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The purpose of this study was to investigate the effect of 1,1,1-trichloro-2,2-bis-(chlorophenyl)ethane (DDT), 1,1-bis-(chlorophenyl)-2,2-dichloroethene (DDE), and 1,1-dichloro-2,2-bis(chlorophenyl)ethane (DDD) isomers on COX-2 expression in a human trophoblast-derived cell line. Cultured HTR-8/SVneo trophoblast cells were exposed to DDT isomers and its metabolites for 24 h, and COX-2 mRNA and protein expression were assessed by RT-PCR, Western blotting, and ELISA. Prostaglandin E₂ production was also measured by ELISA. Both COX-2 mRNA and protein were detected under control (unexposed) conditions in the HTR-8/SVneo cell line. COX-2 protein expression and prostaglandin E₂ production but not COX-2 mRNA levels increased only after DDE and DDD isomers exposure. It is concluded that DDE and DDD exposure induce the expression of COX-2 protein, leading to increased prostaglandin E2 production. Interestingly, the regulation of COX-2 by these organochlorines pesticides appears to be at the translational level., (© 2012 Wiley Periodicals, Inc.)

The potential for anaerobic biodegradation of 1,1,1-trichloro-2,2-bischlorophenylethane (DDT), 1,1-dichloro-2,2,-bischlorophenylethane (DDD), and dichlorodiphenylchloroethylene (DDE) in anoxic sediment slurries collected from the Keelung River was investigated in this study. o,p'- and p,p'-DDT were dechlorinated to o,p'- and p,p'-DDD, respectively, and then transformed to other compound(s). 1-Chloro-2,2-bis (p-chlorophenyl) ethylene (DDMU) and trace amount of dichlorobenzophenone (DBP) were detected in sediment slurries amended with p,p'-DDT or p,p'-DDD. DDMU was also detected in sediment slurries amended with p,p'-DDE. The relative transformation rates for both o,p'- and p,p'-isomers of DDT, DDD, and DDE were DDT>DDD>DDE. Re-addition of DDT, DDD, or DDE to the sediment slurries after initial removal enhanced the respective dechlorination rates. The transformation rates of the p,p'-isomers of both DDT and DDD were faster than those of the respective o,p'-isomers. p,p'-DDT dechlorination in the p,p'-DDT-adapted sediment slurries were inhibited by the addition of molybdate, or molybdate plus sulfate, but not inhibited by the addition of sulfate. Addition of bromoethane-sulfonic acid (BESA) slightly inhibited p,p'-DDT dechlorination. Non-adapted sediment slurries lost the ability to dechlorinate pentachlorophenol during adaptation to p,p'-DDT. p,p'-DDD was the major transformation product of p, p'-DDT in 3,4,4',5-tetrachlorobiphenyl-adapted sediment slurries, which suggested that the microbial community in the 3,4,4',5-CB-adapted sediment was unable to remove chlorine from the aromatic rings of p,p'-DDT.

Isolated rabbit Clara cells and a transformed human bronchial epithelial cell line, BEAS-2B, were used to investigate the mechanism of cytotoxicity of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane (DDD), a persistent insecticide and stable metabolite of 1,1,1-trichloro-2,2- bis(p-chlorophenyl)ethane. Both BEAS-2B cells and rabbit Clara cells were highly susceptible to DDD toxicity and were partially protected by 1-aminobenzotriazole, a suicide substrate inhibitor of cytochrome P450 enzymes. DDD (0.05 mM) killed 47 +/- 1.8% of rabbit Clara cells and 42 +/- 7.9% of BEAS-2B cells after 3 hr and 84 +/- 3.0% of rabbit Clara cells and 80 +/- 14% of BEAS-2B cells after 6 hr. Consequently, DDD is the most potent Clara cell toxicant recognized to date. The cytotoxicity of DDD to these cells was decreased by deuterium substitution at the C-1 position. Rabbit Clara cells and pulmonary microsomes incubated with 14C-DDD produced the fully oxidized acetic acid metabolite 2,2'-bis(p- chlorophenyl)acetic acid (DDA), but DDA was not formed by Clara cells when DDD was coincubated with 1-aminobenzotriazole. These results support the hypothesis that the cytotoxicity of DDD to susceptible subpopulations of rabbit and human lung cells is, at least in part, caused by cytochrome P450-mediated oxidation of DDD at C-1. A required step for the production of the cytotoxic intermediate is proposed to be the formation of a highly reactive acyl halide intermediate that is readily hydrolyzed to a stable, nontoxic metabolite, DDA.

The metabolism of [1-2H]-1,1-dichloro-2,2-bis(p-chlorophenyl)ethane (DDD-d) and [1-2H]-1-chloro-2,2-bis(p-chlorophenyl)ethene (DDMU-d) and their corresponding non-deuterated isomers DDD and DDMU was studied in female Swiss mice over a 96-hr period. The only detected urinary metabolite of DDD-d and DDD was 2,2-bis(p-chlorophenyl)acetic acid (DDA). Animals administered DDD excreted approximately 2.4-fold more DDA than those treated with DDD-d over the total collection period. The initial (0-36 hr) linear excretion rates of DDA for DDD and DDD-d were 17.1 and 5.5 micrograms/hr respectively. DDMU- and DDMU-d-treated mice excreted significant quantities of DDA, 2,2-bis(p-chlorophenyl)ethanol (DDOH) and 2,2-bis(p-chlorophenyl)ethanol (DDCHO). The only quantitative difference between DDMU and DDMU-d was that the non-deuterated isomer afforded approximately 1.8 times more DDA over the 96-hr collection. The initial (0-36 hr) linear excretion rates of DDMU and DDMU-d were 10.7 and 6.2 micrograms/hr respectively. The qualitative and quantitative results are consistent with DDD being metabolized to DDA via enzyme-mediated hydroxylation on the C-1 side chain carbon.

The metabolites of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane (DDD) found in the urine of female Swiss mice are reported. The metabolites of DDT are DDD, 1-chloro-2,2-bis(p-chlorophenyl)ethene (DDMU), 1,1-dichloro-2-bis(p-chlorophenyl)ethene (DDE), 2,2-bis(p-chlorophenyl)acetic acid (DDA), 2-hydroxy-2,2-bis(p-chlorophenyl)acetic acid (alpha OH-DDA) and 2,2-bis(p-chlorophenyl)ethanol (DDOH), while DDD afforded DDMU, DDE, DDA, alpha OH-DDA and DDOH. The relative excreted levels of DDA and DDOH and the absence of 2,2-bis(p-chlorophenyl)acetaldehyde (DDCHO) are not consistent with the generally accepted pathway for DDA formation, which involves sequential metabolism of DDT and DDD via DDOH to afford DDA. The quantitative results are interpreted to mean that DDA is formed by hydroxylation at the chlorinated sp3-side chain carbon of DDD to give 2,2-bis(p-chlorophenyl)acetyl chloride (DDA-Cl), which in turn is hydrolyzed to DDA. The excretion of alpha OH-DDA from both DDT- and DDD-treated mice has never been previously observed. It is suggested that this metabolite arises from the initial epoxidation of DDMU, a metabolite of DDT and DDD, to yield 1,2-epoxy-1-chloro-2,2-bis(p-chlorophenyl)ethane (DDMU-epoxide). This chloroepoxide is then hydrolyzed and oxidized to produce the alpha OH-DDA.