The effects of perinatal/juvenile heptachlor exposure on adult immune and reproductive system function in rats.
This study was performed to determine if developmental exposure of rats to heptachlor (H) during the last half of gestation through puberty adversely affects adult functioning of the immune and reproductive systems. Time-bred pregnant female Sprague-Dawley rats were dosed by gavage with H (0, 30, 300, or 3000 microg/kg/day) from gestation day (GD) 12 to postnatal day (PND) 7, followed by direct dosing of the pups with H through PND 42. Separate groups of rats were evaluated with a battery of immune function tests, while other groups of rats were evaluated for reproductive development and function. Additional groups of rats were euthanized at the end of the dosing period for histological analyses of major organ systems. Some dams and PND 7 pups were euthanized; milk, plasma, fat and/or tissues were assayed for H and heptachlor epoxide B (HEB), a major metabolite of H. The amount of H and HEB found in milk, blood, fat, and tissues was proportional to the dose of H administered. There were no effects on the number or survival of pups born to H-exposed dams nor to pups exposed postnatally. There were no effects on the number of treated dams delivering litters or on litter size, nor were there any effects on any of the reproductive end points examined in the F(0) or F(1) rats. There were no effects of H exposure on lymphoid organ weights, splenic natural killer (NK) cell activity, and splenic lymphoproliferative (LP) responses to mitogens and allogeneic cells in a mixed lymphocyte response (MLR) assay at 8 weeks of age. H exposure did not alter delayed or contact hypersensitivity at 10 or 17 weeks of age, respectively. However, the primary IgM antibody response to sheep red blood cells (SRBCs) was suppressed in a dose-dependent manner in males, but not females, at 8 weeks of age. The percentage of B lymphocytes (OX12(+)OX19(-)) in spleen was also reduced in the high-dose males. The anti-SRBC IgM response was reduced only in males exposed to 30 microg H/kg/day in a separate group of rats 21 weeks of age. In these same rats, at 26 weeks of age, the secondary IgG antibody response to SRBCs was suppressed in all of the H-exposed males, but not females. These data indicate that perinatal exposure of male rats to H results in suppression of the primary IgM and secondary IgG anti-SRBC responses. Suppression of these antibody responses persisted for up to 20 weeks after the last exposure to H, at a total exposure of approximately 1500 microg H/kg/rat.
Smialowicz
R J
RJ
Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, ETD (MD-92), U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. smialowicz.ralph@epa.gov
Williams
W C
WC
Copeland
C B
CB
Harris
M W
MW
Overstreet
D
D
Davis
B J
BJ
Chapin
R E
RE
D000818:Animals; D000831:Animals, Newborn; D000917:Antibody Formation / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005865:Gestational Age; D006533:Heptachlor / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism / Q000633:toxicity*; D006534:Heptachlor Epoxide / Q000032:analysis / Q000378:metabolism / Q000633:toxicity; D006968:Hypersensitivity, Delayed / Q000139:chemically induced; D007107:Immune System / Q000187:drug effects*; D007074:Immunoglobulin G / Q000032:analysis / Q000097:blood; D007075:Immunoglobulin M / Q000032:analysis / Q000097:blood; D007306:Insecticides / Q000633:toxicity; D007694:Killer Cells, Natural / Q000187:drug effects; D008098:Litter Size; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D009929:Organ Size / Q000187:drug effects; D010375:Pedigree; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D012741:Sexual Maturation / Q000187:drug effects*; D013154:Spleen / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects; D014018:Tissue Distribution
D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007306:Insecticides; D006534:Heptachlor Epoxide; D006533:Heptachlor