Disruption of reproductive development in male rat offspring following in utero exposure to phthalate esters

Abstract

Certain Phthalate esters have been shown to produce reproductive toxicity in male rodents with an age dependent sensitivity in effects with foetal animals being more sensitive than neonates which are in turn more sensitive than pubertal and adult animals. While the testicular effects of phthalates in rats have been known for more than 30 years, recent attention has been focused on the ability of these agents to produce effects on reproductive development in male offspring after in utero exposure. These esters and in particular di-butyl, di-(2-ethylhexyl) and butyl benzyl phthalates have been shown to produce a syndrome of reproductive abnormalities characterized by malformations of the epididymis, vas deferens, seminal vesicles, prostate, external genitalia (hypospadias), cryptorchidism and testicular injury together with permanent changes (feminization) in the retention of nipples/areolae (sexually dimorphic structures in rodents) and demasculinization of the growth of the perineum resulting in a reduced anogenital distance (AGD). Critical to the induction of these effects is a marked reduction in foetal testicular testosterone production at the critical window for the development of the reproductive tract normally under androgen control. A second Leydig cell product, insl3, is also significantly down regulated and is likely responsible for the cryptorchidism commonly seen in these phthalate-treated animals. The testosterone decrease is mediated by changes in gene expression of a number of enzymes and transport proteins involved in normal testosterone biosynthesis and transport in the foetal Leydig cell. Alterations in the foetal seminiferous cords are also noted after in utero phthalate treatment with the induction of multinucleate gonocytes that contribute to lowered spermatocyte numbers in postnatal animals. The phthalate syndrome of effects on reproductive development has parallels with the reported human testicular dysgenesis syndrome, although no cause and effect relationship exists after exposure of humans to phthalate esters. However humans are exposed to and produce the critical phthalate metabolites that have been detected in blood of the general population, in children and also human amniotic fluid.

Evidence suggesting that di‐n‐butyl phthalate has antiandrogenic effects in fish

“…For example, in male rats exposed to phthalates in utero, reduced anogenital distance, nipple retention and agenesis of the Wolffian ducts are consistently observed [14,15]. While these effects do not occur with 100% frequency, their dependence on androgens supports the suggestion that phthalates cause anti-androgenic effects in vivo.…”

“…However, the discovery that some phthalates were weakly estrogenic in vitro [13] led to an intense period of study of phthalates as potential endocrine disruptors. After much research, it is now firmly established that di-ethylhexyl phthalate (DEHP), DBP, benzyl-butyl phthalate (BBP), diiso-butyl phthalate, di-iso-nonyl phthalate, di-hexyl phthalate, and di-pentyl phthalate are anti-androgenic endocrine disrupters in mammals [14,15]. However, it appears that they do not act directly as androgen receptor antagonists, or interfere with the genetic expression of the androgen receptor [14,16].…”

“…Since testosterone is critical to the normal development and masculinisation of the male reproductive tract in utero, its reduced production is thought to result in the abnormal development of the internal and external genitalia, symptoms of which include reduced anogenital distance, nipple retention, dysgenic testicular tissue, reduced spermatogenesis, cryptorchidism, and hypospadias [14][15][16].…”

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

“…In mammals, including humans, phthalate exposure is associated with endocrine disruption [15][16][17] and metabolic disorders [18,19]. In rodents, in utero exposure to phthalates results in developmental and reproductive defects similar to those termed testicular dysgenesis syndrome in humans [20][21][22].…”

Le concept de perturbation endocrinienne et la santé humaine

“…Ils sont très répandus dans l'environnement et l'on peut également les trouver dans les aliments, après leur migration à partir d'emballages. Le phtalate de di-n-butyle, le phtalate de butylbenzyle et le phtalate de di-(2-éthylhexyle) peuvent provoquer, via une action anti-androgénique, une atteinte de l'appareil reproducteur mâle (au cours du développe-ment et au stade adulte) et une toxicité embryo-foetale pouvant conduire à une augmentation de la mortalité intra-utérine ou à une diminution du taux de survie postnatale [22,23]. En se liant au récepteur des androgènes, les phtalates bloquent le fonctionnement normal de ces hormones, sans pour autant activer ces récepteurs (effet antagoniste).…”