2. Academic Validation
  3. Genetic variants (LhcgrW495X/+) and environmental toxicants (DEHP) synergistically induce DSD by interfering with steroidogenic gene expression

Genetic variants (LhcgrW495X/+) and environmental toxicants (DEHP) synergistically induce DSD by interfering with steroidogenic gene expression

  • Biol Sex Differ. 2025 Sep 26;16(1):70. doi: 10.1186/s13293-025-00753-0.
Xie Qigen # 1 2,  Xia Kai # 2,  Cao Haiming # 3,  Xu Zhe 4,  Gao Yong 5,  Deng Chunhua 6
Affiliations

Affiliations

  • 1 Department of Pediatric Surgery, First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road 2, Guangzhou, 510080, China.
  • 2 Department of Andrology, First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road 2, Guangzhou, 510080, China.
  • 3 Department of Andrology, Reproductive Center of the Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518000, China.
  • 4 Department of Pediatric Surgery, First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road 2, Guangzhou, 510080, China. xzhe@mail.sysu.edu.cn.
  • 5 Reproductive Medicine Center, The Key Laboratory for Reproductive Medicine of Guangdong Province, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China. gyong@mail.sysu.edu.cn.
  • 6 Department of Andrology, First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road 2, Guangzhou, 510080, China. dengchh@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 41013757 DOI: 10.1186/s13293-025-00753-0
Abstract

Background: Emerging evidence suggests that genetic variants and environmental toxicants may synergistically contribute to DSD. To test this hypothesis, we employed LhcgrW495X/+ (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 LhcgrW495X/+ 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 (LhcgrW495X/+) 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: LhcgrW495X/+ 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 LhcgrW495X/+ 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 LhcgrW495X/+ male offspring.

Conclusions: This study verifies that Genetic variants (LhcgrW495X/+) 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.

Keywords

LHCGR; DEHP; Disorders/differences of sex development; Synergistic effect.

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