Martine Culty, PhD
Faculty Directory

Martine CultyPhD

Martine CultyPhD

Associate Professor of Pharmacology and Pharmaceutical Sciences

Department of Pharmacology and Pharmaceutical Sciences

Martine Culty’s research focuses on two main topics, (1) deciphering the mechanisms regulating early male germ cell development, testicular function and spermatogenesis; and (2) determining the contribution of environmental chemicals and pharmaceuticals perinatal exposures to reproductive diseases such as testicular cancer and infertility. The disruption of perinatal testicular development by chemicals that interfere with androgen and estrogen homeostasis and action has contributed to the increasing trend of male reproductive disorders in the last decades. The goal of Dr. Culty is to discover new aspects of the physiology and toxicology of the male reproductive system that will contribute to a better understanding of the origins of diseases and chemical exposure-related health risks. Culty’s group has identified cellular and molecular mechanisms involved in the regulation of gonocyte and spermatogonial development. They uncovered genes and functional pathways disrupted by perinatal exposure to low doses of endocrine disrupting chemical mixtures, acetaminophen and ibuprofen, that were associated with abnormal reproductive phenotypes and transgenerational adverse effects. These projects are the object of current in vivo and in vitro studies, that will help understanding early phases of spermatogenesis and better assessing the risk posed by environmental chemicals and drugs to the reproductive system.

Areas of Expertise

  • Gonocytes
  • Endocrinology
  • Stem Cells
  • Differentiation
  • Spermatogenesis
  • Testis
  • Signaling Pathways
  • Male Reproduction
  • Toxicology
  • Education

    University of Grenoble

    PhD

  • Links
  • Research Focus

    The Culty Lab

    The Culty lab has two main research interests: 1) deciphering the mechanisms regulating early male germ cell development, testicular function and spermatogenesis 2) determining the effects of environmental chemical mixtures and pharmaceuticals on testis development and function. Perturbation of gonocyte development can result in infertility or testicular tumor. Thus, our first goal is to identify factors and signaling pathways involved in gonocyte proliferation and differentiation, in order to unveil new targets of testicular cancer treatment. This model can also be used to test drug effects on neonatal germ cells. Because testis development is dependent on sex hormones, it is very sensitive to chemicals interfering with androgen and estrogen homeostasis and action. Our second goal is to determine the impact of fetal exposure to common endocrine disruptor mixtures, at doses relevant to human exposure, on testicular development and function across the lifespan, using the rat model. These studies will aid better assessing endocrine disruptor risks to the reproductive system. Our studies involve a variety of molecular, cellular, pharmacological and toxicological approaches, applied on in vivo animal models, primary cells, cell lines and human tissues specimen.

  • Selected Articles

    In vitro Functional screening as a means to identify new plasticizers devoid of reproductive toxicity

    Environmental Research
    Boisvert A, Jones S, Issop L, Erythropel HC, Papadopoulos V, Culty M

    2016 Plasticizers are indispensable additives providing flexibility and malleability to plastics. Among them, several phthalates, including di (2-ethylhexyl) phthalate (DEHP), have emerged as endocrine disruptors, leading to their restriction in consumer products and creating a need for new, safer plasticizers. The goal of this project was to use in vitro functional screening tools to select novel non-toxic plasticizers suitable for further in vivo evaluation. A panel of novel compounds with satisfactory plasticizer properties and biodegradability were tested, along with several commercial plasticizers, such as diisononyl-cyclohexane-1,2-dicarboxylate (DINCH®). MEHP, the monoester metabolite of DEHP was also included as reference compound. Because phthalates target mainly testicular function, including androgen production and spermatogenesis, we used the mouse MA-10 Leydig and C18-4 spermatogonial cell lines as surrogates to examine cell survival, proliferation, steroidogenesis and mitochondrial integrity. The most promising compounds were further assessed on organ cultures of rat fetal and neonatal testes, corresponding to sensitive developmental windows. Dose-response studies revealed the toxicity of most maleates and fumarates, while identifying several dibenzoate and succinate plasticizers as innocuous on Leydig and germ cells. Interestingly, DINCH®, a plasticizer marketed as a safe alternative to phthalates, exerted a biphasic effect on steroid production in MA-10 and fetal Leydig cells. MEHP was the only plasticizer inducing the formation of multinucleated germ cells (MNG) in organ culture. Overall, organ cultures corroborated the cell line data, identifying one dibenzoate and one succinate as the most promising candidates. The adoption of such collaborative approaches for developing new chemicals should help prevent the development of compounds potentially harmful to human health.

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    In-utero Exposure to Low Doses of Genistein and Di-(2-ethylhexyl) Phthalate (DEHP) Alters Innate Immune Cells in Neonatal and Adult Rat Testis.

    Andrology
    Walker C, Ghazisaeidi S, Collet B, Boisvert A, Culty M

    Although humans are exposed to mixtures of endocrine disruptor chemicals, few studies have examined their toxicity on male reproduction. We previously found that fetal exposure to a mixture of the phytoestrogen genistein (GEN) and the plasticizer di(2-ethylhexyl) phthalate (DEHP) altered gene expression in adult rat testes. Our goal was to investigate the effects of fetal exposure to GEN-DEHP mixtures at two doses relevant to humans on testicular function and transcriptome in neonatal and adult rats. Pregnant SD rats were gavaged with vehicle, GEN or DEHP, alone or mixed at 0.1 and 10 mg/kg/day, from gestation day 14 to birth. Fertility, steroid levels, and testis morphology were examined in neonatal and adult rats. Testicular transcriptomes were examined by gene array and functional pathway analyses. Cell-specific genes/proteins were determined by quantitative real-time PCR and immunohistochemistry. GEN-DEHP mixtures increased the rates of infertility and abnormal testes in adult rats. Gene array analysis identified more genes exclusively altered by the mixtures than individual compounds. Altered top canonical pathways included urogenital/reproductive developmental and inflammatory processes. GEN-DEHP mixtures increased innate immune cells and macrophages markers at both doses and ages, more strongly and consistently than DEHP or GEN alone. Genes exclusively increased by the mixture in adult testis related to innate immune cells and macrophages included Kitlg, Rps6ka3 (Rsk2), Nr3c1, Nqo1, Lif, Fyn, Ptprj (Dep-1), Gpr116, Pfn2, and Ptgr1. These findings demonstrate that GEN-DEHP mixtures at doses relevant to human induce adverse testicular phenotypes, concurrent with age-dependent and non-monotonic changes in testicular transcriptomes. The involvement of innate immune cells such as macrophages suggests immediate and delayed inflammatory responses which may contribute to testicular dysfunction. Moreover, these effects are complex and likely involve multiple interactions between immune and non-immune testicular cell types that will entail further studies.

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    Impact of Endocrine-Disrupting Chemicals on steroidogenesis and consequences on testicular function

    Molecular and Cellular Endocrinology.
    Walkers C, Garza S, Papadopoulos V, Culty M

    Testicular steroidogenesis is a tightly regulated process that produces the androgens important for the development, maintenance and function of the male reproductive system. These androgens are also essential for overall health, and well-being. Disruptions in the ability of the testis to form steroids can result in developmental abnormalities, dysfunction, and infertility. Endocrine-disrupting chemicals (EDCs) can interfere with the intricate signaling and metabolizing networks that produce androgens and promote their dysfunction. These chemicals are found ubiquitously in our environment, as they are integral components of products that are used every day. The effects of EDCs, such as bisphenols, phthalates, and alkyl chemicals, have been studied independently, revealing deleterious effects; but the combined influence of these structures on steroidogenesis has yet to be completely elucidated. This manuscript presents an updated review on EDC mixtures and their impact on testicular function and fertility, highlighting new findings that illustrate the anti-androgenic capabilities of EDC mixtures.

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    Impact of Fetal Exposure to Endocrine Disrupting Chemical Mixtures on FOXA3 Gene and Protein Expression in Adult Rat Testes.

    International Journal of Molecular Sciences
    Walker C, Boisvert A, Malusare P, Culty

    Perinatal exposure to endocrine disrupting chemicals (EDCs) has been shown to affect male reproductive functions. However, the effects on male reproduction of exposure to EDC mixtures at doses relevant to humans have not been fully characterized. In previous studies, we found that in utero exposure to mixtures of the plasticizer di(2-ethylhexyl) phthalate (DEHP) and the soy-based phytoestrogen genistein (Gen) induced abnormal testis development in rats. In the present study, we investigated the molecular basis of these effects in adult testes from the offspring of pregnant SD rats gavaged with corn oil or Gen + DEHP mixtures at 0.1 or 10 mg/kg/day. Testicular transcriptomes were determined by microarray and RNA-seq analyses. A protein analysis was performed on paraffin and frozen testis sections, mainly by immunofluorescence. The transcription factor forkhead box protein 3 (FOXA3), a key regulator of Leydig cell function, was identified as the most significantly downregulated gene in testes from rats exposed in utero to Gen + DEHP mixtures. FOXA3 protein levels were decreased in testicular interstitium at a dose previously found to reduce testosterone levels, suggesting a primary effect of fetal exposure to Gen + DEHP on adult Leydig cells, rather than on spermatids and Sertoli cells, also expressing FOXA3. Thus, FOXA3 downregulation in adult testes following fetal exposure to Gen + DEHP may contribute to adverse male reproductive outcomes.

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    IImpact of human-relevant doses of endocrine-disrupting chemical and drug mixtures on testis development and function.

    Reproduction
    Mohajer N and Culty M

    Exposure to EDCs and pharmaceuticals during development has been linked to reproductive dysfunction, reduced semen quality, and infertility. Research indicates that EDC mixtures, which are common in the modern environment, can pose significant risks that may not be fully assessed by studying individual compound toxicity, especially at environmentally relevant doses or concentrations. Understanding the contribution of chemical mixtures to male reproductive toxicity is crucial, given the increasing reliance on pharmaceuticals and pervasiveness of anthropogenic pollution. Recent studies on EDC effects have expanded to a more diverse range of microplastics, pesticides, antimicrobials, phytoestrogens, and pharmaceuticals, such as analgesics, which can collectively impact testicular function and fertility. Adverse outcomes observed across studies include reproductive tract malformations, decreased sperm count and motility, lowered testosterone, delayed-onset puberty, and possible causal effects, such as oxidative stress and altered gene expression. Still, limited data exist on combinations of environmental pollutants and pharmaceuticals with ED potential at human-relevant doses. This review of the recent literature aims to synthesize the toxicological impact of low-dose chemical mixtures on male reproductive health. Overall, humans are exposed to EDCs and drugs through various ways, necessitating an understanding of their concomitant effects on male reproductive health.

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  • Affiliations
    • Adjunct Professor, Department of Medicine, Faculty of Medicine, McGill University

  • Patents

    Peripheral-type benzodiazepine receptor: a tool for detection, diagnosis, prognosis, and treatment of cancer

    US20030157095A1

    1998 The expression and subcellular localization of peripheral-type benzodiazepine receptors (PBR) is shown in this application to correlate with the metastatic potential of cells, and increased cell proliferation. Inhibition of PBR expression, function or stability results in a decrease in cell proliferation. Compositions and methods for regulating and/or monitoring PBR and its expression are useful for the detection, diagnosis, prognosis and treatment of solid tumors, in particular, breast cancer.

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    Method to detect breast cancer cells

    WO2007089880A2

    2007 A quantitative method to detect variant and total peripheral-type benzodiazepine receptor expression is provided.

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  • Multimedia
    • Martine Culty, PhD
  • Selected Media Appearances

    Gonocyte Expert Joins Faculty

    USC School of Pharmacy | 09/04/2017

    Martine Culty, PhD, who has joined USC Mann as an associate professor, has been affectionately called “Madame Gonocyte.” She may not have originated the term for these germ cells that serve as the precursor to sperm formation, but if you Google “gonocyte,” her name appears near the top and in numerous entries.

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USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences
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