Genetic Variation in Susceptibility to Endocrine Disruption by Estrogen in Mice

Abstract

Large (more than 16-fold) differences in susceptibility to disruption of juvenile male reproductive development by 17beta-estradiol (E2) were detected between strains of mice. Effects of strain, E2 dose, and the interaction of strain and E2 dose on testes weight and spermatogenesis were all highly significant (P < 0.0001). Spermatid maturation was eliminated by low doses of E2 in strains such as C57BL/6J and C17/Jls. In contrast, mice of the widely used CD-1 line, which has been selected for large litter size, showed little or no inhibition of spermatid maturation even in response to 16 times as much E2. Product safety bioassays conducted with animals selected for fecundity may greatly underestimate disruption of male reproductive development by estradiol and environmental estrogenic compounds.

Risk for Premenstrual Dysphoric Disorder Is Associated with Genetic Variation in ESR1, the Estrogen Receptor Alpha Gene

“…Fourth, and perhaps most important, PMDD has been shown to be a disorder of hormone sensitivity; i.e., individuals with the disorder display an abnormal behavioral response to normal levels of estradiol and progesterone . Examples of differential sensitivity to the actions of hormones exist in both the human and animal literatures, with both environmental (Meaney et al 2005;Meaney et al 1991;Ladd et al 1996), and genetic sources identified (Bailey et al 2002;Svare 1998;Spearow et al 1999). Of particular note are demonstrations of polymorphic variants in genes encoding reproductive steroid hormone receptors that are associated with both altered transcriptional activity and phenotypic variation.…”

“…These gonadal steroid receptor polymorphisms have been shown to alter receptor transcriptional efficacy (e.g., CAG repeat in exon 1 of the androgen receptor; progins insertion in intron 7 of the progesterone receptor) and are associated with differential illness risk (i.e., prostate cancer, breast cancer) (Zhang et al 2004;Beilin et al 1999;Giovannucci et al 1997;Wang-Gohrke et al 2000). Additionally, the susceptibility to the disruptive effects of estradiol on reproductive development differs enormously (up to 100-fold) between mouse strains, with genotype controlling more of the variance than the dose of estradiol employed (Spearow et al 1999). There is precedent, then, for inferring that polymorphisms in genes in the gonadal steroid signaling pathway or in gonadal steroid-regulated genes may alter the nature or strength of the steroid signal as well as the clinical and behavioral phenotype.…”

Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium

“…1 Genes make humans more or less likely to respond to a given pharmacological treatment and/or to present a certain side-effect profile. [2][3][4] Thus, selecting research subjects based on common patterns of response or non-response to a given pharmacological treatment may be useful to define genetically more homogeneous subgroups. We have been using such an approach, focusing on bipolar patients who present an excellent response to lithium prophylaxis.…”

Molecular Mechanisms of Bladder Outlet Obstruction in Transgenic Male Mice Overexpressing Aromatase (Cyp19a1)

“…Similarly to AROMϩ/N males, 29,35 the AROMϩ/6J males showed high serum E 2 and low testosterone levels, decreased androgen/estrogen ratio, and disrupted reproductive development and spermatogenesis, putatively due to estrogen susceptibility of the C57Bl/6J genetic background. 28 Androgen receptor has been detected in bladder detrusor, 42 and muscle cells showed androgen response. Thus, the detrusor muscular atrophy in the AROMϩ/6J mice could have also resulted from androgen deficiency and decreased androgen/estrogen ratio.…”

“…27 Differential effects of estrogens on the male urogenital tract and spermatogenesis have been demonstrated in mice with different genetic backgrounds. 28 Because the C57Bl/6J mouse strain is reported to be more estrogen-sensitive than other strains, 28 we hypothesized that Tg overexpression of Cyp19a1 in this background (AROMϩ/6J) could intensify the previously documented mild bladder intravesical obstruction observed in the FVB/N background (AROMϩ/N), and would lead to full-blown BOO, allowing us to investigate the etiology and molecular mechanisms of this condition. To demonstrate and test the relevance of the AROMϩ/6J murine model to human BOO disease, we also studied severe human BOO samples for the molecular changes observed in the AROMϩ/6J bladders.…”