Genetic variants (Lhcgr^W495X/+) and environmental toxicants (DEHP) synergistically induce DSD by interfering with steroidogenic gene expression.

IF 5.1 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Biology of Sex Differences Pub Date : 2025-09-26 DOI:10.1186/s13293-025-00753-0

Xie Qigen, Xia Kai, Cao Haiming, Xu Zhe, Gao Yong, Deng Chunhua

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引用次数: 0

Abstract

Background: Emerging evidence suggests that genetic variants and environmental toxicants may synergistically contribute to DSD. To test this hypothesis, we employed Lhcgr^W495X/+ (luteinizing hormone/chorionic gonadotropin receptor) male mice subjected to prenatal Di-(2-ethylhexyl) phthalate (DEHP) exposure, a model designed to investigate steroidogenic gene expression in gene-environment interactions.

Methods: Pregnant wild-type (WT) dams (mated with Lhcgr^W495X/+ heterozygote (HET) received varying levels of DEHP: no exposure, low-dose (100 mg/kg/d) DEHP, and high-dose (1000 mg/kg/d) DEHP during gestation, which led to prenatal exposure in male offspring. Male offspring were divided into HET (Lhcgr^W495X/+) and WT groups based on genotype in three levels of DEHP exposure. The study assessed phenotypic characteristics (DSD, testosterone levels, and semen quality) and examined the expression of steroidogenic genes (Lhcgr, Star, Cyp11a1, Cyp17a1, Hsd17b3, and Hsd3b2).

Results: Lhcgr^W495X/+ male offspring without DEHP exposure exhibited normal phenotypes and steroidogenic gene profiles. Low-dose DEHP had no detectable effects on WT offspring, but synergistically induced DSD in Lhcgr^W495X/+ male offspring by interfering with steroidogenic gene expression (Lhcgr, Hsd17b3, Hsd3b2). High-dose DEHP caused DSD in both genotypes, but the severity of DSD and interference with steroidogenic gene expression were more pronounced in Lhcgr^W495X/+ male offspring.

Conclusions: This study verifies that Genetic variants (Lhcgr^W495X/+) and environmental toxicants (DEHP) synergistically induce DSD, thereby elucidating the pathogenesis of DSD. Interfering with steroidogenic gene expression may be an important synergistical mechanism. This finding highlights the clinical imperative to minimize prenatal exposure to endocrine disruptors, particularly in pregnancies with variants of DSD.

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遗传变异（LhcgrW495X/+）和环境毒物（DEHP）通过干扰类固醇基因表达协同诱导DSD。

背景：越来越多的证据表明，遗传变异和环境毒物可能协同促进DSD。为了验证这一假设，我们使用了LhcgrW495X/+（黄体生成素/绒毛膜促性腺激素受体）雄性小鼠，这些小鼠在产前暴露于二-（2-乙基己基）邻苯二甲酸二酯（DEHP），这是一个旨在研究基因-环境相互作用中类固醇基因表达的模型。方法：妊娠野生型（WT）坝（与LhcgrW495X/+杂合子（HET）交配）在妊娠期间接受不同水平的DEHP：未暴露、低剂量（100 mg/kg/d） DEHP和高剂量（1000 mg/kg/d） DEHP，导致雄性后代产前暴露。在三个DEHP暴露水平下，根据基因型将雄性后代分为hhcgrw495x /+和WT组。该研究评估了表型特征（DSD、睾酮水平和精液质量），并检测了类固醇基因（Lhcgr、Star、Cyp11a1、Cyp17a1、Hsd17b3和Hsd3b2）的表达。结果：未暴露DEHP的LhcgrW495X/+雄性后代表现出正常的表型和类固醇基因谱。低剂量DEHP对WT子代无明显影响，但通过干扰类固醇基因表达（Lhcgr, Hsd17b3, Hsd3b2），可协同诱导LhcgrW495X/+雄性子代的DSD。高剂量DEHP在两种基因型中均引起DSD，但在LhcgrW495X/+雄性后代中，DSD的严重程度和对甾体源性基因表达的干扰更为明显。结论：本研究验证了遗传变异（LhcgrW495X/+）和环境毒物（DEHP）协同诱导DSD，从而阐明了DSD的发病机制。干扰类固醇基因表达可能是其重要的协同作用机制。这一发现强调了减少产前暴露于内分泌干扰物的临床必要性，特别是在患有DSD变异的妊娠中。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY

CiteScore

12.10

自引率

1.30%

发文量

审稿时长

14 weeks

期刊介绍： Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.