Table 1.
Phthalate Effects Reported in Mouse, Rat, and Human Fetal Testis Models. The table provides a comprehensive list of reported effects of phthalates on mouse fetal testis and in human fetal testis tissue culture and xenograft models and selected reports on rat fetal testis.
| Species / Reference | Compound | Model | Antiandrogenic effects⁑ | Seminiferous cord effects⁑ | DYG | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| T | LC #† | LC GPE | MAS | MNG | GC #‡ | SC # | SC GPE | dcord | |||||
| Mouse | |||||||||||||
| Gaido et al. (2007) | DBP | IU | NC (1500) | ↑ (250) | ↑ (250) | ||||||||
| van den Driesche et al. (2012b) | DBP | IU | NC (500) | NC (500) | |||||||||
| Heger et al. (2012) | DBP | IU | NC (500) | ||||||||||
| Saffarini et al. (2012) | DBP | IU | ↑ (500) | ||||||||||
| Ungewitter et al. (2017) | DEHP | IU | NC (250) | ↓ (5) | ↑ (250) | ↑ (5) | NC (250) | ↑↓ (5) | |||||
| Gaido et al. (2007) | MBP | IU | NC (1000) | ||||||||||
| Gaido et al. (2007) | MEHP | IU | NC (1000) | ↑↓ (500) | ↑↓ (500) | ||||||||
| Muczynski et al. (2012) | MEHP | IU | ↓ (720) | ||||||||||
| Lehraiki et al. (2009) | MEHP | EV | ↑↓ (200 μM) | NC (200 μM) | ↑↓ (200 μM) | ↑ (200 μM) | ↓ (20 μM) | ||||||
| Muczynski et al. (2012) | MEHP | EV | ↓ (10 μM) | ||||||||||
| Heger et al. (2012) | DBP | XG | NC (500) | NC (500)* | ↑ (250) | NC (500) | |||||||
| Human | |||||||||||||
| Habert et al. (2014) | MEHP | EV | NC (100 μM) | ||||||||||
| Lambrot et al. (2009) | MEHP | EV | NC (100 μM) | NC (100 μM) | ↓ (100 μM) | NC (100 μM) | ↑ (100 μM) | ||||||
| Muczynski et al. (2012) | MEHP | EV | ↓ (20 μM) | ||||||||||
| Mitchell et al. (2012) | DBP | XG | NC (500) | NC (500) | |||||||||
| Heger et al. (2012) | DBP | XG | NC (500) | ↑ (100) | NC (500) | ||||||||
| Spade et al. (2014) | DBP | XG | NC (500) | NC (500) | NC (500) | ↑ (500)** | ↑↓ (500) | ||||||
| Mitchell et al. (2012) | MBP | XG | NC (500) | NC (500) | |||||||||
| Rat | |||||||||||||
| Spade et al. (2018) | BBP | IU | ↓ (750) | ↑ (750) | |||||||||
| Wilson et al. (2004) | BBP | IU | ↓ (1000) | ||||||||||
| Spade et al. (2018) | DBP | IU | ↓ (750) | ↑ (750) | |||||||||
| Mahood et al. (2005) | DBP | IU | ↑ (500) | ||||||||||
| Mahood et al. (2007) | DBP | IU | ↑ (100) | ↑ (100) | ↑ (100) | ||||||||
| Mylchreest et al. (2002) | DBP | IU | ↓ (500) | ↑ (500) | ↑↓ (500) | ↑ (500) | |||||||
| Wilson et al. (2004) | DBP | IU | ↓ (1000) | ||||||||||
| Johnson et al. (2007) | DBP | IU | ↓ (500) | ↓ (100) | ↓ (500) | ||||||||
| Barlow et al. (2003) | DBP | IU | ↑ (500) | ↓ (500) | ↑ (500) | ||||||||
| Shultz et al. (2001) | DBP | IU | ↓ (500) | ↓ (500) | ↑ (500) | ||||||||
| Kuhl et al. (2007) | DBP | IU | ↓ (100) | ↓ (100) | |||||||||
| Thompson et al. (2005) | DBP | IU | ↓ (500) | ↓ (500) | |||||||||
| van den Driesche et al. (2012a) | DBP | IU | ↓ (500) | ↑ (500) | ↓ (500) | ↑ (500) | |||||||
| van den Driesche et al. (2012b) | DBP | IU | ↓ (100) | ↑ (500) | ↑ (20) | ↓ (500) | |||||||
| Lara et al. (2017) | DBP | IU | ↑ (750) | ||||||||||
| Boekelheide et al. (2009) | DBP | IU | ↑ (500) | ↑ (100) | ↓ (500) | ↓ (100) | |||||||
| Kleymenova et al. (2005) | DBP | IU | ↑ (500) | ↓ (500) | |||||||||
| Spade et al. (2015) | DBP | IU | ↑ (500) | ↓ (500) | ↓ (500) | ||||||||
| Spade et al. (2018) | DEHP | IU | ↓ (750) | ↑ (750) | |||||||||
| Parks et al. (2000) | DEHP | IU | ↓ (750) | ↑ (750) | ↑ (750) | ||||||||
| Wilson et al. (2004) | DEHP | IU | ↓ (1000) | ↓ (750) | |||||||||
| Borch et al. (2006) | DEHP | IU | ↓ (300) | ↓ (100) | ↓ (300) | ||||||||
| Spade et al. (2018) | DPeP | IU | ↓ (300) | ↑ (300) | |||||||||
| Furr et al. (2014) | many## | IU | ↓ | ||||||||||
| Hannas et al. (2012) | many## | IU | ↓ | ↓ | |||||||||
| Shono et al. (2000) | MBP | IU | ↓ (1000) | ||||||||||
| Howdeshell et al. (2015) | mixture# | IU | ↓ (215)*** | ↓ (65) | |||||||||
| Heger et al. (2012) | MBP | EV | ↓ (250) | ||||||||||
| Habert et al. (2014) | MEHP | EV | ↓ (10 μM) | ||||||||||
| Heger et al. (2012) | DBP | XGt | ↓ (500) | ↓ (500) | ↑ (250) | NC (500) | |||||||
| Mitchell et al. (2012) | DBP | XG | NC (500)**** | ↓ (500) | ↓ (500) | ||||||||
IU, in utero; EV; ex vivo; XG, xenograft; BBP, benzyl butyl phthalate; DBP, di-n-butyl phthalate; DEHP, di-(2-ethylhexyl) phthalate; DPeP, dipentyl phthalate; MBP, mono-n-butyl phthalate; MEHP, mono-(2-ethylhexyl) phthalate; T, testosterone; NC, no change; ↑ increase; ↓ decrease; ↑↓ dose-response was non-monotonic; LC, Leydig cell; GPE, gene and/or protein expression; SC, Sertoli cell; dcord: seminiferous cord diameter; MAS, masculinization, including anogenital distance, testis descent, or weights of accessory sex organs; DYG, dysgenesis, explicitly identified in the manuscript as such and including non-intact seminiferous cords, ectopic cells, or regions lacking discernable seminiferous cord structure. Dysgenesis is classified separately from Leydig cell and cord effects because it involves both compartments and is associated with exposure during the masculinization programming window.
The lowest dose or concentration at which an effect was reported is presented in parentheses (mg/kg/d unless otherwise noted). Some changes listed are approximations of holistic change such as directional changes in “Leydig cell” or “Sertoli cell” genes in transcriptomic studies.
refers to LC numbers and to effects explicitly described as clustering or as Leydig cell hyperplasia
refers to GC number or apoptosis
Exposure consisted of a mixture of BBP, DBP, DEHP, diisobutyl phthalate (DiBP), and DPeP.
Paper reports dose-response data for many phthalates. No specific effect doses are listed in the table.
1 of 5 genes decreased significantly.
Reported with p=0.051.
Calculated based on the ED50 as a percent of the maximum mixture dose.
Reported with p=0.062.