Cardiopathic effects of dichloroacetate in the fetal long‐evans rat

Abstract

Dichloroacetic acid (DCA) is a by-product of the chlorine disinfection of water and may occur in treated water at levels exceeding 100 micrograms/L. Previous studies revealed teratogenic effects, particularly heart malformations, at high doses (900-2,400 mg/kg given on days 6-15 of pregnancy). In a series of three studies, groups of 7-10 Long-Evans rats were dosed with 1,900 mg/kg of DCA on days 6-8, 9-11, or 12-15; with 2,400 mg/kg on days 10, 11, 12, or 13; and with 3,500 mg/kg on days 9, 10, 11, 12, or 13, in an attempt to determine the most sensitive period and further characterize the heart defect. In a fourth study, six dams were treated with 1,900 mg/kg of DCA days 6-15 of pregnancy, and 56 fetuses were harvested for light microscopy of the heart. Eight control fetuses from four litters were also examined. No heart malformations were seen in the groups treated with 1,900 mg/kg DCA days 6-8 but were present in the group treated on days 9-11 and 12-15, with the higher incidence occurring on days 12-15. Single doses of 2,400 mg/kg DCA given on days 10, 11, 12, or 13 resulted in a much lower incidence of cardiac malformations, which occurred only on days 10 and 12. The high dose of DCA (3,500 mg/kg) did not increase the incidence of heart defects but showed that dosing on day 9 as well as on days 10 and 12 would produce the defect. The defects seen were characterized as high interventricular septal defects (H-IVSD). Light microscopy showed that the defect was caudal to the semilunar valves, with the anterior right wall of the aorta communicating with the right ventricle. Another aspect of the defect is at the level of the semilunar valves, with the right cusp or sinus of Valsalva in communication with the right ventricle. The defects are discussed more fully and methods for further study suggested.

Dichloroacetate‐induced developmental toxicity and production of reactive oxygen species in zebrafish embryos

“…Also, early embryonic development of zebrafish has been found to be similar to other mammalian species in many aspects [21]. Furthermore, the results of the present study indicate responsiveness of this species to the compound through production of types of developmental toxic effects, such as yolk sac edema, mouth malformation, and behavioral changes that have not been previously reported, besides the pre- viously observed effects in the head and heart regions of rodent embryos [11][12][13].…”

“…However, others have described its developmental toxicity in rodents [11][12][13]. In this report, DCA developmental toxicity has been demonstrated in another species, namely the zebrafish (Danio rerio).…”

Early lifestage exposure and potential developmental susceptibility to tetrachloroethylene

“…The results remained significantly elevated (aRR 5 3.74; 95% CI 5 1.21-11.62) when infants with Down syndrome were excluded from the analysis. Given the evidence for heart defects reported in animal studies with exposure to TCE and its metabolites, TCA and DCA (Epstein et al, 1992;Johnson et al, 1998a,b;Smith et al, 1989Smith et al, , 1992, there is a need for additional study of heart defects after exposure to perc.…”

Evaluating noncancer effects of trichloroethylene: dosimetry, mode of action, and risk assessment.

“…The cardiac malformations studies are particularly difficult to interpret because of the lack of clear dose-response and temporal relationships (i.e., exposures prior to pregnancy, during pregnancy, or for both periods) (42). Developmental studies with TCA and dichloroacetate (DCA) also observed cardiac malformation (47)(48)(49)(50), but estimates of maternal blood TCA levels do not appear consistent between the TCA and TCE studies (21). No effects were observed with other TCE metabolites, notably chloral hydrate and dichlorovinylcysteine (DCVC) (49,50 (46,48).…”