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.
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."
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.
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
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."
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.
would lead to standards likely to be insufficiently protective.