Diverse developmental toxicity of di-n-butyl phthalate in both sexes of rat offspring after maternal exposure during the period from late gestation through lactation.
To evaluate developmental toxicity of di-n-butyl phthalate (DBP) with exposure during the period from late gestation to following lactation, maternal rats were given DBP at dietary concentrations of 0, 20, 200, 2000 and 10,000 ppm from gestational day 15 to postnatal day (PND) 21. At 10,000 ppm, male offspring showed a decreased neonatal anogenital distance and retention of nipples (PND 14), while females showed a slight non-significant delay in the onset of puberty. At PND 21, reduction of testicular spermatocyte development was evident from 20 ppm, as well as mammary gland changes at low incidence in both sexes. At this time point, population changes of pituitary hormone-immunoreactive cells were observed at 10,000 ppm with a similar pattern of increase in the percentages of luteinizing hormone (LH)-positive and decrease in follicle-stimulating hormone (FSH) and prolactin producing cells in both sexes, effects also being evident on FSH from 200 ppm and LH from 2000 ppm in females. During postnatal week (PNW) 8-11, marginal increase of the number of cases with extended diestrus was found at 10,000 ppm. At adult stage necropsy, testicular lesions appeared to be very faint in most cases, but degeneration and atrophy of mammary gland alveoli were observed in males from 20 ppm. Although without clear monotonic dose-dependence, relative pituitary weights were increased with the intermediate doses in males at PNW 11. In females, relative pituitary weights were decreased after 10,000 ppm at PNW 11, and from 200 ppm at PNW 20. The proportion of FSH-positive cells in the pituitaries at PNW 11 was increased in both sexes at 10,000 ppm. Thus, developmental exposure to DBP affected female sexual development involving pituitary function, while in males testicular toxicity was mostly reversible but mammary gland toxicity was persistent at a dose level as low as 20 ppm.
Lee
Kyoung-Youl
KY
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Shibutani
Makoto
M
Takagi
Hironori
H
Kato
Natsumi
N
Takigami
Shu
S
Uneyama
Chikako
C
Hirose
Masao
M
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003993:Dibutyl Phthalate / Q000633:toxicity*; D004032:Diet; D004702:Endocrine Glands / Q000187:drug effects / Q000254:growth & development; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005835:Genitalia / Q000187:drug effects / Q000254:growth & development; D005865:Gestational Age; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006128:Growth / Q000187:drug effects*; D007150:Immunohistochemistry; D007774:Lactation / Q000502:physiology*; D008297:Male; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000254:growth & development; D009929:Organ Size / Q000187:drug effects; D010907:Pituitary Hormones / Q000502:physiology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D012727:Sex Characteristics; D012733:Sex Differentiation / Q000187:drug effects; D012741:Sexual Maturation / Q000187:drug effects
D012739:Gonadal Steroid Hormones; D010907:Pituitary Hormones; D003993:Dibutyl Phthalate