Effects of bromodichloromethane on ex vivo and in vitro luteal function and bromodichloromethane tissue dosimetry in the pregnant F344 rat.
Bromodichloromethane (BDCM), a drinking water disinfection by-product, causes pregnancy loss, i.e. full-litter resorption, in F344 rats when treated during the luteinizing hormone (LH)-dependent period. This effect is associated with reduced maternal serum progesterone (P) and LH levels, suggesting that BDCM disrupts secretion of LH. To test the hypothesis that BDCM also affects luteal responsiveness to LH, we used ex vivo and in vitro approaches. For the ex vivo study (i.e., in vivo exposure followed by in vitro assessment), dams were dosed by gavage on gestation days (GD) 6-9 (plug day=GD 0) at 0 or 100 mg/kg/d. One hour after the GD-9 dose, rats were killed, blood was collected, and tissue concentrations of BDCM were assessed. Corpora lutea (CL) were incubated with or without hCG, an LH agonist, to stimulate P secretion. For the in vitro study, CL were pooled from untreated F344 rats on GD 9 and cultured with BDCM at 0, 0.01, 0.10 or 3.0 mM. BDCM was found at highest concentrations in adrenal, ovarian, adipose, and hypothalamic tissues. BDCM treatment decreased serum P and LH levels in vivo. Ex vivo, however, BDCM-exposed CL showed >2-fold increases in P secretion relative to controls. Both control and BDCM-exposed CL displayed a 2.4-fold increase in P secretion in response to hCG challenge. In contrast, in vitro exposures reduced CL responsiveness in a dose-related fashion while baseline levels were unaffected. It is unclear if the ex vivo 'rebound' reflects the removal of the CL from a possible direct inhibitory influence of BDCM, or a response to diminished LH stimulation in vivo. Thus, these data suggest that BDCM disrupts pregnancy in F344 rats via two modes: disruption of LH secretion, and disruption of the CL's ability to respond to LH.
Bielmeier
S R
SR
Curriculum of Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Murr
A S
AS
Best
D S
DS
Harrison
R A
RA
Pegram
R A
RA
Goldman
J M
JM
Narotsky
M G
MG
D000818:Animals; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D003338:Corpus Luteum / Q000187:drug effects*; D004202:Disinfectants / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000097:blood; D005260:Female; D007118:Immunoassay; D007986:Luteinizing Hormone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011247:Pregnancy; D011374:Progesterone / Q000097:blood; D011388:Prolactin / Q000097:blood; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution; D022882:Trihalomethanes / Q000493:pharmacokinetics / Q000633:toxicity
D006063:Chorionic Gonadotropin; D004202:Disinfectants; D022882:Trihalomethanes; D011374:Progesterone; D004958:Estradiol; C025191:bromodichloromethane; D011388:Prolactin; D007986:Luteinizing Hormone