The OECD validation program of the H295R steroidogenesis assay: Phase 3. Final inter-laboratory validation study

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Abstract

BACKGROUND, GOALS, AND SCOPE: In response to increasing concerns regarding the potential of chemicals to interact with the endocrine system of humans and wildlife, various national and international programs have been initiated with the aim to develop new guidelines for the screening and testing of these chemicals in vertebrates. Here, we report on the validation of an in vitro assay, the H295R steroidogenesis assay, to detect chemicals with the potential to inhibit or induce the production of the sex steroid hormones testosterone (T) and 17β-estradiol (E2) in preparation for the development of an Organization for Economic Cooperation and Development (OECD) test guideline.

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Di-(2-ethylhexyl) phthalate suppresses estradiol and ovulation in cycling rats.

B Davis, R R Maronpot, J Heindel (1994)

Di-(2-ethylhexyl) phthalate (DEHP) is a known reproductive toxicant and a carcinogen in rodent animal models. DEHP may also be a reproductive toxicant in women. Its action in female animal models is undetermined, although its potential to target the ovary has recently been shown. We have identified the ovarian toxicity and target cells of DEHP in the female rat. Adult, regularly cycling Sprague-Dawley rats were dosed daily with 2 g/kg DEHP in corn oil by gavage for 1 to 12 days. Ovarian morphology and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and progesterone levels were analyzed. DEHP exposure resulted in prolonged estrous cycles. Specifically, 35 of 42 DEHP-treated rats had 5- or 6-day cycles and only 7 of 42 had a 4-day cycle compared to 44 of 45 control rats with 4-day cycle lengths. DEHP treatment also suppressed or delayed ovulations by the first proestrus/estrus after metestrus-initiated dosing. Microscopic evaluation of the ovaries determined that 7 of 10 DEHP-exposed rats had not ovulated by vaginal estrus, whereas 13 of 13 control rats had ovulated by vaginal estrus. Thus, DEHP treatment significantly altered natural ovulation times. Preovulatory follicles were also quantitatively smaller in DEHP-exposed rats than in controls because the granulosa cells were smaller. The mean control rat preovulatory follicle granulosa cell area was 16 +/- 3 x 10(3) microns, whereas the mean DEHP-treated rat preovulatory follicle granulosa cell area was 12 +/- 4 x 10(3) microns. DEHP exposure significantly suppressed preovulatory follicle granulosa cell estradiol production over 8 days of exposure. Suppressed serum estradiol levels caused secondary increases in FSH levels and did not stimulate the LH surge necessary for ovulation. Consequently, ovulation did not occur in DEHP-treated rats, although DEHP-treated rats ovulated after treatment with human chorionic hormone. Vaginal lavage cytology from rats treated with DEHP did not detect the ovarian toxicity as shown by histology and hormone analysis. In summary, exposure to DEHP resulted in hypoestrogenic anovulatory cycles and polycystic ovaries in adult female rats.

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The relative bioavailability and metabolism of bisphenol A in rats is dependent upon the route of administration.

M. Hansen, S Cagen, J Domoradzki … (2000)

Bisphenol A (BPA) is used to produce polymers for food contact applications, thus there is potential for oral exposure of humans to trace amounts via the diet. BPA was weakly estrogenic in screening assays measuring uterine weight/response, although much higher oral doses of BPA were required to elicit a uterotropic response as compared to other routes of administration. The objective of this study was to determine if a route dependency exists in the pharmacokinetics and metabolism of 14C-labeled BPA following single oral (po), intraperitoneal (ip), or subcutaneous (sc) doses of either 10 or 100 mg/kg to Fischer 344 rats. Results indicated a marked route dependency in the pharmacokinetics of BPA. The relative bioavailability of BPA and plasma radioactivity was markedly lower following oral administration as compared to sc or ip administration. The major fraction of plasma radioactivity following oral dosing was the monoglucuronide conjugate of BPA (68-100% of plasma radioactivity). BPA was the major component in plasma at Cmax following sc or ip administration exceeded only by BPA-monoglucuronide in females dosed ip. Up to four additional unidentified metabolites were present only in the plasma of animals dosed ip or sc. One of these, found only following ip administration, was tentatively identified as the monosulfate conjugate of BPA. The monoglucuronide conjugate was the major urinary metabolite; unchanged BPA was the principal component excreted in feces. These results demonstrated a route dependency of BPA bioavailability in rats, with oral administration resulting in the lowest bioavailability, and offer an explanation for the apparent route differences in estrogenic potency observed for BPA.

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Effects of the pesticides carbofuran, chlorpyrifos, dimethoate, lindane, triallate, trifluralin, 2,4-D, and pentachlorophenol on the metabolic endocrine and reproductive endocrine system in ewes.

D Waldbillig, Norman Rawlings, Linda Cook (1998)

Many pesticides are used in the agricultural environment, and some may have the potential to disrupt reproductive or endocrine function. Ewes, in separate groups of 6, received orally into their rumen either empty gelatin capsules or capsules containing chlorpyrifos (12.5 mg/kg), trifluralin (17.5 mg/kg), lindane (2.5 mg/kg), or pentachlorophenol (2 mg/kg) 2 times per week for 43 d. Dimethoate (0.2 mg/kg), carbofuran (0.30 mg/kg), 2,4-dichlorophenoxyacetic acid (10 mg/kg), or triallate (5 mg/kg) was given 3 times per week. After 36 d of treatment, blood samples were taken every 12 min for 6 h for hormone analysis. Ewes were euthanized at the end of the study for necropsy and histopathology. No overt signs of toxicity were seen, and body weight was not affected by treatment. Carbofuran caused a significant increase in serum concentrations of thyroxine compared to control ewes, but all other pesticides, except trifluralin, resulted in a marked decrease in thyroxine concentrations. Serum concentrations of cortisol were significantly increased by trifluralin and chlorpyrifos. Concentrations of insulin in serum were markedly increased in ewes given dimethoate, lindane, trifluralin, triallate, and pentachlorophenol, and concentrations of estradiol were also significantly increased in ewes given lindane and trifluralin. Mean serum concentrations of LH were markedly decreased by trifluralin, and basal LH concentrations were significantly decreased by lindane, dimethoate, and trifluralin but increased by triallate. Both pentachlorophenol and triallate caused a significant increase in severity of oviductal intraepithelial cysts in ewes. Data suggest that several currently used pesticides could influence serum concentrations of reproductive and metabolic hormones, particularly thyroxine, the major secretory product of the thyroid and a principal regulator of metabolism.