Abstract
Measures of cognitive and other behaviors not specifically related to reproduction are often sex-linked. Males and females perform differently on many tasks and often interact with members of their species in dissimilar ways. If such differences are diminished, reversed, or widened by prenatal chemical exposures, a reasonable inference is that exposure interfered with sexual differentiation of the brain, largely, but not exclusively, through interference with the actions of gonadal hormones. Explicit recognition of sex differences in performance is not a prominent feature of toxicity testing, however, except for reproduction studies, and is not a recognized criterion in developmental neurotoxicity testing. In contrast to the low visibility accorded sex differences in testing protocols for the assessment of developmental neurotoxicity, the literature is filled with examples showing that the developing male and female respond differently to many chemical agents, with subsequent expression in behavior. Quite often, even when such differences are reported, further analyses are not carried out nor are subsequent studies conducted for clarification. Moreover, many investigators include only male subjects. Both polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) studies provide several examples of striking differences between the behavioral responses of male and female offspring to developmental exposure. They offer examples, as well, of how to approach the study and analysis of such differences. Given the societal importance of risk assessments applied to potential developmental neurotoxicants, studies should be deemed questionable if they fail to include outcome measures based on sexual dimorphisms in nonreproductive behaviors.
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Selected References
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- Beatty W. W. Gonadal hormones and sex differences in nonreproductive behaviors in rodents: organizational and activational influences. Horm Behav. 1979 Apr;12(2):112–163. doi: 10.1016/0018-506x(79)90017-5. [DOI] [PubMed] [Google Scholar]
- Berenbaum S. A. Effects of early androgens on sex-typed activities and interests in adolescents with congenital adrenal hyperplasia. Horm Behav. 1999 Feb;35(1):102–110. doi: 10.1006/hbeh.1998.1503. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Diamond M. C. Hormonal effects on the development or cerebral lateralization. Psychoneuroendocrinology. 1991;16(1-3):121–129. doi: 10.1016/0306-4530(91)90074-4. [DOI] [PubMed] [Google Scholar]
- Geller A. M., Bushnell P. J., Rice D. C. Behavioral and electrophysiological estimates of visual thresholds in awake rats treated with 3,3',4,4',5-pentachlorobiphenyl (PCB 126). Neurotoxicol Teratol. 2000 Jul-Aug;22(4):521–531. doi: 10.1016/s0892-0362(00)00067-2. [DOI] [PubMed] [Google Scholar]
- Geller A. M., Oshiro W. M., Haykal-Coates N., Kodavanti P. R., Bushnell P. J. Gender-dependent behavioral and sensory effects of a commercial mixture of polychlorinated biphenyls (Aroclor 1254) in rats. Toxicol Sci. 2001 Feb;59(2):268–277. doi: 10.1093/toxsci/59.2.268. [DOI] [PubMed] [Google Scholar]
- Gorski R. A. Sexual differentiation of the brain: a model for drug-induced alterations of the reproductive system. Environ Health Perspect. 1986 Dec;70:163–175. doi: 10.1289/ehp.8670163. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Hofman M. A., Swaab D. F. Sexual dimorphism of the human brain: myth and reality. Exp Clin Endocrinol. 1991;98(2):161–170. doi: 10.1055/s-0029-1211113. [DOI] [PubMed] [Google Scholar]
- Hojo Rieko, Stern Sander, Zareba Grazyna, Markowski Vincent P., Cox Christopher, Kost James T., Weiss Bernard. Sexually dimorphic behavioral responses to prenatal dioxin exposure. Environ Health Perspect. 2002 Mar;110(3):247–254. doi: 10.1289/ehp.02110247. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kremer H., Lilienthal H., Hany J., Roth-Härer A., Winneke G. Sex-dependent effects of maternal PCB exposure on the electroretinogram in adult rats. Neurotoxicol Teratol. 1999 Jan-Feb;21(1):13–19. doi: 10.1016/s0892-0362(98)00030-0. [DOI] [PubMed] [Google Scholar]
- Kulynych J. J., Vladar K., Jones D. W., Weinberger D. R. Gender differences in the normal lateralization of the supratemporal cortex: MRI surface-rendering morphometry of Heschl's gyrus and the planum temporale. Cereb Cortex. 1994 Mar-Apr;4(2):107–118. doi: 10.1093/cercor/4.2.107. [DOI] [PubMed] [Google Scholar]
- MacLusky N. J., Brown T. J., Schantz S., Seo B. W., Peterson R. E. Hormonal interactions in the effects of halogenated aromatic hydrocarbons on the developing brain. Toxicol Ind Health. 1998 Jan-Apr;14(1-2):185–208. doi: 10.1177/074823379801400112. [DOI] [PubMed] [Google Scholar]
- Madeira M. D., Leal S., Paula-Barbosa M. M. Stereological evaluation and Golgi study of the sexual dimorphisms in the volume, cell numbers, and cell size in the medial preoptic nucleus of the rat. J Neurocytol. 1999 Feb;28(2):131–148. doi: 10.1023/a:1007076206828. [DOI] [PubMed] [Google Scholar]
- 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]
- McEwen B. S. Steroid hormones and brain development: some guidelines for understanding actions of pseudohormones and other toxic agents. Environ Health Perspect. 1987 Oct;74:177–184. doi: 10.1289/ehp.8774177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McGivern R. F., Handa R. J. Prenatal exposure to drugs of abuse: methodological considerations and effects on sexual differentiation. NIDA Res Monogr. 1996;164:78–124. [PubMed] [Google Scholar]
- Roegge C. S., Seo B. W., Crofton K. M., Schantz S. L. Gestational-lactational exposure to Aroclor 1254 impairs radial-arm maze performance in male rats. Toxicol Sci. 2000 Sep;57(1):121–130. doi: 10.1093/toxsci/57.1.121. [DOI] [PubMed] [Google Scholar]
- Roof R. L. The dentate gyrus is sexually dimorphic in prepubescent rats: testosterone plays a significant role. Brain Res. 1993 Apr 30;610(1):148–151. doi: 10.1016/0006-8993(93)91228-k. [DOI] [PubMed] [Google Scholar]
- Schantz S. L., Moshtaghian J., Ness D. K. Spatial learning deficits in adult rats exposed to ortho-substituted PCB congeners during gestation and lactation. Fundam Appl Toxicol. 1995 Jun;26(1):117–126. doi: 10.1006/faat.1995.1081. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- Stern S., Cox C., Preston R., Sharma A., Inglis G. B., Balys M., Weiss B. Perinatal methanol exposure in the rat. II. Behavioral effects in neonates and adults. Fundam Appl Toxicol. 1997 Apr;36(2):163–176. [PubMed] [Google Scholar]
- Tabibnia G., Cooke B. M., Breedlove S. M. Sex difference and laterality in the volume of mouse dentate gyrus granule cell layer. Brain Res. 1999 May 8;827(1-2):41–45. doi: 10.1016/s0006-8993(99)01262-7. [DOI] [PubMed] [Google Scholar]
- Weiss B. Endocrine disruptors and sexually dimorphic behaviors: a question of heads and tails. Neurotoxicology. 1997;18(2):581–586. [PubMed] [Google Scholar]
- Weiss B., Laties V. G., Siegel L., Goldstein D. A computer analysis of serial interactions in spaced responding. J Exp Anal Behav. 1966 Nov;9(6):619–626. doi: 10.1901/jeab.1966.9-619. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Widholm J. J., Clarkson G. B., Strupp B. J., Crofton K. M., Seegal R. F., Schantz S. L. Spatial reversal learning in Aroclor 1254-exposed rats: sex-specific deficits in associative ability and inhibitory control. Toxicol Appl Pharmacol. 2001 Jul 15;174(2):188–198. doi: 10.1006/taap.2001.9199. [DOI] [PubMed] [Google Scholar]
- Williams C. L., Meck W. H. The organizational effects of gonadal steroids on sexually dimorphic spatial ability. Psychoneuroendocrinology. 1991;16(1-3):155–176. doi: 10.1016/0306-4530(91)90076-6. [DOI] [PubMed] [Google Scholar]
- Wisniewski A. B. Sexually-dimorphic patterns of cortical asymmetry, and the role for sex steroid hormones in determining cortical patterns of lateralization. Psychoneuroendocrinology. 1998 Jul;23(5):519–547. doi: 10.1016/s0306-4530(98)00019-5. [DOI] [PubMed] [Google Scholar]
- Zhou J. N., Hofman M. A., Gooren L. J., Swaab D. F. A sex difference in the human brain and its relation to transsexuality. Nature. 1995 Nov 2;378(6552):68–70. doi: 10.1038/378068a0. [DOI] [PubMed] [Google Scholar]
- de Courten-Myers G. M. The human cerebral cortex: gender differences in structure and function. J Neuropathol Exp Neurol. 1999 Mar;58(3):217–226. doi: 10.1097/00005072-199903000-00001. [DOI] [PubMed] [Google Scholar]
- van Haaren F., van Hest A., Heinsbroek R. P. Behavioral differences between male and female rats: effects of gonadal hormones on learning and memory. Neurosci Biobehav Rev. 1990 Spring;14(1):23–33. doi: 10.1016/s0149-7634(05)80157-5. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
