Trichloroethylene, Trichloroacetic Acid, and Dichloroacetic Acid: Do They Affect Fetal Rat Heart Development?

Abstract

Trichloroethylene (TCE), trichloroacetic acid (TCA), and dichloroacetic acid (DCA) are commonly found as groundwater contaminants in many regions of the United States. Cardiac birth defects in children have been associated with TCE, and laboratory studies with rodents report an increased incidence of fetal cardiac malformations resulting from maternal exposures to TCE, TCA, and DCA. The objective of this study was to orally treat pregnant CDR(CD) Sprague-Dawley rats with large bolus doses of either TCE (500 mg/kg), TCA (300 mg/kg), or DCA (300 mg/kg) once per day on days 6 through 15 of gestation to determine the effectiveness of these materials to induce cardiac defects in the fetus. All-trans retinoic acid (RA) dissolved in soybean oil was used as a positive control. Soybean oil is commonly used as a dosing vehicle for RA teratology studies and was also used in this study as a dosing vehicle for TCE. Water was used as the dosing vehicle for TCA and DCA. Fetal hearts were examined on gestation day (GD) 21 by an initial in situ, cardiovascular stereomicroscope examination, and then followed by a microscopic dissection and examination of the formalin-fixed heart. The doses selected for TCA and DCA resulted in a modest decrease in maternal weight gain during gestation (3% to 8%). The fetal weights on GD 21 in the TCA and DCA treatment groups were decreased 8% and 9%, respectively, compared to the water control group and 21% in the RA treatment group compared to soybean oil control group. The heart malformation incidence for fetuses from the TCE-, TCA-, and DCA-treated dams did not differ from control values on a per fetus or per litter basis. The rate of heart malformations, on a per fetus basis, ranged from 3% to 5% for TCE, TCA, and DCA treatment groups compared to 6.5% and 2.9% for soybean oil and water control groups. The RA treatment group was significantly higher with 33% of the fetuses displaying heart defects. For TCE, TCA, and DCA treatment groups 42% to 60% of the litters contained at least one fetus with a heart malformation, compared to 52% and 37% of the litters in the soybean oil and water control groups. For the RA treatment group, 11 of 12 litters contained at least one fetus with a heart malformation. Further research is needed to quantify the spontaneous rates of heart defects for vehicle control rats and to explain the disparity between findings in the present study and other reported findings on the fetal cardiac teratogenicity of TCE, TCA, and DCA.

Trichloroethylene and dichloroethylene: A critical review of teratogenicity

“…In well-designed and -conducted studies using experimental techniques recognized by regulatory agencies as useful for identifying developmental hazards, rats, mice, and rabbits have been exposed to TCE by inhalation at up to 1800 ppm (Schwetz et al, 1975;Dorfmueller et al, 1979;Beliles et al, 1980;Healy et al, 1982;Zablotny et al, 2002), rats have been exposed to t-DCE by inhalation at up to 12,000 ppm (Hurtt et al, 1993), and rats have been treated by gavage at 500 mg TCE/kg/day (Fisher et al, 2001). None of these studies found any suggestion of exposurerelated developmental toxicity, even in the presence of maternal toxicity.…”

“…None of these studies found any suggestion of exposurerelated developmental toxicity, even in the presence of maternal toxicity. None of these studies found any evidence of specific cardiac teratogenicity, even when (Fisher et al, 2001) the microdissection technique of Dawson et al (1990Dawson et al ( , 1993 was used and a member of that research group was part of the study team.…”

“…Rats were dosed on GD 6 -15 with TCE at 500 mg/kg/day, TCA at 300 mg/kg/day, or DCA at 300 mg/ kg/day (Fisher et al, 2001). These investigators used the previous chick studies (Bross et al, 1983).…”

Effects of trichloroethylene and its metabolite trichloroacetic acid on the expression of vimentin in the rat H9c2 cell line

“…The discrepancy may be explained by two major differences in the exposure protocols used by the authors: In the Dawson et al study, rats were exposed to TCE via drinking water, as opposed to gavage (Fisher et al, 2001). Additionally, in Dawson's protocol the dams were exposed to the toxicant starting at day 0 of conception (with a regimen of 7 days/week exposure), whereas Fisher's study started the exposure at day 6, and used a regimen of 5 days/week.…”

“…Human exposure to TCE through contaminated drinking water has been associated with a 3-fold increase in congenital heart malformations in children born to exposed mothers . Animal studies have confirmed that TCE, and its metabolites DCE (dichloroethylene) and TCAA are specific cardiac teratogens in chicks and rats (Dawson et al, 1990(Dawson et al, , 1993Goldberg et al, 1990Goldberg et al, , 1992Johnson et al, 1998), although some controversy still exists stemming from a study reporting no significant teratogenic effects of TCE in rat embryonic heart (Fisher et al, 2001).…”