Table 2.

Key characteristics of male reproductive toxicants and examples from chemicals known to affect the male reproductive system.

Key characteristic	Example toxicants	Known mechanism/pathway associated with adverse male reproductive outcomes	References
1. Alters germ cell development, function, or death	B[a]P	Increased spermatogenic cell apoptosis; altered sperm motility and acrosome reaction	Ramesh et al. 2017; U.S. EPA 2017
	Cadmium	Increased spermatogenic cell apoptosis, reduced sperm count, altered sperm motility	ATSDR 2012; Jenardhanan et al. 2016
	Phthalates	Germ cell degeneration and reduced cell number	Howdeshell et al. 2008; Martino-Andrade and Chahoud 2010; Habert et al. 2014
	4-Methylbenzylidenecamphor	Altered sperm motility via disrupted ${\mathrm{Ca}}^{2+}$ channel function	Schiffer et al. 2014
	Cocaine, sirolimus, sulfasalazine, cannabinoids, DES	Decreased sperm count and motility, altered sperm morphology	Li et al. 2003; Semet et al. 2017
2. Alters somatic cell development, functions, or death	B[a]P	Increased Sertoli cell apoptosis	Ramesh et al. 2017
	Phthalates	Altered Sertoli-germ cell interactions; decreased testosterone production in Leydig cells	Boekelheide et al. 2005; Scott et al. 2009
	Cadmium	Disruption of the blood–testis barrier via alterations in Sertoli cell actin filaments, and assembly of tight junctions	Siu et al. 2009; Gao et al. 2015; Li et al. 2016; de Angelis et al. 2017
	PCBs	Decreased Sertoli cell metabolic functions and viability	Jenardhanan et al. 2016
	Alcohol, phthalates	Increased Fas-mediated Sertoli and germ cell apoptosis	Lucas et al. 2009; Pourmasumi et al. 2017; Sansone et al. 2018
3. Alters production and levels of reproductive hormones	DDT	Increased hepatic expression of CYP3A4 and metabolism of sex hormones	Laurenzana et al. 2002; Medina-Díaz et al. 2007
	Linuron	Decreased fetal androgen production/levels	Hotchkiss et al. 2008; Wilson et al. 2008; Scott et al. 2009; Dent et al. 2015
	Phthalates, sirolimus	Decreased expression of steroidogenic enzymes and reduced androgen production	Hotchkiss et al. 2008; Bergman et al. 2013; Semet et al. 2017
	Ketoconazole, prochloraz	Inhibition of the steroidogenic enzyme CYP17A1 activity	Scott et al. 2009; Dent et al. 2015
	PCBs, B[a]P	Decreased serum levels of reproductive hormones; decreased androgen production in Leydig cells	Meeker and Hauser 2010; Jenardhanan et al. 2016; Ramesh et al. 2017; U.S. EPA 2017
	Opiates	Reduced androgen levels and secretion of gonadotropin-releasing hormone; increased aromatase expression	Bawor et al. 2015; Drobnis and Nangia 2017; Semet et al. 2017
	Cadmium	Alterations in LH associated with changes in prolactin secretion; decreased Leydig cell steroidogenic enzyme activity, cAMP levels, and expression of the LH receptor	Siu et al. 2009; Lafuente 2013
4. Alters hormone receptor levels/functions	Prochloraz, linuron, procymidone, vinclozolin, flutamide, cyproterone acetate, DDT	AR antagonism	ATSDR 2002; Hotchkiss et al. 2008; Wilson et al. 2008; Scott et al. 2009; Dent et al. 2015; Semet et al. 2017
	DES	Activation of estrogen receptor	Henley and Korach 2006
	B[a]P	Activation of AHR resulting in increased expression of xenobiotic metabolic enzymes and formation of reactive metabolites and ROS	Ramesh et al. 2017
	Cadmium	Reduced levels of the LH Receptor	Gunnarsson et al. 2007; Wan et al. 2011
5. Is genotoxic	Acrylamide	Increased germ cell formation of gylcidamide-DNA adducts	Estill and Krawetz 2016
	Cadmium, PCBs	Chromatin fragmentation, and ROS-dependent DNA damage in germ cells	Meeker and Hauser 2010; Tavares et al. 2016; de Angelis et al. 2017
	B[a]P, cisplatin, carboplatin	Increased DNA adducts and DNA fragmentation in spermatozoa and testicular tissue	Vakalopoulos et al. 2015; Tavares et al. 2016; Ramesh et al. 2017; U.S. EPA 2017
	Alcohol	Altered sperm chromosome number (aneuploidy), and increased DNA fragmentation	Kapp 2010; Pourmasumi et al. 2017
	Chlorambucil, cyclophosphamide, procarbazine, melphalan	DNA alkylation, altered DNA structure and function	Vakalopoulos et al. 2015
	Ethane-methane sulfonate	Increased/irreversible spermatogonia DNA damage resulting in necrosis	Woldemeskel 2017
6. Induces epigenetic alterations	TCDD, methoxychlor, alcohol	Altered germ cell DNA methylation patterns	Anway et al. 2005; Paoloni-Giacobino 2014; Skinner 2016; Chastain and Sarkar 2017; Pilsner et al. 2017; Ding et al. 2018
	Vinclozolin	Altered sperm ncRNAs, DNA methylation, histone retention sites	Brieño-Enríquez et al. 2015, 2016; Ben Maamar et al. 2018
	Diethylhexyl phthalate	Altered sperm ncRNAs associated with testicular dysgenesis syndrome in mice	Stenz et al. 2017
7. Induces oxidative stress	Cadmium, B[a]P	Reduction in antioxidant enzyme activity, and antioxidant levels	Kapp 2010; Rezk and Sikka 2011; Lafuente 2013; de Angelis et al. 2017; Ramesh et al. 2017
	TCDD	Decreased tissue antioxidant levels	Lavranos et al. 2012
	Lindane, methoxychlor	Reduction in antioxidant enzyme activity	Jenardhanan et al. 2016
8. Induces inflammation	Cadmium, TCDD, silver nanoparticles	Increased testicular expression/levels of pro-inflammatory markers. Increased testicular edema	Siu et al. 2009; Sengupta 2013; de Angelis et al. 2017; Pilsner et al. 2017
	TCDD	Increased testicular prostaglandin levels	Bruner-Tran et al. 2014

Note: AHR, aryl hydrocarbon receptor; AR, androgen receptor; B[a]P, benzo[a]pyrene; ${\mathrm{Ca}}^{2+}$, calcium ion; cAMP, cyclic adenosine monophosphate; CYP3A4, cytochrome P450 family 3 subfamily A member 4; CYP17A1, cytochrome P450 family 17 subfamily A member 1; DDT, dichlorodiphenyltrichloroethane; DES, diethylstilbestrol; LH, luteinizing hormone; ncRNA, noncoding RNA; PCBs, polychlorinated biphenyls; ROS, reactive oxygen species; TCDD, tetrachlorodibenzodioxin.