Differential effects of bisphenol A and diethylstilbestrol on human, rat and mouse fetal leydig cell function.
Level 5 - mechanism / opinion, no new human data
Bench/ex vivo organotypic tissue culture study
PubMed 23284716 · doi:10.1371/journal.pone.0051579
What was done
Fetal testes explanted from humans (6.5–10.5 gestational weeks), rats (14.5 days post-coitum), and mice (12.5 days post-coitum) were cultured in an organotypic system for 1 to 3 days. Tissues were exposed to bisphenol A (BPA) at concentrations ranging from 10^-12 M to 10^-5 M or to diethylstilbestrol (DES) at 10^-6 M and 10^-5 M. Researchers measured testosterone secretion and INSL3 mRNA levels across species, and tested BPA's dependence on estrogen receptor alpha (ERα) using ERα-deficient mouse fetal testes.
What was found
BPA concentrations as low as 10^-8 M reduced testosterone secretion from day 1 onward and decreased INSL3 mRNA levels in human fetal testes. In contrast, rat and mouse fetal testes required 10^-5 M BPA to reduce testosterone secretion. Conversely, DES (10^-6 M and 10^-5 M) suppressed testosterone secretion in rat and mouse testis cultures but had no effect in human testis cultures. BPA's inhibitory effect on mouse fetal testosterone production persisted despite the knockout of ERα.
Why it matters
This study reveals major species differences in endocrine disruption sensitivity, showing that human fetal Leydig cells are substantially more vulnerable to BPA than rodent models. It indicates that relying on rodent toxicology data may underestimate risks of BPA to human male fetal development.
Limits
The study is limited to short-term (1–3 days) ex vivo explant culture, which does not reflect maternal-fetal pharmacokinetics, tissue metabolism, or chronic in vivo exposure. The abstract does not report the total number of human and rodent fetal specimens used or quantitative point estimates and variance for hormone levels.
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