We know that different chemicals affect the sexual dimorphic development of the fetus but just how do they do it?

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From - Biology of sex and gender, Eric Vilain, MD, PhD 254)

"What role do hormones play in gender identity?

Hormones have always been thought as the unique or major factor influencing the development of a male or female brain. We now know that hormones cannot explain everything in the making of a brain, whether it's masculine or a feminine brain. But we don't know really what the other factors are.

We suppose that some of these factors may be genetic. Maybe pieces of the Y chromosome are important at some level in the brain sexual differentiation. Maybe some environmental factors are also important: there are compounds in the environment that are hormone-like, they're estrogen-like for instance, that might play a role in this. These are purely speculative arguments, but those are the kind of things that we are trying to decipher.

To give you an example, we found that SRY, the main gene triggering male differentiation, is also expressed in the brain. We don't know why it's expressed in the brain but it is. We are wondering what it does and to study this we are creating animal models such as a mouse that would have a piece of a Y chromosome in her brain. If it's a female mouse, we would look at her behavior and look at her brain structure to see if somehow this mouse brain has been masculinized. This would show that there is a direct role of the Y chromosome on brain sexual differentiation independently from hormones. "

"Can you talk about WNT4, another gene that is involved in female development?

We recently identified in humans a gene named WNT4, which seems to have the same function as DAX1. That is if you have too much of WNT4 in an XY individual, this XY individual will become female. It seems that again WNT4 is another example of an anti-male factor. We actually showed that WNT4 and DAX1 interact with each other at the molecular level so they're part of this anti-male and possibly pro-female pathway, both antagonizing the effect of pro-male genes such as SRY."

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Now tie the above highlighted statement with the high lighted statement in the following 2 quotes

From - The emergence of molecular gynecology: homeobox and Wnt genes in the female reproductive tract.
J Kitajewski and D Sassoon  259)

"Reproductive tissues respond to steroid hormones and thus are particularly vulnerable to the effects of exogenous steroid 'mimic' compounds (endocrine disrupters). One such endocrine disrupter, diethylstilbestrol (DES), is linked to gynecological cancers and changes in uterine structure that reduce or completely abrogate reproductive competence. Until recently, little was known about the identity of target genes and signaling pathways involved in pathologies linked to endocrine disrupters such as DES. We outline genetic, cellular and molecular roles for patterning genes, with emphasis on homeobox and Wnt genes. There is evidence that changes in the expression of Wnt and homeogenes underlie many of the defects induced by DES. Data obtained from murine systems will likely apply to a broad spectrum of gynecological pathologies involving abnormal cell behaviors ranging from fibroids to malignant tumors. Knowledge garnered from modern molecular genetics should lead to progress in the emerging field of molecular gynecology."

 

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From - Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans. Jordan BK, Mohammed M, Ching ST, Delot E, Chen XN, Dewing P, Swain A, Rao PN, Elejalde BR, Vilain E. UCLA, Department of Human Genetics, Los Angeles, CA, 90095, USA. 261)

"Wnt-4, a member of the Wnt family of locally acting secreted growth factors, is the first signaling molecule shown to influence the sex-determination cascade. In mice, a targeted deletion of Wnt-4 causes the masculinization of XX pups. Therefore, WNT-4, the human homologue of murine Wnt-4, is a strong candidate gene for sex-reversal phenotypes in humans. In this article, we show that, in testicular Sertoli and Leydig cells, Wnt-4 up-regulates Dax1, a gene known to antagonize the testis-determining factor, Sry. Furthermore, we elucidate a possible mechanism for human XY sex reversal associated with a 1p31-p35 duplication including WNT-4. Overexpression of WNT-4 leads to up-regulation of DAX1, which results in an XY female phenotype. Thus, WNT-4, a novel sex-determining gene, and DAX1 play a concerted role in both the control of female development and the prevention of testes formation. These observations suggest that mammalian sex determination is sensitive to dosage, at multiple steps in its pathway."

 

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From - Sexually dimorphic gene expression in mouse brain precedes gonadal differentiation 255)

"Dewing P, Shi T, Horvath S, Vilain E.

Department of Human Genetics, University of California, Los Angeles, CA 90095, USA.

The classic view of brain sexual differentiation and behavior is that gonadal steroid hormones act directly to promote sex differences in neural and behavioral development. In particular, the actions of testosterone and its metabolites induce a masculine pattern of brain development, while inhibiting feminine neural and behavioral patterns of differentiation. However, recent evidence indicates that gonadal hormones may not solely be responsible for sex differences in brain development and behavior between males and females. Here we examine an alternative hypothesis that genes, by directly inducing sexually dimorphic patterns of neural development, can influence the sexual differences between male and female brains. Using microarrays and RT-PCR, we have detected over 50 candidate genes for differential sex expression, and confirmed at least seven murine genes which show differential expression between the developing brains of male and female mice at stage 10.5 days post coitum (dpc), before any gonadal hormone influence. The identification of genes differentially expressed between male and female brains prior to gonadal formation suggests that genetic factors may have roles in influencing brain sexual differentiation."

 

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From - Gene imprinting in developmental toxicology: a possible interface between physiology and pathology. JA McLachlan, M Burow, TC Chiang, and SF Li 256)

"Gene imprinting is an epigenetic mechanism for accomplishing persistent change in gene expression. In this brief paper, we explore the mechanisms for imprinting genes and present data showing that the synthetic estrogen, diethylstilbestrol (DES) can developmentally imprint genes by changing the pattern of DNA methylation. We further discuss the implications of this and other findings for non-mutagenic aspects of developmental toxicology, and suggest ways to use this concept in modifying in vitro screening for developmental toxicants."

 

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From - Gestational and Lactational Exposure of Male Mice to Diethylstilbestrol Causes Long-Term Effects on the Testis, Sperm Fertilizing Ability in Vitro, and Testicular Gene Expression  Mark R. Fielden, Robert G. Halgren, Cora J. Fong, Christophe Staub, Larry Johnson, Karen Chou and Tim R. Zacharewski. 257)

"The objective of the study was to determine the long-term effects of gestational and lactational exposure to diethylstilbestrol (DES; 0, 0.1, 1, and 10 µg/kg maternal body weight) on mouse testicular growth, epididymal sperm count, in vitro fertilizing ability, and testicular gene expression using cDNA microarrays and real-time PCR in mice on postnatal day (PND) 21, 105, and 315. In the high dose group there was a persistent decrease in the number of Sertoli cells, and sperm count was decreased on PND315 (P < 0.05). Sperm motion was unaffected; however, the in vitro fertilizing ability of epididymal sperm was decreased in the high dose group on both PND105 (P < 0.001) and PND315 (P < 0.05). Early and latent alterations in the expression of genes involved in estrogen signaling (estrogen receptor-hydroxylase/C17,20-lyase, P450 side chain cleavage, steroidogenic acute regulatory protein, and scavenger receptor class B1), lysosomal function (LGP85 an prosaposin), and regulation of testicular development (testicular receptor 2, inhibin/activin ß C, and Hoxa10) were confirmed by real-time PCR. The results demonstrate that early exposure to DES causes long-term adverse effects on testicular development and sperm function, and these effects are associated with changes in testicular gene expression, even long after the cessation of DES exposure. "

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From - In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing müllerian system .
KAREN BLOCK, ANDREW KARDANA*, PETER IGARASHI and HUGH S. TAYLOR 258)

"Diethylstilbestrol (DES) was widely used to treat pregnant women through 1971. The reproductive tracts of their female offspring exposed to DES in utero are characterized by anatomic abnormalities. Here we show that DES administered to mice in utero produces changes in the expression pattern of several Hox genes that are involved in patterning of the reproductive tract. DES produces posterior shifts in Hox gene expression and homeotic anterior transformations of the reproductive tract. In human uterine or cervical cell cultures, DES induces HOXA9 or HOXA10 gene expression, respectively, to levels approximately twofold that induced by estradiol. The DES-induced expression is not inhibited by cyclohexamide. Estrogens are novel morphogens that directly regulate the expression pattern of posterior Hox genes in a manner analogous to retinoic acid regulation of anterior Hox genes. Alterations in HOX gene expression are a molecular mechanism by which DES affects reproductive tract development. Changes in Hox gene expression are a potential marker for the effects of in utero drug use that may become apparent only at late stages of development.—Block, K., Kardana, A., Igarashi, P., Taylor, H. S. In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing müllerian system. "

 

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From - Gene-Teratogen Interactions in Chemically Induced Congenital Malformations, Erminio Giavini, Elena Menegola,
University of Milan, Department of Biology, Milan, Italy" 260)

"Exposure of the embryo to environmental chemicals can result in congenital malformations or abortion. Although experimental teratology data are considered sufficient for risk assessment, only knowledge of their mechanisms of action permits a justifiable extrapolation of animal data to humans. Mechanistic studies of some teratogenic agents such as retinoic acids, valproic acid, diethylstilbestrol, and cyclopamine provided evidence of interference with regulation of genes controlling the embryonic development. The new genomic technologies are important tools in this field and may represent a real improvement in understanding the mechanisms of action of chemical teratogens."

 

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From - Single gene removes sex differences in mice brains 12:48 31 August 2004 NewScientist.com news service Peter Farley 265)

 

"Extensive research in rats has demonstrated that these differences are determined by the presence or absence of the hormone testosterone in early life.

If a male rat is castrated shortly after birth, its BNST and AVPV will develop in the female pattern. Conversely, if a female rat pup is treated with testosterone its adult brain will be indistinguishable from a male’s.

Scientists are unsure how testosterone exerts these effects in the brain, but many have suspected that the hormone might fine-tune the pruning of neurons in different brain regions.

“During development of the nervous system, you get this large overproduction of nerve cells, followed by a period of cell death,” says Nancy Forger, lead author of the study. “Anywhere from 20% to 80% of the neurons that are initially generated will die.”

Much of this “sculpting” of the nervous system is directed by proteins in the Bcl-2 family, some of which promote survival of neurons, while others, such as Bax, prompt cells to self-destruct.

In the Bax-deprived “knockout” mice used by Forger and her colleagues, both the BNST and AVPV had many more cells than are seen in normal mice and the number of cells was equal in males and females."

 

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From - Sex steroid-related genes and male-to-female transsexualism
Susanne Henningssona, Lars Westberga, Staffan Nilssonb, Bengt Lundströmc, Lisa Ekseliusd, Owe Bodlunde, Eva Lindströmd, Monika Hellstranda, Roland Rosmondf, Elias Erikssona and Mikael Landéng 275)

 

"Transsexualism is characterised by lifelong discomfort with the assigned sex and a strong identification with the opposite sex. The cause of transsexualism is unknown, but it has been suggested that an aberration in the early sexual differentiation of various brain structures may be involved. Animal experiments have revealed that the sexual differentiation of the brain is mainly due to an influence of testosterone, acting both via androgen receptors (ARs) and—after aromatase-catalyzed conversion to estradiol—via estrogen receptors (ERs). The present study examined the possible importance of three polymorphisms and their pairwise interactions for the development of male-to-female transsexualism: a CAG repeat sequence in the first exon of the AR gene, a tetra nucleotide repeat polymorphism in intron 4 of the aromatase gene, and a CA repeat polymorphism in intron 5 of the ERβ gene. Subjects were 29 Caucasian male-to-female transsexuals and 229 healthy male controls. Transsexuals differed from controls with respect to the mean length of the ERβ repeat polymorphism, but not with respect to the length of the other two studied polymorphisms. However, binary logistic regression analysis revealed significant partial effects for all three polymorphisms, as well as for the interaction between the AR and aromatase gene polymorphisms, on the risk of developing transsexualism. Given the small number of transsexuals in the study, the results should be interpreted with the utmost caution. Further study of the putative role of these and other sex steroid-related genes for the development of transsexualism may, however, be worthwhile. "

 

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