Our Stolen Futurea book by Theo Colborn, Dianne Dumanoski, and John Peterson Myers
 
 

 

  Gray, LE, J Ostby, E Monosson and WR Kelce. 1999. Environmental antiandrogens: low doses of the fungicide vinclozolin alter sexual differentiation of the male rat. Toxicology and Industrial Health 15: 48-64.

What is vinclozolin?
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Gray et al. demonstrate that a few parts per million levels of vinclozolin contamination profoundly alter sexual development in male rats, producing significant feminization of the male reproductive tract, hypospadias, low sperm counts and other deformations.

During sexual development in mammals, the androgen hormones are critically involved in the development of the male reproductive tract. Androgen-like compounds can masculanize fetal females (including human), while anti-androgens can feminize males. "Laboratory studies demonstrate that chemicals that inhibit or mimic the action of androgens also produce predictable alterations of sexual differentiation in rodents."

When vinclozolin enters the body it is degraded into two metabolites. These metabolites then act as anti-androgens, i.e., compounds that interfere with the activity of androgen hormones like testosterone. The metabolites do this by binding with the androgen receptor without then provoking the transcriptional activity that is activated by an androgen binding with the receptor.

The experimental protocol employed involved delivering different dosages of vinclozolin to pregnant rats via corn oil administered by gavage. Doses ranged from 0 (control) to 3.125 mg/kg/day and up to 100 mg/kg/day. The lowest dose produced statistically significant effects for anal-genital distance and number of males with areolas. Ejaculated sperm counts were reduced by 90% in males exposed to 50 mg/kg/day, while sperm were absent from females with male offspring exposed to 100 mg/kg/day. Retained nipples, normally never seen in male rats, were detected at all levels of exposure: one at the lowest, several at 6.25 and 12.5 mg/kg/day and most males at 50 mg/kg/day or above.

Gray et al. note that vinclozolin is not the only synthetic anti-androgen. Anti-androgenic activity has been reported for three other pesticides: p,p'-DDE (a metabolite of DDT), procymidone and linuron. Several other natural and synthetic estrogens bind to the androgen receptor, including estradiol, DES and an active metabolite of methoxychlor. Several phthalates (e.g., DBP and DEHP) have also been shown to produce anti-androgenic effects.

"Increases in the incidence of hypospadias and testicular cancer and reports of declining sperm counts in humans in some geographical areas have been linked to possible exposure to endocrine disruptors. It is apparent that in utero exposure to vinclozolin induces some of these effects in the rat. It is likely that human males would be similarly effected if exposed to similar levels of the active metabolites of vinclozolin... during the critical period of reproductive development in utero. There is no biochemical basis to support the concept that rats respond in a unique fashion to vinclozolin metalites because [these metabolites] bind human AR [androgen receptor] as well as they bind rat AR. Furthermore, given the high degree of conservation of function of the role of androgens and the role of AR in mammalian sexual differentiation, interference of androgenic action in humans would have very predictable, adverse effects."

Gray et al. conclude that old multi-generational studies of compounds interfere with testosterone, like vinclozolin, could have indicated that the "no effect level" for these compounds was at least 10 times higher than more sensitive testing would reveal.

This would lead to standards likely to be insufficiently protective.

 

 

 

 

 

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