Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer Di(2-ethylhexyl) phthalate.

Abstract

Several members of the phthalate ester family have antiandrogenic properties, yet little is known about how exposure to these ubiquitous environmental contaminants early in development may affect sexual development. We conducted experiments to determine effects of in utero and lactational exposure to the most prevalent phthalate ester, di(2-ethylhexyl) phthalate (DEHP), on male reproductive system development and sexual behavior. Sprague-Dawley rats were dosed with corn oil or DEHP (0, 375, 750, or 1,500 mg/kg/day, per os) from gestation day 3 through postnatal day (PND) 21. Dose-related effects on male offspring included reduced anogenital distance, areola and nipple retention, undescended testes, and permanently incomplete preputial separation. Testis, epididymis, glans penis, ventral prostate, dorsolateral prostate, anterior prostate, and seminal vesicle weights were reduced at PND 21, 63, and/or 105-112. Additional dose-related effects included a high incidence of anterior prostate agenesis, a lower incidence of partial or complete ventral prostate agenesis, occasional dorsolateral prostate and seminal vesicle agenesis, reduced sperm counts, and testicular, epididymal, and penile malformations. Many DEHP-exposed males were sexually inactive in the presence of receptive control females, but sexual inactivity did not correlate with abnormal male reproductive organs. These results suggest that in utero and lactational DEHP exposure also inhibited sexually dimorphic central nervous system development. No major abnormalities were found in any of eight control litters, but DEHP caused severe male reproductive system toxicity in five of eight litters at 375 mg/kg/day, seven of eight litters at 750 mg/kg/day, and five of five litters at 1,500 mg/kg/day. These results demonstrate that the male reproductive system is far more sensitive to DEHP early in development than when animals are exposed as juveniles or adults. The effects of DEHP on male reproductive organs and sexual behaviors and the lack of significant effects on time to vaginal opening and first estrus in their littermates demonstrate that DEHP (and/or its metabolites) affects development of the male reproductive system primarily by acting as an antiandrogen. The pattern of effects of in utero and lactational DEHP exposure differed from patterns caused by other phthalate esters, and the preponderance of anterior prostate agenesis appears to be unique among all chemicals. These results suggest that DEHP acts partly by mechanisms distinct from those of other antiandrogens.

Autoreactive responses to environmental factors: 3. Mouse strain-specific differences in induction and regulation of anti-DNA antibody responses due to phthalate-isomers

“…Their teratogenicity is also well established as reproductive toxicants [35,36]. Our results show the biological effects of unconjugated DEHP on the induction of autoimmunity.…”

Flame ionization gas chromatographic determination of phthalate esters in water, surface sediments and fish species in the Ogun river catchments, Ketu, Lagos, Nigeria

“…In recent years, however, phthalate esters have been implicated in a number of adverse health effects such as cancer (IARC 2000;Dearman et al 1996) and damage to the reproductive system as endocrine disruptors (Yang et al 2009;Swan 2008;Silva et al 2005;Kato et al 2005;Duty et al 2005;Moore et al 2001;Call et al 2001;Blount et al 2000;Ema et al 2000;Harris et al 1997).…”

Distribution of phthalate esters in the groundwater of Jianghan plain, Hubei, China

“…Several PAEs are carcinogenic in animal models (Huber et al, 1996). In addition, some PAEs and their metabolic products act functionally as antiandrogens during the prenatal period (Mylchreest et al, 1998;Moore et al, 2001) and cause reproductive and developmental toxicities in animals (Agarwal et al, 1986). Recent investigations have shown that several PAEs are environmental hormones (Kambia et al, 2001).…”