammation and cell survival. These effects were found at doses below those which caused still births (10E6 CFU and above). Apoptosis (a type of cell death) in the placenta was also increased with doses greater than or equal to 10E6 CFU. The results show that liver injury and cell death in the placenta are associated with still births in guinea pigs exposed to Listeria monocytogenes and indicate that the guinea pig can be a useful animal model for studying this disease.

Technical Abstract: Listeriosis, resulting from Listeria monocytogenes infection, primarily targets the elderly, immunocompromised persons and pregnant women; the latter accounting for one-third of the 2500 cases reported annually. When a pregnant woman is exposed to this food borne pathogen, her risk of having a stillbirth is about 20-30%. Humans and guinea pigs have hemochorionic placentas and share identical amino acid sequences at the active site of cadherin E, a critical protein for mediating gastrointestinal invasion and transmission of the organism. Pregnancy outcomes in guinea pigs given L. monocytogenes (> 10E6 colony forming units (CFUs)) have been shown to mimic those of humans. To more fully characterize the guinea pig as a nonprimate animal model for Listeriosis, timed pregnant guinea pigs were given an oral dose of 10E4 to 10E8 CFUs L. monocytogenes on gestation day (gd) 35 and killed on gd 56 to assess selected maternal effects and placental apoptosis. Stillbirths occurred in 11 (1/9), 30 (3/10) and 75 (3/4) percent of the dams dosed with 10E6, 10E7, and 10E8 CFUs and the stillbirths were delivered increasingly prematurely as the dose increased. Apoptosis was detected in a significantly higher number of placentas from dams treated with > 10E6 CFUs compared to the controls, including placentas from all dams given the highest dose. Focal areas of necrosis were found in the livers of dams given 10E5 CFUs and above and the degree of hepatic injury, as judged using a subjective scoring system, increased with dose. In addition, maternal serum concentrations of the cytokine TNF-alpha were significantly decreased in all exposed groups. Together, the results showed that increased hepatic necrosis and placental apoptosis were associated with stillbirths caused by L. monocytogenes infection and that maternal effects occurred at doses lower than those inducing stillbirths. The results give further evidence that the guinea pig is a suitable nonprimate model for studying the adverse effects of L. monocytogenes during pregnancy.