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. 2002 Mar;110(3):247–254. doi: 10.1289/ehp.02110247

Sexually dimorphic behavioral responses to prenatal dioxin exposure.

Rieko Hojo 1, Sander Stern 1, Grazyna Zareba 1, Vincent P Markowski 1, Christopher Cox 1, James T Kost 1, Bernard Weiss 1
PMCID: PMC1240764  PMID: 11882475

Abstract

Pregnant Sprague-Dawley rats received a single oral dose of 0, 20, 60, or 180 ng/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin on day 8 of gestation. Each litter contributed a single male-female pair trained to press a lever to obtain food pellets under two operant behavior procedures. Initially, each lever press was reinforced. The fixed-ratio (FR) requirement was then increased every four sessions from the initial setting of 1 to values between 6 and 71. We then studied responses for 30 days under a multiple schedule combining FR 11 and another schedule requiring a pause of at least 10 sec between responses (DRL 10-sec). TCDD evoked a sexually dimorphic response pattern. Generally, TCDD-exposed males responded at lower rates than control males. In contrast, exposed females responded at higher rates than controls. Each response measure from the mult-FR DRL schedule yielded a male-female difference score. We used the differences in response rate to calculate benchmark doses based on the relative displacement from modeled zero-dose performance of the effective dose at 1% (ED(01)) and 10% (ED(10)), as determined by a second-order polynomial fit to the dose-effect function. For the male-female difference in FR rate of responding, the mean ED(10) was 2.77 ng/kg with a 95% lower bound of 1.81 ng/kg. The corresponding ED(01) was 0.27 ng/kg with a 95% lower bound of 0.18 ng/kg. For the male-female difference in DRL rate, the mean ED(10) was 2.97 ng/kg with a 95% lower bound of 2.02 ng/kg. The corresponding ED(01) was 0.30 ng/kg with a 95% lower bound of 0.20 ng/kg. These values fall close to, but below, current estimates of human body burdens of 13 ng/kg, based on TCDD toxic equivalents.

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Selected References

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  1. Abbott B. D., Birnbaum L. S., Perdew G. H. Developmental expression of two members of a new class of transcription factors: I. Expression of aryl hydrocarbon receptor in the C57BL/6N mouse embryo. Dev Dyn. 1995 Oct;204(2):133–143. doi: 10.1002/aja.1002040204. [DOI] [PubMed] [Google Scholar]
  2. Abbott B. D., Probst M. R. Developmental expression of two members of a new class of transcription factors: II. Expression of aryl hydrocarbon receptor nuclear translocator in the C57BL/6N mouse embryo. Dev Dyn. 1995 Oct;204(2):144–155. doi: 10.1002/aja.1002040205. [DOI] [PubMed] [Google Scholar]
  3. Abbott B. D., Schmid J. E., Pitt J. A., Buckalew A. R., Wood C. R., Held G. A., Diliberto J. J. Adverse reproductive outcomes in the transgenic Ah receptor-deficient mouse. Toxicol Appl Pharmacol. 1999 Feb 15;155(1):62–70. doi: 10.1006/taap.1998.8601. [DOI] [PubMed] [Google Scholar]
  4. Bjerke D. L., Peterson R. E. Reproductive toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male rats: different effects of in utero versus lactational exposure. Toxicol Appl Pharmacol. 1994 Aug;127(2):241–249. doi: 10.1006/taap.1994.1158. [DOI] [PubMed] [Google Scholar]
  5. Bushnell P. J., Bowman R. E. Effects of chronic lead ingestion on social development in infant rhesus monkeys. Neurobehav Toxicol. 1979 Fall;1(3):207–219. [PubMed] [Google Scholar]
  6. Bushnell P. J., Bowman R. E. Persistence of impaired reversal learning in young monkeys exposed to low levels of dietary lead. J Toxicol Environ Health. 1979 Nov;5(6):1015–1023. doi: 10.1080/15287397909529810. [DOI] [PubMed] [Google Scholar]
  7. Calabrese E. J., Baldwin L. A. The frequency of U-shaped dose responses in the toxicological literature. Toxicol Sci. 2001 Aug;62(2):330–338. doi: 10.1093/toxsci/62.2.330. [DOI] [PubMed] [Google Scholar]
  8. Calabrese E. J., Baldwin L. A. U-shaped dose-responses in biology, toxicology, and public health. Annu Rev Public Health. 2001;22:15–33. doi: 10.1146/annurev.publhealth.22.1.15. [DOI] [PubMed] [Google Scholar]
  9. Cohn J., Cory-Slechta D. A. Lead exposure potentiates the effects of NMDA on repeated learning. Neurotoxicol Teratol. 1994 Sep-Oct;16(5):455–465. doi: 10.1016/0892-0362(94)90123-6. [DOI] [PubMed] [Google Scholar]
  10. Crump K. S. A new method for determining allowable daily intakes. Fundam Appl Toxicol. 1984 Oct;4(5):854–871. doi: 10.1016/0272-0590(84)90107-6. [DOI] [PubMed] [Google Scholar]
  11. Davis J. M., Svendsgaard D. J. U-shaped dose-response curves: their occurrence and implications for risk assessment. J Toxicol Environ Health. 1990 Jun;30(2):71–83. doi: 10.1080/15287399009531412. [DOI] [PubMed] [Google Scholar]
  12. DeVito M. J., Birnbaum L. S., Farland W. H., Gasiewicz T. A. Comparisons of estimated human body burdens of dioxinlike chemicals and TCDD body burdens in experimentally exposed animals. Environ Health Perspect. 1995 Sep;103(9):820–831. doi: 10.1289/ehp.95103820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gentry G. D., Middaugh L. D. Prenatal ethanol weakens the efficacy of reinforcers for adult mice. Teratology. 1988 Feb;37(2):135–144. doi: 10.1002/tera.1420370206. [DOI] [PubMed] [Google Scholar]
  14. Gonzalez F. J., Fernandez-Salguero P. The aryl hydrocarbon receptor: studies using the AHR-null mice. Drug Metab Dispos. 1998 Dec;26(12):1194–1198. [PubMed] [Google Scholar]
  15. Gray L. E., Jr, Kelce W. R., Monosson E., Ostby J. S., Birnbaum L. S. Exposure to TCDD during development permanently alters reproductive function in male Long Evans rats and hamsters: reduced ejaculated and epididymal sperm numbers and sex accessory gland weights in offspring with normal androgenic status. Toxicol Appl Pharmacol. 1995 Mar;131(1):108–118. doi: 10.1006/taap.1995.1052. [DOI] [PubMed] [Google Scholar]
  16. Gray L. E., Jr, Ostby J. S., Ferrell J. M., Sigmon E. R., Goldman J. M. Methoxychlor induces estrogen-like alterations of behavior and the reproductive tract in the female rat and hamster: effects on sex behavior, running wheel activity, and uterine morphology. Toxicol Appl Pharmacol. 1988 Dec;96(3):525–540. doi: 10.1016/0041-008x(88)90012-9. [DOI] [PubMed] [Google Scholar]
  17. Hattis D., Glowa J., Tilson H., Ulbrich B. Risk assessment for neurobehavioral toxicity: SGOMSEC joint report. Environ Health Perspect. 1996 Apr;104 (Suppl 2):217–226. doi: 10.1289/ehp.96104s2217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Heinsbroek R. P., van Haaren F., Zantvoord F., van de Poll N. E. Effects of pentobarbital and progesterone on random ratio responding in male and female rats. Psychopharmacology (Berl) 1987;93(2):178–181. doi: 10.1007/BF00179930. [DOI] [PubMed] [Google Scholar]
  19. Heinsbroek R. P., van Haaren F., Zantvoord F., van de Poll N. E. Sex differences in response rates during random ratio acquisition: effects of gonadectomy. Physiol Behav. 1987;39(2):269–272. doi: 10.1016/0031-9384(87)90020-5. [DOI] [PubMed] [Google Scholar]
  20. Hughes J. A., Sparber S. B. d-Amphetamine unmasks postnatal consequences of exposure to methylmercury in utero: methods for studying behavioral teratogenesis. Pharmacol Biochem Behav. 1978 Apr;8(4):365–375. doi: 10.1016/0091-3057(78)90072-2. [DOI] [PubMed] [Google Scholar]
  21. Hurst C. H., Abbott B. D., DeVito M. J., Birnbaum L. S. 2,3,7,8-Tetrachlorodibenzo-p-dioxin in pregnant Long Evans rats: disposition to maternal and embryo/fetal tissues. Toxicol Sci. 1998 Oct;45(2):129–136. doi: 10.1006/toxs.1998.2520. [DOI] [PubMed] [Google Scholar]
  22. Jacobson J. L., Jacobson S. W. Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N Engl J Med. 1996 Sep 12;335(11):783–789. doi: 10.1056/NEJM199609123351104. [DOI] [PubMed] [Google Scholar]
  23. Mably T. A., Bjerke D. L., Moore R. W., Gendron-Fitzpatrick A., Peterson R. E. In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin. 3. Effects on spermatogenesis and reproductive capability. Toxicol Appl Pharmacol. 1992 May;114(1):118–126. doi: 10.1016/0041-008x(92)90103-y. [DOI] [PubMed] [Google Scholar]
  24. Mably T. A., Moore R. W., Goy R. W., Peterson R. E. In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin. 2. Effects on sexual behavior and the regulation of luteinizing hormone secretion in adulthood. Toxicol Appl Pharmacol. 1992 May;114(1):108–117. doi: 10.1016/0041-008x(92)90102-x. [DOI] [PubMed] [Google Scholar]
  25. Mably T. A., Moore R. W., Peterson R. E. In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin. 1. Effects on androgenic status. Toxicol Appl Pharmacol. 1992 May;114(1):97–107. doi: 10.1016/0041-008x(92)90101-w. [DOI] [PubMed] [Google Scholar]
  26. Markowski V. P., Zareba G., Stern S., Cox C., Weiss B. Altered operant responding for motor reinforcement and the determination of benchmark doses following perinatal exposure to low-level 2,3,7,8-tetrachlorodibenzo-p-dioxin. Environ Health Perspect. 2001 Jun;109(6):621–627. doi: 10.1289/ehp.01109621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nau H., Bass R., Neubert D. Transfer of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) via placenta and milk, and postnatal toxicity in the mouse. Arch Toxicol. 1986 May;59(1):36–40. doi: 10.1007/BF00263955. [DOI] [PubMed] [Google Scholar]
  28. Newland M. C., Ng W. W., Baggs R. B., Gentry G. D., Weiss B., Miller R. K. Operant behavior in transition reflects neonatal exposure to cadmium. Teratology. 1986 Dec;34(3):231–241. doi: 10.1002/tera.1420340302. [DOI] [PubMed] [Google Scholar]
  29. Newland M. C., Rasmussen E. B. Aging unmasks adverse effects of gestational exposure to methylmercury in rats. Neurotoxicol Teratol. 2000 Nov-Dec;22(6):819–828. doi: 10.1016/s0892-0362(00)00107-0. [DOI] [PubMed] [Google Scholar]
  30. Newland M. C., Warfvinge K., Berlin M. Behavioral consequences of in utero exposure to mercury vapor: alterations in lever-press durations and learning in squirrel monkeys. Toxicol Appl Pharmacol. 1996 Aug;139(2):374–386. doi: 10.1006/taap.1996.0178. [DOI] [PubMed] [Google Scholar]
  31. Newland M. C., Yezhou S., Lögdberg B., Berlin M. Prolonged behavioral effects of in utero exposure to lead or methyl mercury: reduced sensitivity to changes in reinforcement contingencies during behavioral transitions and in steady state. Toxicol Appl Pharmacol. 1994 May;126(1):6–15. doi: 10.1006/taap.1994.1084. [DOI] [PubMed] [Google Scholar]
  32. Patandin S., Lanting C. I., Mulder P. G., Boersma E. R., Sauer P. J., Weisglas-Kuperus N. Effects of environmental exposure to polychlorinated biphenyls and dioxins on cognitive abilities in Dutch children at 42 months of age. J Pediatr. 1999 Jan;134(1):33–41. doi: 10.1016/s0022-3476(99)70369-0. [DOI] [PubMed] [Google Scholar]
  33. Pohjanvirta R., Viluksela M., Tuomisto J. T., Unkila M., Karasinska J., Franc M. A., Holowenko M., Giannone J. V., Harper P. A., Tuomisto J. Physicochemical differences in the AH receptors of the most TCDD-susceptible and the most TCDD-resistant rat strains. Toxicol Appl Pharmacol. 1999 Feb 15;155(1):82–95. doi: 10.1006/taap.1998.8565. [DOI] [PubMed] [Google Scholar]
  34. Rice D. C., Gilbert S. G. Low lead exposure from birth produces behavioral toxicity (DRL) in monkeys. Toxicol Appl Pharmacol. 1985 Sep 30;80(3):421–426. doi: 10.1016/0041-008x(85)90386-2. [DOI] [PubMed] [Google Scholar]
  35. Schantz S. L., Bowman R. E. Learning in monkeys exposed perinatally to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Neurotoxicol Teratol. 1989 Jan-Feb;11(1):13–19. doi: 10.1016/0892-0362(89)90080-9. [DOI] [PubMed] [Google Scholar]
  36. Schantz S. L., Seo B. W., Moshtaghian J., Peterson R. E., Moore R. W. Effects of gestational and lactational exposure to TCDD or coplanar PCBs on spatial learning. Neurotoxicol Teratol. 1996 May-Jun;18(3):305–313. doi: 10.1016/s0892-0362(96)90033-1. [DOI] [PubMed] [Google Scholar]
  37. Seo B. W., Powers B. E., Widholm J. J., Schantz S. L. Radial arm maze performance in rats following gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Neurotoxicol Teratol. 2000 Jul-Aug;22(4):511–519. doi: 10.1016/s0892-0362(00)00070-2. [DOI] [PubMed] [Google Scholar]
  38. Seo B. W., Sparks A. J., Medora K., Amin S., Schantz S. L. Learning and memory in rats gestationally and lactationally exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Neurotoxicol Teratol. 1999 May-Jun;21(3):231–239. doi: 10.1016/s0892-0362(98)00049-x. [DOI] [PubMed] [Google Scholar]
  39. Sewall C. H., Bell D. A., Clark G. C., Tritscher A. M., Tully D. B., Vanden Heuvel J., Lucier G. W. Induced gene transcription: implications for biomarkers. Clin Chem. 1995 Dec;41(12 Pt 2):1829–1834. [PubMed] [Google Scholar]
  40. Spear L. P. Assessment of the effects of developmental toxicants: pharmacological and stress vulnerability of offspring. NIDA Res Monogr. 1996;164:125–145. [PubMed] [Google Scholar]
  41. Wood R. W., Rees D. C., Laties V. G. Behavioral effects of toluene are modulated by stimulus control. Toxicol Appl Pharmacol. 1983 May;68(3):462–472. doi: 10.1016/0041-008x(83)90291-0. [DOI] [PubMed] [Google Scholar]
  42. van Haaren F., Haworth S. C., Bennett S. M., Cody B. A., Hoy J. B., Karlix J. L., Tebbett I. R. The effects of pyridostigmine bromide, permethrin, and DEET alone, or in combination, on fixed-ratio and fixed-interval behavior in male and female rats. Pharmacol Biochem Behav. 2001 May-Jun;69(1-2):23–33. doi: 10.1016/s0091-3057(01)00504-4. [DOI] [PubMed] [Google Scholar]
  43. van Haaren F., Heinsbroek R. P., Louwerse A., van de Poll N. E. d-Amphetamine differentially affects low, but not high response rates of male and female Wistar rats. Psychopharmacology (Berl) 1986;89(1):73–76. doi: 10.1007/BF00175193. [DOI] [PubMed] [Google Scholar]
  44. van Hest A., van Haaren F., van de Poll N. E. Behavioral differences between male and female Wistar rats in food rewarded lever holding. Physiol Behav. 1987;39(2):263–267. doi: 10.1016/0031-9384(87)90019-9. [DOI] [PubMed] [Google Scholar]
  45. van Hest A., van Haaren F., van de Poll N. E. Perseverative responding in male and female Wistar rats: effects of gonadal hormones. Horm Behav. 1989 Mar;23(1):57–67. doi: 10.1016/0018-506x(89)90074-3. [DOI] [PubMed] [Google Scholar]
  46. van Hest A., van Haaren F., van de Poll N. E. The behavior of male and female Wistar rats pressing a lever for food is not affected by sex differences in food motivation. Behav Brain Res. 1988 Mar;27(3):215–221. doi: 10.1016/0166-4328(88)90118-0. [DOI] [PubMed] [Google Scholar]
  47. vom Saal F. S., Nagel S. C., Palanza P., Boechler M., Parmigiani S., Welshons W. V. Estrogenic pesticides: binding relative to estradiol in MCF-7 cells and effects of exposure during fetal life on subsequent territorial behaviour in male mice. Toxicol Lett. 1995 May;77(1-3):343–350. doi: 10.1016/0378-4274(95)03316-5. [DOI] [PubMed] [Google Scholar]
  48. vom Saal F. S., Timms B. G., Montano M. M., Palanza P., Thayer K. A., Nagel S. C., Dhar M. D., Ganjam V. K., Parmigiani S., Welshons W. V. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):2056–2061. doi: 10.1073/pnas.94.5.2056. [DOI] [PMC free article] [PubMed] [Google Scholar]

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