Effect of Di(2-Ethylhexyl) Phthalate (DEHP) on Genital Organs from Juvenile Common Marmosets: I. Morphological and Biochemical Investigation in 65-Week Toxicity Study

Abstract

Recent studies demonstrated that preadolescent male rats are more sensitive to testicular damage from exposure to DEHP than adults. Male and female marmosets were treated daily with 0, 100, 500, or 2500 mg/kg DEHP by oral gavage for 65 wk from weaning (3 mo of age) to sexual maturity (18 mo). No treatment-related changes were observed in male organ weights, and no microscopic changes were found in male gonads or secondary sex organs. Sperm head counts, zinc levels, glutathione levels, and testicular enzyme activities were comparable between groups. Electron microscopic examination revealed no treatment-related abnormalities in Leydig, Sertoli, or spermatogenic cells. Histochemical examination of the testis after 3beta-hydroxysteroid dehydrogenase (3beta-HSD) staining did not reveal any alterations in steroid synthesis in the Leydig cells. Thus, although marmoset monkeys were treated with 2500 mg/kg DEHP, throughout the pre- and periadolescent period, no histological changes were noted in the testes. For females, increased ovarian and uterine weights and elevated blood estradiol level were observed in higher dosage groups, 500 and 2500 mg/kg. These increased weights were associated with the presence of large corpus luteum, a common finding in older female marmosets. Although an effect on the female ovary cannot be completely ruled out, no abnormal histological changes were observed in the ovaries or uteri in comparison to controls. No increases in hepatic peroxisomal enzyme activities were noted in treated groups; isolated hepatic enzyme activities (P-450 contents, testosterone 6beta-hydroxylase, and lauric acid omega-1omega-hydroxylase activities) were increased in males and/or females of either the mid- or high-dose groups, but no consistent dose-related trend was observed.

Environmental Factors and Puberty Timing: Expert Panel Research Needs

“…The MOA of many phthalate esters, including diethylhexyl phthalate, dibutyl phthalate, and benzyl butyl phthalate, is to inhibit fetal testis Leydig cell steroidogenesis and insl3 synthesis, leading to male developmental and reproductive system malformations (eg, retained nipples, reduced or absent reproductive organs, undescended testes, hypospadias, delayed PPS) with in utero exposure and delays in puberty with peripubertal exposure. 75 Administration of phthalates during puberty to marmosets induced ovarian and uterine alterations in females and reduced peripubertal testosterone levels in males 76 ; however, the effect on androgen levels was not significant because of the extreme variability in this measure in this species.…”

Di(2‐ethylhexyl) phthalate (DEHP) [MAK Value Documentation, 2016]

“…Species-specific toxicodynamics seem to be the reason for the different sensitivity of the rat and mouse foetal Leydig cells; for example, inhibited hormone production in Leydig cells in rats and non-impaired or even increased hormone production in mice. The different sensitivity of the individual species is confirmed by mechanistic studies and molecular signalling pathways (Johnson et al 2012).Young adult Sprague Dawley rats are far more sensitive to the testicular toxicity of DEHP after oral administration than adult marmosets (rats: NOAEL (no observed adverse effect level): 3.7 mg/kg body weight after administration with the diet (Poon et al 1997); marmosets: no effects at 2500 mg/kg body weight with gavage administration (Kurata et al 1998;Tomonari et al 2006)). According to the authors, the difference in sensitivity cannot be explained by toxicokinetics alone.…”

“…Young adult Sprague Dawley rats are far more sensitive to the testicular toxicity of DEHP after oral administration than adult marmosets (rats: NOAEL (no observed adverse effect level): 3.7 mg/kg body weight after administration with the diet (Poon et al 1997); marmosets: no effects at 2500 mg/kg body weight with gavage administration (Kurata et al 1998;Tomonari et al 2006)). According to the authors, the difference in sensitivity cannot be explained by toxicokinetics alone.…”

Di‐(2‐ethylhexyl)phthalat (DEHP) [MAK Value Documentation in German language, 2016]

“…Die unterschiedliche Sensitivität der einzelnen Spezies ist durch mechanistische Studien und molekulare Signalwege zu belegen (Johnson et al 2012). Junge adulte Sprague-Dawley-Ratten sind weitaus empfindlicher gegenüber der hodentoxischen Wirkung von DEHP nach oraler Gabe als adulte Marmosetten (Ratten: NOAEL 3,7 mg/kg KG nach Gabe über das Futter (Poon et al 1997); Marmosetten: keine Effekte bei 2500 mg/kg KG bei Gavage (Kurata et al 1998;Tomonari et al 2006)). Den Autoren zufolge kann die unterschiedliche Sensitivität nicht alleine durch die Toxikokinetik erklärt werden, sondern es dürften auch toxikodynamische Faktoren, wie mögliche Interaktionen von MEHP mit Rezeptor-vermittelten Prozessen, zu den unterschiedlichen Reaktionen der Nager-und Primatenspezies beitragen (Kessler et al 2004).…”