Persistent DDT metabolite p,p'–DDE is a potent androgen receptor antagonist

@article{Kelce1995PersistentDM,
  title={Persistent DDT metabolite p,p'–DDE is a potent androgen receptor antagonist},
  author={William R. Kelce and Christy R. Stone and Susan C. Laws and Leon Earl Gray and Jon A. Kemppainen and Elizabeth M. Wilson},
  journal={Nature},
  year={1995},
  volume={375},
  pages={581-585}
}
THE increase in the number of reports of abnormalities in male sex development in wildlife and humans coincided with the introduction of 'oestrogenic' chemicals such as DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane) into the environment. Although these phenotypic alterations are thought to be mediated by the oestrogen receptor, they are also consistent with inhibition of androgen receptor-mediated events. Here we report that the major and persistent DDT metabolite,P,P′-DDE (l,l-dichloro-2… 

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References

SHOWING 1-10 OF 27 REFERENCES

Estrogenic activities of chlorinated hydrocarbons.

TLDR
Some DDT analogs are estrogenic, particularly o,p'-DDT, which comprises approximately 15-20% of the commercial DDT mixture, and it is probable that phenolic metabolites are responsible for its estrogenic activity.

Environmental hormone disruptors: evidence that vinclozolin developmental toxicity is mediated by antiandrogenic metabolites.

TLDR
As the concentrations of M1 in the serum of pregnant rats and their pups on Postnatal Day 3 meet or exceed the in vitro Ki for androgen receptor inhibition, it is suggested that the demasculinizing effects of vinclozolin exposure in vivo also may be mediated via the antiandrogenic metabolites M1 and/or M2.

Developmental effects of an environmental antiandrogen: the fungicide vinclozolin alters sex differentiation of the male rat.

TLDR
The observation of perinatal-induced agenesis of the prostate and blocked testicular descent, a pattern of malformations nearly identical to that reported for the antiandrogen flutamide, is consistent with other recent evidence that this fungicide is an androgen-receptor antagonist.

DDT homologues: estrogen-like effects on the vagina, uterus and pituitary of the rat.

TLDR
It is demonstrated that o,p′-DDT and one of its major metabolites, DDA, exert estrogenic activity by stimulating uterine and vaginal tissue and reduce serum LH, pr...

Estrogenic action of DDT and its analogs.

Treatment with antiandrogens induces an androgen‐repressed gene in the rat ventral prostate

TLDR
The results suggest that while neither cyproterone acetate nor flutamide fully repress the androgen‐dependent functions of the prostate, they do induce some of the androgens‐repressed sequences in the prostate that have been implicated in the process of cell death.

Comparison of the effects of the 5 alpha-reductase inhibitor finasteride and the antiandrogen flutamide on prostate and genital differentiation: dose-response studies.

TLDR
Results suggest that testosterone (T) can compensate for DHT to some degree at the level of the androgen receptor, despite increasingly higher doses of the antiandrogen flutamide.

Absorption, storage, and metabolic conversion of ingested DDT and DDT metabolites in man.

TLDR
Serum and adipose concentrations of DDT and DDT metabolites in response to these dosings have indicated that the initial dechlorinated DDT is of critical importance to its metabolic fate, and conversion to the saturated p,p′-DDD makes possible further degradation to the readily excreted p, p′-DDA.