Nanoparticles and Spermatogenesis: How do Nanoparticles Affect Spermatogenesis and Penetrate the Blood–testis Barrier

Zhou Lan; Wan-Xi Yang

Nanomedicine. 2012;7(4):579-596.

Abstract and Introduction

Abstract

Due to the widespread use of nanomaterials in medical, industrial and military applications, the question as to whether nanoparticles (NPs) cause harmful disturbances in human health, especially on the reproductive system, remains a matter of concern. In this review, we focus mainly on the in vivo and in vitro effects of NPs on spermatogenesis at the clinical, cellular and molecular levels. In general, most NPs display adverse effects on spermatogenesis at these various levels; but, some NPs show no adverse effects. However, the mechanism underlying NP disruption of spermatogenesis and penetration of the blood–testis barrier remains unclear. In this review, we raise many hypotheses for experimental testing in order to elucidate the mechanism.

Introduction

Nanotechnology is a rapidly emerging industrial area that studies and develops materials with surface structure and chemical properties on the nanoscale dimension and with special properties arising from this. One of the definitions of the term nanoscale is particles that are <100 nm in at least one dimension^[1] and which are therefore called nanoparticles (NPs). However, some particles that are >100 nm but <1000 nm are also called NPs if the particles demonstrate some special properties. For example, recent advances in nanotechnology allowed the production of a unique copper nanostructure that combines two special properties of strength and ductility that are often mutually exclusive.^[2]

In the past decade, the nanotechnology industry has grown rapidly worldwide and predictions indicate continued growth in the future. The cause of this rapid growth involves the ever-expanding applications of nanomaterials/NPs in the following areas: catalysts, fuel lubricants, paints, conductive inks, cosmetics, drug delivery, hydrogen storage, sensor devices, structural materials, medical therapeutics, UV light absorption, and free-radical scavengers.^[3] Recently, the applications of NPs have expanded to include measurement science,^[4] dermatology,^[5] cancer therapy^[6] and even cosmetics.^[7] This rapid growth calls into question not only the health of workers at the manufacturing plant but also the health of the public due to the release of nanomaterials/NPs in the environment.

Stern and McNeil reviewed NP safety issues and identified areas of agreement and disagreement with regard to NP risk, NP exposure and NP hazards.^[8] They not only indicated that a paucity of NP safety studies exist but also that the NP safety studies are predominantly acute toxicology studies, not chronic studies. In addition, the current paradigm of NP safety focuses only on NP size as the determining factor in toxicity to the exclusion of other important NP properties (e.g., surface structure, surface chemistry, inorganic or organic surface coatings) that significantly change NP biocompatibility. Other studies and reviews have also addressed the issue of safety concerns and NP toxicology.^[9–14]

Epidemiologists have taken an active interest in male reproductive health because young men in some regions demonstrate suboptimal sperm quality and sperm number.^[15,16] The alarming fact is that both human sperm quality and sperm number have declined in recent years and the cause is unknown in the majority of cases. The possibility of public exposure must be considered. Hoover et al. indicates that the potential routes of exposure to NPs include inhalation, dermal and possibly ingestion exposures, and that a wide range of NP sizes, shapes, functionalities, concentrations, exposure frequencies and durations are involved.^[17] Despite the abovementioned findings, the role that NPs play as a reproductive toxicant in spermatogenesis remains largely unknown. In this regard, Ema et al. reviewed the reproductive and developmental toxicity of NPs.^[9] Ema et al. indicated that in vivo studies show that titanium dioxide (TiO₂) NPs injected subcutaneously into pregnant mice result in male offspring with altered spermatogenesis and histopathological changes in the testes, and that carbon black (CB) NPs instilled within the trachea of pregnant mice result in male offspring with altered spermatogenesis.^[9] In addition, Ema et al. indicated that in vitro studies show that: TiO₂ and CB NPs affect Leydig cell viability; gold NPs reduce human sperm motility; and silver, aluminum and molybdenum trioxide NPs damage spermatogonia stem cells.^[9] However, we admit that no obvious clinical evidence shows a direct cause–effect relationship between the problem of human sperm quality/quantity and NPs. Cormier et al. pointed out that particles will affect the human reproductive system, but what kind of particles (NPs or non-NPs) affect the human reproductive system were not pointed out.^[18] The fact that the problem of human sperm quality and quantity could be caused by multiple factors makes it impossible to come to an absolute conclusion. However, the many experimental results on model animals and considerable exposure of humans to NPs make it reasonable for us to consider that NPs may be one of the factors. Bonde et al.^[19] points out that less-appropriate parameters, incomplete data and insufficient statistical methods have led to the inaccurate conclusion that the quantity as well as the quality of sperm has been declining, which was made by Farrow in 1994.^[16] Bonde et al. also thought that not only environmental toxicants, but also the wide range of behavioral, medical and other factors that have the potential to damage human reproduction should be taken into consideration.^[19] Our conclusion is, that according to the previous result that NPs affect animal spermatogenesis and the fact that NPs exist in our environment, we can at least give a warning that NPs may be a threat to people who are largely exposed to them.

By contrast, not all NPs will necessarily demonstrate an adverse effect leading to toxicity. For example, Shi et al. reported that nanoselenium (nano-Se) diet supplementation produced positive effects on various parameters of sperm quality in male goats.^[20] Thus, NPs must be investigated on a case-by-case basis without a predetermined bias as to whether a NP will have a positive or negative effect on a particular system or parameter.

In addition, spermatogenesis occurs in a very safe environment because of the blood–testis barrier (BTB).^[21] NPs, theoretically speaking, cannot penetrate the BTB. However, the following studies discussed in this article show that NPs have the capacity to penetrate the BTB while non-NPs do not.

In order to summarize the extent of our knowledge at the present time, this review mainly focuses on how NPs affect spermatogenesis at the clinical, cellular and molecular levels, and how NPs penetrate the BTB.

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Table 1. Summary of the effects of nanoparticles on spermatogenesis on all three levels (clinical, cellular and molecular).
Nanoparticle	Features of material	Size (nm)	Test animals (age)	Dose	Administration	Time after administration or test time	Body weight	Relative reproductive organ (testis)	Oxidative stress indicator (testis)	Distribution features and detection	Seminiferous tubule damage	Sperm damage	Locations of nanoparticles	Ref.
Selenium (Se)	Normal	60–80	Boer goat (2 month)	0.3 mg/kg every day	Oral	12 weeks	NM	NM	GSH-Px (SH)	Detected				[20]
	Normal	60–80	Black taihang goat (90 ± 3 days)	2500 mg/animal every day	Oral	90 days	SH	NM	NM	Detected				[22]
	Normal	20–60	Sprague–Dawley rats (4 weeks)	0.22, 0.31, 0.42 mg/kg body weight per day	Oral	13 weeks	NA	NA	NM	Detected	NM	The control: the membranes enveloping the elongated nucleus of spermatozoon and mitochondria are abnormal	NM	[29]
Magnetic (Fe₃O₄)	Within a silica shell	50	ICR mice (6 weeks)	100, 50 and 25 mg/kg	Intraperitoneally	4 weeks	NA	NM	NM	Detected				[37]
	Fluorescent	50	ICR mice (5 weeks)	4.89 × 10⁵ ± 2.37 × 10⁴/cm³ and 9.34 × 10⁵ ± 5.11 × 10⁴/cm³	Air	4 weeks (4 h/day 5 day/week)	NM	NM	NM	Detected				[38]
Carbon (C)	Nanotube	14, 56, 95	ICR mice (5 weeks)	0.1 mg/mouse and 1.46 µg/mouse, both ten-times per week	Intratracheally		NA	NA	NM	Detected	Nanotreated groups: the rate is higher than the control	NM	NM	[48]
	Amine (NH₂) and carboxylate (COOH)	20–30	Adult male BALB/c mice	Scheme 1: a single dose of 5 mg/kg Scheme 2: five doses over 13 days at 5 mg/kg	Intratracheally	90 days	NA	NA	MDA of 15 days, MWCNT-COOH Scheme 2 group (SH)	Detected; a repairing mechanism found	Higher in the 15th day; returns to normal after 60 days	NA	NM	[49]
Silver (Ag)	Normal	56	F344 rats (5 weeks)	30, 125, 500 mg/kg	Oral	90 days	High dose: 4, 5, 7 weeks (SL); low dose: 10 weeks (SL)	High dose: left testis 90 days (SH)	NM	NM				[54]
	Normal	22, 42, 71, 232	ICR mice (6 weeks)	1 mg/kg	Oral	14 days	NM	NA	NM	Detected; size dependence				[23]
Titanium dioxide (TiO₂)	Normal	25–70	Pregnant Slc:ICR mice	100 µl of 1 mg/ml at 3, 7, 10 and 14 days postcoitum	Subcutaneous injected	Offspring at 4 days or 6 weeks	SL	NA	NM	Detected	The control: the number of Sertoli cells is decreased and the damaged Sertoli cell mitochondria numbers are significantly higher	NA	Spermatids, Sertoli cells and Leydig cells	[60]
Fullerene (C₆₀)	C₆₀HyFn		Rat	4 µg/kg daily for 5 weeks	Oral	5 weeks	NM	NA	MDA (NA) GSH level has a restore mechanism	Detected				[61]
Silicon dioxide (SiO₂)	Normal	10–20	Wistar rats	7.5 mg/kg (high group) and 1.5 mg/kg (low group)	Intratracheally	5 weeks	High group (SL)	NA	MDA high and low (SH) GSH low (SH)	Detected				[63]
	Normal	10 ± 5	Wistar rats	100 mg/kg (low) and 300 mg/kg (high)	Air	65 days	Both high and low groups (SL)	Low (SL)	High: LDH-C4, SDH, MDA and SOD (SH)	Detected	NM	The nano-treated groups: the mobility and normality of the sperm are higher	NM	[65]

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