Environmental Research 213 (2022) 113666

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Environmental Research
journal homepage: www.elsevier.com/locate/envres

Review article

Adverse reproductive and developmental consequences of quantum dots

Yongshuai Yao a, Zhaofang Chen b, Ting Zhang a, **, Meng Tang a, *
a
Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, People’s Republic of China
b
State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, People’s Republic of China

A R T I C L E I N F O A B S T R A C T

Keywords: Quantum dots (QDs), with a size of 1–10 nm, are luminescent semiconductor nanocrystals characterized by a
Ecological problems shell-core structure. Notably, QDs have potential application in bioimaging owing to their higher fluorescence
Cellular mechanism performance than conventional fluorescent dyes. To date, QDs has been widely used in photovoltaic devices,
Population and community
supercapacitors, electrocatalysis, photocatalysis. In recent years, scientists have focused on whether the use of
Quantum dots (QDs)
QDs can interfere with the reproductive and developmental processes of organisms, resulting in serious popu­
Reproductive and developmental toxicity
lation and community problems. In this study, we first analyze the possible reproductive and development
toxicity of QDs. Next, we summarize the possible mechanisms underlying QDs’ interference with reproduction
and development, including oxidative stress, altered gametogenesis and fetal development gene expression,
autophagy and apoptosis, and release of metal ions. Thereafter, we highlight some potential aspects that can be
used to eliminate or reduce QDs toxicity. Based on QDs’ unique physical and chemical properties, a compre­
hensive range of toxicity test data is urgently needed to build structure-activity relationship to quickly evaluate
the ecological safety of each kind of QDs.

1. Introduction application will undoubtedly generate more opportunities of environ­

Quantum dots (QDs), which are composed of a group of chemical
elements of group III-V or group II-VI, are semiconductor nanoparticles
with fluorescent properties. The particles are generally made of one
semiconductor material as the core, and another as the shell to increase
its core stability and bio-compatibility. Some of the examples include
CdTe/ZnS QDs composed of CdTe core and ZnS shell. Typical QDs have a
small size, ranging from 1 to 10 nm, which confers them with high
specific surface area and reactivity (Alivisatos, 1996). At present, QDs
have been applied across a wide range of fields, including fabrication of
solar cells, supercapacitors and light emitting diodes (Li et al., 2015; Lim
et al., 2015; Zhou and Coleman, 2016; Zhu et al., 2020). In the field of
bio-medicine, QDs were first used for biological imaging as early as 1998
(Rocha et al., 2017). Consequently, they have become promising diag­
nostic and therapeutic biomaterials for use in drug delivery and bio­
logical imaging (Matea et al., 2017), owing to their high light stability,
narrow and symmetrical emission peaks, as well as a wide absorption
spectrum, emission wavelength tunability, and biodegradability (Ple­
skova et al., 2018). The basic structure and biological uses of QDs are
illustrated in Fig. 1. It is envisaged that future increase in demand and
mental leakage in the process of synthetic, utilization and disposal.
Consequently, biological communities could contact QDs through
breathing, ingestion, and skin contact. Among all types, cadmium
(Cd)-based QDs have become the most studied in biological imaging,
such as CdSe/ZnS QDs and CdTe/ZnS QDs, due to their excellent lumi­
nous efficiency. However, Cd-based QDs that had been in the environ­
ment for a long-time release Cd2+. Based on these insights, QDs
properties, such as nano characteristics, more contact opportunities and
heavy metal ions release, have raised concerns regarding their ecolog­
ical safety. Previous studies have demonstrated that QDs have obvious
toxicity, such as cytotoxicity (Katubi et al., 2019), genotoxicity (Alaraby
et al., 2015; Wang et al., 2015), neurotoxicity (He et al., 2019), and
organ toxicity (Wang et al., 2016, 2016; Zhao et al., 2019).
In the field of reproduction and development, there were several
reports have shown that the future of humanity may be threatened by
infertility (Sengupta et al., 2017; Talmor and Dunphy, 2015). QDs may
help to provide insight into the mechanisms of reproductive and
developmental diseases. Currently, Feugang et al. (2015) proved that
mammalian gamete labeling for coupled or uncoupled QDs was effective
for in vitro monitoring and in vivo target imaging. On the other hand,

* Corresponding author.
** Corresponding author.
E-mail addresses: zhangting@seu.edu.cn (T. Zhang), tm@seu.edu.cn (M. Tang).

https://doi.org/10.1016/j.envres.2022.113666
Received 17 March 2022; Received in revised form 16 May 2022; Accepted 9 June 2022
Available online 10 June 2022
0013-9351/© 2022 Elsevier Inc. All rights reserved.
Y. Yao et al. Environmental Research 213 (2022) 113666

QDs may pass from generation to generation, with larval exposed to

Fig. 1. Basic structure of a typical QD and its biological applications.
Dubertret et al. (2002) have performed in vivo imaging with
QDs-micelles by microinjecting in early-stage Xenopus embryos.
Conversely, some researchers found that nanomaterials interfered with
reproductive and development when the concentration and exposure
time exceed a certain threshold. For example, Orbea et al. (2017)
demonstrated that silver nanoparticles (NPs) reduced the fertility of fish,
thereby causing embryo deaths and deformity. On the other hand, gra­
phene oxide-engineered nanomaterials promoted germ cell apoptosis
and cell cycle stagnation in Caenorhabditis elegans (C. elegans), which was
attributed to DNA damage (Zhao et al., 2016). Moreover, Kong et al.
(2017) found that exposure to nickel NPs markedly reduced offspring,
zygote, spermatid activation and increased intergenerational time and
out-of-round spermatids in C. elegans. This suggested the need to care­
fully assess the potential effects of QDs to reproduction and development
prior to their use for disease diagnosis and treatment. Moreover,
reproduction and development are fundamental events in all living or­
ganisms, which are also related to the maintenance of populations and
communities in ecosystems. To date, however, it is not known whether
QDs leaking into the environment can cause serious ecological problems
after large scale commercialization. Therefore, we provide an overview
on the possible ecological problems associated with QDs from a repro­
duction and developmental standpoint. In this review, we first summa­
rize the effects of QDs on reproduction and development, then discuss
several mechanisms through which QDs disrupt the aforementioned
processes. Finally, we suggest potential ways of solving these problems
with regards to physicochemical properties of QDs.
them found to exhibit abnormal phenotypes and growth inhibition.
Notably, these phenomena have been attributed to nutrition storage
failure, especially fat. After exposure to E. coli food source of 200 nM
CdSe/ZnS QDs from L1, Kim et al. (2018) found C. elegans at stage of
lethal BOW (eggs retained and hatched inside parental body (Pluskota
et al., 2009)) transferred QDs to offspring; because germline stem cell
(GSC) proliferation was regulated by lipid (Chen et al., 2016, 2016b),
early reproductive senescence occurred in the second generation may be
due to decreased fat storage at the L2/L3 stage (Kim et al., 2018).
Exposure of adult C. elegans to 1 μM CdSe/ZnS QDs-MSA resulted in
larvae that exhibited abnormal phenotypes, such as internal, pharyngeal
and posterior deformities, as well as growth inhibition (Hsu et al., 2012).
Notably, Wang et al. (2016) attributed the adverse effects on growth
caused by acute 10 nM CdTe QDs exposure to disrupted basal endosome
recycling and nutrition storage in intestinal cells. The aforementioned
defects on spawning of parental C. elegans as well as destruction of
endocytosis process and nutrient savings shortened the lifespan. In
contrast, some reports have indicated that exposure of C. elegans to
E. coli exposed to 20 nM Carboxyl CdSe@ZnS QDs for 48h resulted in no
dramatic effect on reproduction and development (Kim et al., 2016).
This discrepancy in results across studies might be attributed to the
exposure method, dosage used and the exposure time. The effects of QDs
on reproduction and development across various stages of C. elegans
growth are illustrated in Fig. 2, while details on C. elegans are outlined in
Table 1.
2.2. Fish
QDs have adverse effects on reproduction and development of fish,
which may threat high-level organisms, aquatic organism communities
and ecological environment. Among all fish, zebrafish embryos and
larval are the most studied. As Bai and Tang (2020) said, zebrafish is
playing an increasingly important role in nanotoxicology due to its
excellent properties. During 4 nM carboxylated CdSe/ZnS QDs exposure
for 12 days, aggregates comprising QDs and mucus induced mechanical

2. QDs toxicity on reproduction and development in different

organisms

2.1. Caenorhabditis elegans

The gradual increase in application of QDs has affected the charac­

teristics of inhabiting soil and sediments thereby making C. elegans an
important system for studying QDs’ ecotoxicity in soil of terrestrial bi­
omes. In addition, C. elegans have an evolutionary conservative genetic
background which ensures that results obtained from their research
were of great value to humans (Park et al., 2017). Accumulating
research evidence has shown that QDs affect reproduction and differ­
entiation of germ cells, thereby reducing fertility of C. elegans. Prolonged
exposure (from L1 to adult day 1) to >50 mg/L CdTe QDs was associated
with reduced germ cells undergoing mitotic and meiotic (pachytene and
diakinesis), decreased production and ovulation of fertilized eggs, as
well as reduced brood size and egg-laying rate (Qu et al., 2019).
Moreover, QDs destroyed immature eggs and affected the spawning
process. Qu et al. (2011) found that chronic exposure (16 days) to 200
μM CdTe QDs caused damage to eggs left in the vulva, eggs with broken
shell and difficulty in spawning. Another research showed 1 μM
QDs-mercaptosuccinic acid (MSA) induced constitutive hyperactive
egg-laying phenotype (less than 10 embryos retained in the womb Fig. 2. Toxic effects of QDs on reproduction and development of C. elegans
(Schafer, 2006)) after 3 days exposure, these C. elegans gave birth to across various stages, modified images from Wormatlas database (WormAtlas,
Altun, Z.F., Herndon, L.A., Wolkow, C.A., Crocker, C., Lints, R. and Hall, D.H.
immature embryos (Hsu et al., 2012).
(ed.s) 2002–2021. http://www.wormatlas.org).

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Y. Yao et al. Environmental Research 213 (2022) 113666

Table 1
Detailed data on Caenorhabditis elegans and fish.
Quantum Dots Size Dose Exposure duration Model Results Reference

3-Mercaptopropionic acid 3.5 ± 0.49 5, 25, 50 and 100 Prolonged exposure C. elegans Defects of reproductive capacity, Qu et al.,
(MPA)- nm mg/L dysfunctional proliferation and (2019)
capped CdTe QDs differentiation of germ cell (≥50 mg/L).
Imbalanced oogenesis.
SPO-11 and PCH-2 were shown to
mediate toxicity mechanism and GLP-1/
Notch was shown to mediate a productive
mechanism.
CdSe QDs 3.4 nm Cd: 10, 50, 100 mg/ Start from L4 C. elegans Decreased brood size in CdSe QDs group Contreras
CdSe/ZnS QDs 4.1 nm L throughout their life of generation 1. et al., (2013)
Hydrody- span C. elegans can acclimate to low QDs
namic exposure e.g., fertility, length after
diameter multigeneration.
(HD): both Biological effects of CdSe QDs were
were: ~17 related to Cd.
nm
Three sized CdTe QDs 3.2 ± 0.2 nm 1×10− 6 ~ Short-term: C. elegans Chronic exposure of QDs impaired bowel Wang et al.,
QD520 5.5 ± 0.35 10×10− 6 M L2-L4 cell function, affected substance intake, (2016)
QD660 nm Long term: L1-young storage and reuse, thereby reduced
QD755 7.4 ± 0.5 nm adult animal growth (after 24h) and life span
(after 72 h).
QD660 also resulted food avoidance
behavior.
MPA-CdTe QDs, HD:10 nm 20, 200 nM 2, 12, 24, 48 h, or C. elegans The accumulation of QDs in the uterus Qu et al.,
MPA- and 2-mercaptoe­ longer time and vulva caused problem to the (2011)
thylamine (MEA)- immature eggs and difficulty in egg-
CdSe@ZnS QDs layin’g process.
CdSe/ZnS Dry state: 0.0, 0.01, 0.1 and 1 Egg-laying defects: 3d C. elegans Egg-laying defect led by disrupted of Hsu et al.,
QDs-MSA 5.8 nm μM Others: 6d Hermaphrodite-specific motor neurons. (2012)
HD: ~6.5 High embryonic mortality and reduced
nm life span (1 μM QDs-MSA). Larval
abnormal phenotypes.
CdSe/ZnS Not 200 nM 48h C. elegans BOW phenotype at F0 influenced inter- Kim et al.,
with COO− mentioned generation transfer, F2 (d) generation (2018)
showed early
reproductive senescence caused by
abnormal GSC and more reproductive
abnormalities.
Carboxyl- CdSe/ZnS 15–20 nm. 0, 1, 5, 10, 15, 20 48 h C. elegans QDs were limited to the intestine Kim et al.,
HD: 20 nm nM intestinal lumen without internalization (2016)
into the reproductive.
No significant effect on survival and
reproduction.
InP/ZnS QDs with a ~4.5 nm 0, 50, 100, 200, From blastocyst stage Rare Low survival rate. Abnormal hatching. Chen et al.,
carboxylate ligand 400, 800 nmol/L to 96 h post Minnow embryos Development toxicity. Malformation was (2018)
fertilization (hpf) and larval related to increased expression level of
Wnt8α and Mstn. Oxidative stress.
CuInS2/ZnS ~4.5 nm 0, 50, 100, From 4- to 32-cell Rare Abnormal hatching. Death and Liu et al.,
QDs -MPA 200, 400, stages minnow development toxicity. Decreased heart (2017)
800 nmol/L to 96hpf embryos and rate. Oxidative stress, influenced
larval expression of Wnt8α and Mstn explained
body malformations.
CDs 2–6 nm 0, 1, 5, 10, 20, 40, From blastocyst stage Rare Embryo yolk turbidity/agglutination. Xiao et al.,
and 80 mg/L to minnow embryos Development toxicity was related to (2016)
96hpf and larval oxidative stress and altered expression of
Wnt8α and Mstn.
Ca2+-ATPase and Na+/K+-ATPase
activity decreased.
GQDs 1~9 nm 25,50 or 100 mg/ Illumina high Zebrafish embryos Excessive activated complement system Deng et al.,
mL -throughput RNA- and larvae and renin-angiotensin system. GQDs may (2018)
Sequencing. induced ROS-AP1-Il8 signaling pathway.
qPCRs GQDs activated the redox-sensitive
analysis:7d signaling pathway. Apoptosis was
AO/EB double probably regulated through AP-1-
staining:48h mediated FasL signaling pathway.
CdSe QDs- ~3.5 nm 0, 0.05, 0.15, 0.45, 6–120 hpf Zebrafish embryos High mortality. Low hatch rate. Zhang et al.,
MPA 1.35, and larvae Malformation. Cell apoptosis in the head (2012)
4.05, 12.15, and tail. Abnormal vascular pattern.
31.25 mg/L Altered neurobehavior.
Non-doped, nitrogen- 4.0, 2.5 and Non- 24–96 h Zebrafish embryos N-doped and N, S doped CQDs: yolk sac Chousidis
doped, nitrogen, sulfur-co- 8.0 nm doped:150–1200 edema, tail bending. et al., (2020)
doped CQD μg/mL, Non-doped: yolk sac edema.
N- doped: Low growth rate and length.
250–1000
(continued on next page)

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Y. Yao et al. Environmental Research 213 (2022) 113666

Table 1 (continued )
Quantum Dots Size Dose Exposure duration Model Results Reference

μg/mL, More active in the dark than in the light,

N, S-doped 75–400 especially doped QDs.
μg/mL.
Lecithin- Not Low QDs: Twice a day dietary Fundulus Increased malondialdehyde (MDA) level Blickley
CdSe/ZnS mentioned 0.5 μg QDs + 5 μg exposure for 85 days heteroclitus in males. et al., (2014)
QD lecithin Hepatic vitellogenin(vtg) transcription of
High QDs: males was elevated in high QDs diet.
5.0μgQDs + 5 μg Cadmium was detected in embryos that
lecithin. were spawned during the fourth spawn,
but no teratogenic effects.
Carboxylate HD: 50–100 4 nM Rainbow trout: from Embryos of pearl QDs did not get into the embryo. Rotomskis
CdSe/ZnS QDs nm 24 to 26 to 36-day- gourami, QDs agglomerated with mucus, et al., (2018)
post fertilization. zebrafish, and separated from chorionic, which
Zebrafish: rainbow trout. destroyed the integrity of the chorion.
1 to 3d. Malformation, DNA damage in rainbow
Pearlgourami: 1d trout embryos.
CdSe/ZnS- ~5–7 nm 4 × 10− 9mol/L 1, 4, 14 days Embryos of QDs were localized in the larval head(gill) Jurgelene
polyethylene glycol (PEG) Rainbow Trout region. et al., (2018)
QDs Oncorhynchus Increased mortality and gill ventilation
mykiss frequency. Not nesting.
Decreased relative body mass. Blood clots
in the head area and yolk sac.
Reduced graphene oxide Lateral:10 0, 25, 50 and 100 7 days Zebrafish rGOQDs were mostly distributed in the Zhang et al.,
QDs nM, μg/mL yolk sac of embryos and the abdomen of (2017)
(rGOQDs) Height the larvae.
: 1 nm Altered heart rate and teratogenic effect
at 100 μg/mL.
GQDs 2–5 nm 12.5, 25, 50, 4–96 hpf Zebrafish QDs accumulation in the heart and Wang et al.,
100, and 200 μg/ embryo intestines. Malformation. (2015)
mL Disturbed neurobehavior.
ZnSe/ZnS QDs 10 nm 0–800 nmol/L Single Rare minnow Damaged male reproductive system of Ding et al.,
for 0.20 intraperitoneal parents and F1 generation. (2021)
mL/100 g injection.

damage to the chorion membrane that has a protective effect on embryo
(Rotomskis et al., 2018). Exposure to QDs during embryonic life,
numerous studies have demonstrated that QDs passed through the
chorion and accumulated in embryos; QDs-based toxic effects on
zebrafish embryos and larvae include decreased survival rates, disturbed
neurological behavior, hatching inhibition, increased prevalence of
malformations and abnormal vascular patterns; some studies have also
demonstrated that QDs conferred cardiotoxicity to zebrafish embryos
and larvae, evidenced by pericardial edema and abnormal heart rates
(Chen et al., 2018; Chousidis et al., 2020; Jurgelene et al., 2018; Liu
et al., 2017; Wang et al., 2015; Xiao et al., 2016; Zhang et al., 2017).
Profiles of QDs toxicity on embryos and several typical teratogenic
manifestations in zebrafish models are illustrated in Fig. 3. Deformity
caused by exposure to 25–200 μg/mL graphene QDs (GQDs) for 7 days
or 12.15 mg/L CdSe QDs for 3 days is partly attributed to apoptosis in
embryonic cells or larvae that was not destined to be part of the
developmental process (Deng et al., 2018; Zhang et al., 2012a,b). Pre­
vious studies have reported that embryonic hatching relies on mem­
brane lipid peroxidation and incubation enzymes to reduce the ductility
of the membrane, and this is followed by autonomous movement of the

Fig. 3. (a) Profiles of QDs embryotoxicity in zebrafish. (b) Normal larvae; (c–e) abnormal larvae. MT, metallothionein; PE, pericardial edema; VC, vitelline cyst; BS,
bent spine; BT, bent tail (Wang et al., 2015).

4
Y. Yao et al.
embryo to cause mechanical tearing of the chorion (Yamagami, 1988).
Notably, >40 mg/L Carbon QDs (CDs), >50 nmol/L CuInS2/ZnS QDs
and >400 nmol/L InP/ZnS QDs exposure for 96h may disturb these two
processes in rainbow trout, thereby resulting in abnormal hatching
(Chen et al., 2018; Liu et al., 2017; Xiao et al., 2016).
In addition, 10 μg CdSe/ZnS QDs/day for 85 days were found to not
only mediate a reduction in female spawning ability in Fundulus heter­
oclitus, but also reduce the size of testes in males (Blickley et al., 2014).
In addition, >50 nmol/L ZnSe/ZnS QDs via intraperitoneal injection
were implicated in sperm DNA damage and decreased sperm motility in
rare minnow, phenomena that were also observed in the F1 generation
(Ding et al., 2021). Detailed data on fish are shown in Table 1.
2.3. Mammals
2.3.1. Males
Previous studies have revealed that males treated with QDs exhibit a
decline in reproductive function in rats/mice, evidenced by pathological
injury in their testes, reproductive endocrine disorders, sperm damage
and harmed females mated with treated males and their offspring. CdSe/
ZnS QDs have been shown to cross the blood-testis barrier and accu­
mulated in testis after single intravenous injection of 2 nmol/kg QDs (Li
et al., 2021). Moreover, single injection of 0.2 or 2 nmol CdTe QDs or 40
mg/kg CdSe/ZnS QDs induced degenerated interstitial tissue and pa­
thology for seminiferous tubules, such as destruction of spermatogenesis
layers, apoptosis of Sertoli cells, vacuolation, deformation and atrophy
of seminiferous tubules, larger space between seminiferous tubules and
blood vessels (Amiri et al., 2016; Li et al., 2016). However, daily in­
jection of 100 mg/kg dextrin-coated cadmium sulfide nano-particles
(CdS-Dx/QDs) for a week did not show any histopathological changes
(Reyes-Esparza et al., 2015). Considering that sex hormones regulate
various molecular events during spermatogenesis (Kumar et al., 2018),
studies have focused on changes in hormonal levels and found that
GOQDs and GQDs affect growth of TM-4 cells (derived from mouse
sertoli cells) and TM-3 cells (mouse testicular stromal cells) after expo­
sure to 100 μg/mL and 0.5 mg/mL for 24h respectively (Ji et al., 2016;
Zhang et al., 2019). Notably, single intravenous injection of 0.2 and 2.0
nmol CdTe QDs was associated with marked changes in levels of estro­
gens, serum testosterone (T), follicle-stimulating hormone (FSH) and
luteinizing hormone (LH) in male rats (Li et al., 2016). Intraperitoneal
single injection 5 and 10 mg/kg CdTe QDs altered steroid hormone
biosynthesis (Khoshkam et al., 2018).
With regards to effect on sperm, results from in vitro experiments
revealed that, after incubation of 1 or 5 nM bioluminescent resonance
energy transfer-conjugated (BRET)-QDs for 30 min, BRET-QDs mostly
appeared on the pig sperm plasma membrane and were rarely distrib­
uted in the cytoplasm of the head (Feugang et al., 2012). Moreover, after
100 μg/mL CdTe QDs incubation for 2 h, CdTe QDs entered the cell
depths (~10 nm or deeper) of mice sperm (Akhavan et al., 2016). Direct
interaction between QDs and sperm, pathological changes of repro­
ductive organs and changes in hormone levels inevitably have adverse
effects on spermatogenesis. Reports have shown that 0.2 or 2 nmol/mice
CdTe QDs or 0.5 mg/kg CdTe QDs reduce viability and velocity of
sperms, alter their morphology (evidenced by abnormal and loose
heads), induce DNA fragmentation as well as lower acrosome integrity
of the sperm (Akhavan et al., 2016; Li et al., 2016). In addition, QDs
exposure was associated with reduced number of germ cells. Studies
have demonstrated that 100 mg/mL GOQDs exposure for 24h caused
apoptosis in mouse GC-2 Cells (immortalized mouse spermatogonia) in
vitro (Ji et al., 2016). Tail vein injection at 2 nM/day CdSe/ZnS QDs in
200 mL phosphate buffer for 5 consecutive days induced apoptosis in
mouse spermatocytes (Yang et al., 2020). Akhavan et al. (2016) reported
that single intravenous injection of 0.5 mg/kg CdTe QDs-treated male
mice exhibited a 34% reduction in total sperm count than their un­
treated counterparts. Amiri et al. (2016) discovered that single intra­
peritoneal injection of 40 mg/kg CdSe/ZnS QDs mediated a marked
5
Environmental Research 213 (2022) 113666
decrease in the mean number of spermatogonia, spermatocytes I and
spermatids.
Interestingly, exposure of male mice to QDs has been found to affect
hormone levels and conception of pregnant females as well as offspring
survival. For example, pregnant female mice mated with 0.5 mg/kg
CdTe QDs-treated male mice exhibited an overall reduction in hormone
secretion, with FSH, LH, progesterone and prolactin hormones found to
reduce by 21, 34, 14 and 26%, respectively. In addition, pups recorded
~26 and ~39% reduction in fertility and viability, respectively (Akha­
van et al., 2016). In general, GQDs have very low effects on male rats’
fertility and offspring viability (Zhang et al., 2019).
2.3.2. Females and offspring
Previous studies have shown that QDs can disrupt female endocrine,
inhibit oocyte development and maturity as well as suppress fertilization
ability. CdTe/ZnTe QDs-Transferrin (Tf) bioconjugates can enter both
theca and granulosa cells, although the zona pellucida prevents QDs
from entering the oocyte; QDs-Tf (>2.8 mol/L) changed 17β-estradiol
production of preantral follicle culture media after 4 days culture,
thereby compromising oocyte cytoplasmic maturation (Xu et al., 2012).
On the other hand, after subcutaneous injections of CdSe/ZnS QDs for 14
consecutive days, Xu et al. (2016) found that CdSe/ZnS QDs with a dose
of 5.0 pmol/mouse appeared in the ovaries, a phenomenon that was
accompanied by significant downregulation of follicle-stimulating hor­
mone receptor (FSHr) and luteinizing hormone receptor (LHr) mRNAs in
the ovaries as well as a reduction in the numbers of matured oocytes
when concentration of QDs at 1.0 pmol, which may contribute to
decreased fertilization ability of oocytes after QDs treatment. Based on
these results, changes in reproductive endocrine may partly explain the
decreased ratio of matured oocytes and fertilization ability. Besides, Lin
et al. (2019) demonstrated that 1.0 and 1.5 mg/mL GQDs disrupted
spindle positioning and actin cap formation after 8.5h exposure, thereby
inhibiting oocyte maturation in mice after 12h exposure. Moreover, tail
vein injection of 0.5 μM CdSe/ZnS QDs of 100 μL at gestation day (GD)
16 and 18 also suppressed the level of pregnancy-related sex hormones
and placenta polypeptides, including placental lactogen (PL), proges­
terone (Prog), estradiol (E2) and pregnancy specific β1-glycoprotein
(PAPP-A), thereby causing deterioration of the pregnancy environment
(Zhang et al., 2016).
Studies on QDs effects on growth and development of offspring can
be roughly classified into three categories, namely complete in vitro
experiments; in vitro exposure followed by embryo transplantation into
recipient mice; and complete in vivo experiments. In the first category,
researchers employed the murine limb bud culture system to demon­
strate that although 100 nM QD-MPA did not pass through the skin, they
inhibited limb development and chondrogenesis after 6 days exposure
(Bigaeva et al., 2015). In the second category, researchers have mostly
focused on the effects of QDs on development of the embryo sac, from
fertilization to post-implantation. It is evident that QDs, such as CdSe
QDs, inhibited early embryonic growth and development or even lead
embryonic death. Notably, 500 nM CdSe QDs pretreatment of oocytes
ready for fertilization for 24 h led to a significant decrease in tro­
phectoderm (TE) cells instead of inner cell mass (ICM), while 250 and
500 nM CdSe QDs pretreatment of blastocysts for 24h induced apoptosis
in the ICM but not in the TE (Chan and Shiao, 2008; Hsieh et al., 2009).
Results from experiments conducted entirely in vivo have revealed
that QDs can affect offspring development in a variety of ways, including
(1) reaching the offspring through the placenta or milk and directly
causing toxicity to pups; (2) causing maternal systemic injury; and (3)
causing placental injury. Chu et al. (2010) demonstrated that MPA-,
PEG- and SiO2– CdTe/CdS QDs (containing 125 μg Cd atoms) could cross
the placenta, following complete formation of a placenta barrier, and
subsequently reach the fetus thereby causing death of the offspring (Chu
et al., 2010). Other research evidences have shown that PEGylated
phospholipid micelle-encapsulated CdSe/CdS/ZnS QDs successfully
passed through the placenta of mice after intravenous injection at a
Y. Yao et al.
dosage of 100 mg/kg at embryonic day 17(E 17), although they were not
associated with any direct pregnancy complications (Ye et al., 2019).
Apart from passing through the placenta, Yang et al. (2018) reported for
the first time that a small number of CdSe/ZnS QDs and Cd reached the
descendant stomach and intestine through milk after two tail vein in­
jections of 0.5 or 1 nmol QDs in postnatal day 2 and day 3, thereby
restricting growth and development of offspring. Although some QDs
cannot reach offspring through either the placenta or milk, they can still
harm the fetus through the pregnant mother. After intravenous injection
of 2.5 mg/kg PEGylated phospholipid micelle-encapsulated
CdSe/CdS/ZnS QDs at a gestational age of 100 days, Ye et al. (2019)
found that the abortion rate in macaque monkeys was 4 times the nat­
ural rate, possibly due to QDs-induced acute hepatocellular injury in the
parents. The placenta not only plays an important role in material ex­
change between the mother and the pregnant body, but also functions to
provide nutrients, gas exchange and waste discharge. Injection of QDs
during gestational period, such as CdSe QDs (0.5 μM, 100μL/mice/day
at GD16 and 17), CdSe/ZnS QDs (0.125 μM, 100μL/mice/day at
GD13~18) and CdTe QDs (10 and 20 mg/kg at GD13), can directly
impair placental function, thereby affecting the fetus. These studies have
revealed decreased weight and diameter, and some histopathological
changes of placenta, such as large vacuoles in the placenta junction area,
decreased blood cells in the labyrinth zone, necrotic or deformed tro­
phoblasts, which resulted in fetal death, declined body weight and
length, as well as ossification disorders in limbs and other fetal dysplasia
(Hong et al., 2019; Zalgeviciene et al., 2017; Zhang et al., 2016).
Research advances with respect to reproduction and development of
mammals are summarized in Table 2, the toxic effects of QDs in repro­
duction and development in both males and females are illustrated in
Fig. 4.
3. Mechanisms underlying QDs effects on reproduction and
development
3.1. Oxidative stress
Oxidative stress, induced by excess ROS levels, is the most widely
studied mechanism of QDs action. Under normal physiological condi­
tions, the body maintains a dynamic balance between oxidative and
antioxidant systems (Wang and Tang, 2018). QDs can induce excessive
ROS production. ROS first stimulate the antioxidant defense system,
resulting in the upregulation of several antioxidant-related genes and
proteins, including Nrf 2, HO-1, superoxide dismutase (SOD), catalase
(CAT), and glutathione peroxidase (GPX) (Hong et al., 2019; Zhang
et al., 2016; Chen et al., 2018; Liu et al., 2017; Xiao et al., 2016). When
ROS production exceeds the antioxidant capacity, ROS damage bio­
molecules such as lipids and DNA (Chen et al., 2018; Liu et al., 2017;
Xiao et al., 2016), which may trigger mitochondrial and
lysosomal-mediated apoptosis and autophagy (Yan et al., 2016). DNA
double-strand breaks resulting from ROS accumulation can cause failure
of spindle migration and actin cap formation, thereby inhibiting oocyte
maturation by failing to extrude the first polar body (Lin et al., 2019). In
addition, ROS can induce inflammatory responses via the ROS-AP1-Il-8
pathway in Zebrafish (Deng et al., 2018). Collectively, these results
indicate that antioxidant capacity is related to the magnitude of the toxic
effect during ROS accumulation (Falanga et al., 2018; King-Heiden
et al., 2009; Tian et al., 2019). Therefore, it is possible that improving
antioxidant capacity could suppress adverse effects of QDs on repro­
duction and development.
3.2. Altered gametogenesis and fetal development gene expression
Abnormal expression of genes affects the entire growth process, from
gametogenesis to offspring development. For example, Qu et al. (2019)
found that SPO-11 and PCH-2 were markedly upregulated in MPA-CdTe
QDs group, which caused more DNA and chromosome damage and
6
Environmental Research 213 (2022) 113666
oocytes apoptosis in pachytene. Considering that development results
from expression of various genes according to a rigorous space-time
plan, any interference on gene expression is expected to affect preg­
nancy tissue, or growth and development of the offspring, thereby
causing its deformity or death.
In the sea anemone, Nematostella vectensis, CdTe QDs achieved its
teratogenic effect by mediating upregulation of key genes during em­
bryonic and larval development, such as NvAnthox1a, NvBra1a and
NvMyc (Ambrosone et al., 2014). Vitellogenin (Vtg), the precursor of
yolk protein, is the main nutrient source for early embryo and larval
development. Maselli et al. (2017) found that intergenerational down­
regulation of vtg expression was associated with less newborn from F0 to
F2 of Daphnia magna treated QDs-Indolizidine. Previous studies have
also shown that Wnt8α can promote body length extension by inducing
Wnt/β-catenin signaling (Zhao and Duester, 2009), while Mstn acts as a
negative regulator of growth and development of skeletal muscles in
mammals and fish (McPherron et al., 1997). Bending of the tail and
spine in rare minnow was largely attributed to their uncoordinated
expression, while downregulation of vascular endothelial zinc finger
(Vezf1) reportedly affected development of the cardiovascular system
during early growth stages of the rare minnow (Chen et al., 2018; Liu
et al., 2017; Xiao et al., 2016). Sonic Hedgehog Signaling (SHH) was
closely associated with development of mammal pup (Lee et al., 2017,
2018), whereas upregulation of ptch 1 as well as downregulation of Gli1
and Gli2 indicated off state of the shh signaling pathway after CdSe/ZnS
QDs treatment, a phenomenon that inhibited placenta development.
Meanwhile, inactivation of Gli1 and Gli2 inhibited transcription of
downstream genes that regulate fetal development (Hong et al., 2019).
Upregulation of insulin like growth factor-1 (IGF-1) and epidermal
growth factor (EGF) indicated that CdSe QDs also had an effect on tissue
development in mice (Zhang et al., 2016).
3.3. Autophagy and apoptosis
Autophagy is a dynamic process through which organelles are
delivered to the lysosome for digestion and recycling. Studies have
shown that autophagy plays an important role in survival of spermato­
zoa. Ji et al. (2016) reported that GOQDs weakened lysosomal proteo­
lytic capacity, thereby suppressing the autophagic pathway and
elevating apoptosis of TM-4 cell as well as GC-2 cell. In addition, Yang
et al. (2020) found that CdSe/ZnS QDs-induced elevation in autophagy
inhibited double-strand breaks repair by down-regulating HR pathway
during meiosis prophase I, thereby disrupting meiotic progression,
causing apoptosis of spermatocytes and reducing sperm concentration.
3.4. Release of metal ions
As previously mentioned, QDs comprise group II and VI elements,
namely CdSe, CdTe, and ZnS, among others, or group III and V elements,
such as InP, InAs, and GaN. Entry of QDs into the body, following a series
of metabolic activities, triggers release of internal toxic heavy metals
ions. Consequently, researchers have previously quantified metal ions
leaking from QDs and found that the leaked heavy metals were one of
the causes of toxicity. Well known as Cd, Cd was classified as a human
carcinogen in 1993 by International Agency for Research on Cancer
(IARC) (IARC, 1993). Cd could disrupt the endocrine system, cause
testicular damage (Wang et al., 2017; Wu et al., 2017), cross placenta,
and lead to growth retardation and cognitive impairment (Espart et al.,
2018; Kurita et al., 2018). Many cadmium-based QDs were found to alter
gene expression of metallothionein (MT) and produce characteristic
signs of cadmium toxicity, for example, alteration pattern on estrogenic
metabolites of male mouse (Khoshkam et al., 2018), some aspects of
toxic reaction on zebrafish and C. elegans (Contreras et al., 2013;
King-Heiden et al., 2009). These proved that leakage of cadmium ions is
an important source of toxicity. Although shell can suppress the release
of heavy metal ions and effectively reduce nanotoxicity, it does not fully
Y. Yao et al. Environmental Research 213 (2022) 113666

Table 2
Summary of reproductive and development toxicity to mammal of QDs.
Quantum Dots Size Dose Exposure time/ Model Results Reference
frequency

CdTe-QDs coated 1.4–30 5, 10 mg/kg Intraperitoneal single Adult male NMRI Alteration of steroid hormone Khoshkam et al.,
with mercapto- nm B. W injection mice. biosynthesis, especially in estrogens, (2018)
succinic- acid progesterone, cortisone, aldosterone,
and several estrogenic metabolites.
QDs toxicity was related to Cd2+ and
oxidative stress.
GOQDs 3.28 ± 0, 1, 10, Exposure time: GC-2 cell, TM-4 cell. The enzymatic activities and amount of Ji et al., (2016)
1.16 nm 100 μg/mL 24 h cathepsin B was decreased, degradation
HD: of autophagic substrates was failure,
41 ± 5.18 autophagic flux was blocked,
nm autophagosome accumulated.
Apoptosis in both cells at 100 mg/mL.
CdSe/ZnS QDs 9.5 nm Injection: 0, 0.2 and 2 Animals: single tail vein CD1 male mice. Autophagy inhibitor (3-MA) restored Yang et al.,
nM injection for 5 days. GC-2 cell. homologous recombination (HR) repair (2020)
Cells:0, 0.2 and 2 nM Cells: 6 h pathway, recovered disrupted meiotic
progression (increased percentage at
pachytene stage and decreased
percentage at diplotene stage), reduced
apoptotic spermatocytes and greatly
improved spermatogenic ability.
GQDs 5.25 ± Cells: 0.05, 0.1, 0.3 and Cells: 2, 12, 24 or 48h. Mouse In vivo: Parent: normal sex reproductive Zhang et al.,
1.63 nm 0.5 mg/L. Oral gavage: Oral gavage: spermatogonial cell structure and hormones. QDs did not (2019)
0, 60, 100, 300 mg/kg. every 24h line easily cross the blood-testes barriers.
Injection: 0, 25, 75,150 for 10 days. (GC-1) cells. Offspring: only alkaline phosphatase
mg/kg Single intravenous TM3 cells. (ALP) in oral gavage group and globulin
injection. Male ICR mice. (GLOB) in injection group of first litter
were abnormal, other was normal in
first, second and third litters.
In vitro: decreased TM3 viability
appeared in 0.5 mg/mL QDs.
CdSe/ZnS QDs 6.11 ± 2.5 or 25 mg/kg BW Intravenous injection Male BALB/c mice. Crossing of the blood-testis barrier. Slow Li et al., (2021)
1.03 × growth and abnormal liver and kidney
11.01 ± function parameters in offspring.
1.77
nm
CdTe QDs ~1.9 ± 0.4 0.2 nmol or 2.0 nmol Single intravenous Male BALB/c mice. Impaired sperm and testicular structure. Li et al., (2016)
HD: ~2.0 per mouse injection T levels decreased and FSH levels
nm increased in a dose-and time-dependent
manner, LH levels fluctuated during
trial. Serum T and FSH levels recovered
on day 90.
CdSe/ZnS QDs 2~3 nm 10, 20, 40 mg/kg Single intraperitoneal Adult male and Pathological changes of testis happened Amiri et al.,
injection pregnant mice only in adult 40 mg/kg treatment group. (2016)
BALB/c mice. Impaired sperm.
CdS QDs ~3 nm 100 μg/kg body weight Intraperitoneal Wistar rat. 1 week: the testis showed intense Reyes-Esparza
injection for a single fluorescence in Leydig cells and reduced et al., (2015)
dose or daily during 1 intensity in the seminiferous tubule.
week
CdTe QDs ~5 nm In vitro: In vitro:2h Male Balb/C mice Sperm damage in vivo and in vitro (≥10 Akhavan et al.,
100, 10, 1 In vivo: single and its sperm. mg/mL), endocrine disorders in (2016)
, 0.1 μg/mL intravenous injection pregnant mothers mated with treated
In vivo: males, low pregnancy rates and
~0.5 mg offspring survival rates. ROS production
/Kg B. W in vivo.
CdSe/ZnS QDs TEM: 100 μL of 12.5 μmol Tail vein injection from Female Kunming P0: maternal injury, damaged placenta. Hong et al.,
13 nm QDs/mice/ gestation day 13 to mice. F1 and F2: decreased placental diameter (2019)
HD: day gestation day 18 or and body weight growth.
~20 nm postnatal day 5 Altered Shh signaling pathway and
oxidative stress participated toxic
effects.
CdSe/ZnS QDs and HD: 0.05μМ Tail vein injection at Female Damaged placental led to brain edema, Zhang et al.,
CdSe QDs coated 20 nm and gestation day 16 and 17 Kunming mice. hemoperitoneum, lower weights, fetal (2016)
with amphiphilic 15 nm resorption, undifferentiated limbs.
polymer. Endocrine dysfunction.
Changes in gene expression related to
cell apoptosis, dysplasia, metal
transport, hormone levels, and oxidative
stress levels.
GQDs 40–45 nm In vivo: In vivo: Kunming strain Decreased first polar body extrusion Lin et al., (2019)
15,30 mg single tail vein mice and oocytes. rates and oocytes spindle failed to
/Kg In vitro: 2, 8.5, 12 h anchor to the cortex at 1.0,1.5 mg/mL.
In vitro: No actin cap after 8.5 h Culture.
0.5, 1.0, or 1.5 mg/mL, Dose-dependent increase in ROS and
(continued on next page)

7
Y. Yao et al. Environmental Research 213 (2022) 113666

Table 2 (continued )
Quantum Dots Size Dose Exposure time/ Model Results Reference
frequency

DNA damage. Mitochondrial swelling

and vacuolation. Cristae alteration.
CdSe QDs ~3.5 nm CdSe QDs Exposure time: 24h Oocytes collected CdSe-core QDs affected oocyte Hsieh et al.,
CdSe/ZnS QDs :125, 250, 500 nM from mice maturation and fertilization, blastocysts (2009)
CdSe/ZnS QDs:500 and placenta development,
nM implantation and post-implantation
embryo development.
ZnS-coated CdSe QDs had low toxicity.
Three sized MPA- 1.67± QDs containing 25, 50, Single injection via the Kunming mice. Smaller QDs were more likely to be Chu et al.,
CdTe/CdS QDs. 0.29 nm, 86, tail vein transferred to the fetuses through the (2010)
PEG-CdTe/CdS 2.59± 125 μg Cd/mice, placental barrier and caused dead pups.
QDs 0.43 nm, respectively The larger the dose, the greater the
SiO2–CdTe/CdS 3.21± amount of transfer.
QDs. 0.32 nm, PEG or SiO2 can reduce transfer but not
4.20± completely prevent transfer.
0.86 nm,
4.09±
1.02 nm.
CdSe QDs ~3.5 nm 0–500 nmol Exposure time: 24h Mouse Apoptosis in the ICM (250 or 500 Chan and Shiao
CdSe/ZnS QDs /L Blastocysts. nmol/L), inhibition of formation of the (2008)
2-layer ICM and ectoplacental cones,
inhibition of morula developed into
blastocyst, high rate of resorption rate,
low surviving fetus rate and decreased
fetal weight. ZnS coat reduced toxicity.
CdTe/ZnTe QDs- ~4 nm 0.0289, 0.289, 2.89, Exposure time: 2, 4, 6, Preantral follicles Reduced rate of oocytes antrum cavities Xu et al., (2012)
transferrin 28.9 nM 8d (PFs) in vitro culture and the ratio of matured oocytes with
system. first polar body when the concentration
exceeded 2.89 nmol L− 1.
Carboxylat-ed 9.79 ± 0.1 pmol, Subcutaneous injection Female BABL/mice. QDs accumulated in the ovary(5.0 Xu et al., (2016)
CdSe/ZnS QDs 2.185 1.0 pmol, per day (14 days) pmol).
nm 5.0 pmol Increased rate of immature germinal
HD:14.55 per mouse vesicle breakdown oocyte and
± 4.157 degenerated oocytes.
Nm Matured oocytes had low fertilization
rate (≥1.0 pmol per mouse).
MPA-CdSe/ HD:15.4 3, 30 or 100 nM 1, 3, 24, 72 h or 6 days Murine limb bud QDs only localized at the limb bud Bigaeva et al.,
CdZnS QDs nm culture system. surface. Inhibited expression of markers (2015)
(COL10A1 and COL1A1) of
chondrogenesis and osteogenesis.
Abnormal limb morphology and
differentiation at 100 nM.
PEGylated HD: 60 Mice:25, 50 and 100 Monkey: BALB/c mice. QDs could cross the placenta during Ye et al., (2019)
phospholipid Nm mg/kg at single injection through Cynomolgus pregnancy in both mice and macaques,
micelle- E12 or100 the vein in the left leg. Monkeys. but acute liver injury and possible stress
encapsulated mg/kg at Mice: single caused by the injection may because of
CdSe/CdS/ E17. Monkeys: intravenous injection at high miscarriage rate of macaques.
ZnS QDs 25 mg/kg. E12 or E17.
CdSe/ZnS QDs with 13 nm 2.5nmol/ Tail vein injection in Sprague- Maternal systemic toxicity in a dose- Yang et al.,
surface reactive HD: 20 ± day and 0.5nmol/ postnatal day 2(PD2) Dawley (SD) rats. dependent manner. (2018)
carboxyl group 6.05 day. and PD3. QDs in offspring cannot be absorbed by
Nm MPS (e.g., liver, spleen) and kidney.
MPA- CdTe core QDs TEM: 5 mg/kg Single intraperitoneal Albino Placental tissue damage such as Zalgeviciene
2.3 nm 10 mg/kg injection on GD13. Wistar rats. inflammation, necrosis in the et al., (2017)
HD:4.7 20 mg/kg. trophoblasts in the decidua basalis and
Nm basal zone, cytolysis of glycogen cells
and iron accumulation in cells, reduced
labyrinth and basal layer diameter.
Fetal death and dysplasia

prevent release (Hsieh et al., 2009; Zhang et al., 2016; Zolotarev et al.,
2012). Collectively, these results demonstrate that leaked metal ions
play a crucial role in QDs-induced toxicity in reproduction and
development.
In addition, Xiao et al. (2016) found that deformities in rare minnow
offspring were associated with changes in ion channel (Ca2+-ATPase and
Na+/K+-ATPase) induced by CDs. To date, however, only a handful of
reports have described the underlying mechanisms of action, necessi­
tating further research explorations.
4. Possible physicochemical factors that reduce the toxicity of
QDs
Although QDs’ physicochemical properties endow them with excel­
lent imaging and biocompatibility, some reports have indicated that
their composition, size, surface chemistry, and surface charge have a
significant effect on severity of toxicity (Wu and Tang, 2018). Here, we
summarize methods for elimination or reduction of toxicity in repro­
duction and development with regards to physicochemical characteris­
tics of QDs.

8
Y. Yao et al.
Fig. 4. Categories of QDs toxic effects on reproductive and development in mammals.
4.1. Size
Previous studies have shown that smaller particle sizes ensure easier
access to the target organ and cellular substructures to induce toxicity
(Wu and Tang, 2014). Some pores in organisms, such as those in the
placenta of mammals and chorionic pores of zebrafish embryos, have
nanometer diameter. Therefore, large-sized or aggregated/coagulate
QDs are less likely to pass through the placenta and chorionic pore and
accumulated in embryos, making it more difficult to directly affect
offspring development (Chu et al., 2010; King-Heiden et al., 2009;
Zolotarev et al., 2012). However, the migration and transformation of
QDs in the environment has been associated with dramatic changes in
their particle size, which may lead to agglomeration or other changes.
Future studies are expected to elucidate the migration and trans­
formation processes of QDs in the environment with a view of identi­
fying the association between QDs’ ecological problems with their initial
particle size.
4.2. Surface chemistry
Results from toxicological analyses have demonstrated that surface
modification, either shell or chemical functional groups, can also be
used to control the interaction between QDs and organisms. For
example, more shells are expected to lower QDs toxicity. Like ZnS shell,
CdSe QDs were found to cause adverse effects on reproductive and fetal
development on mouse. However, CdSe/ZnS QDs did not cause signifi­
cant toxicity, possibly because ZnS shell reduced the surface oxidation of
QDs and the release of Cd2+(Chan and Shiao, 2008; Hsieh et al., 2009;
Zhang et al., 2016). Zolotarev et al. (2012) compared their experimental
results with those from single-layered QDs, and found that
double-layered QDs were less toxic to zebrafish larvae than
single-layered counterparts.
With regards to chemical functional groups, Yan et al. (2016) found
that alanine- and glycine-conjugated CdTe QDs were associated with
markedly lower ROS levels and downregulated transcription levels of
autophagy regulation signaling genes compared to CdTe QDs. It seemed
that presence of functionalized surface group makes QDs having a less
toxic, nevertheless, the toxicity of functionalized surface group cannot
be ignored. For example, poly-L-lysine, CdSe/ZnS-poly-L-lysine QDs
were highly toxic to zebrafish embryos and larvae, although a low Cd
burden in zebrafish (King-Heiden et al., 2009). Collectively, these phe­
nomena may be explained by the fact that alanine and glycine are
neutral in charge under biological PH, whereas lysine is positively
9
Environmental Research 213 (2022) 113666
charged. Positively charged QDs come into easy contact with negatively
charged cells. Neutral charges tend to cause agglomeration of QDs which
may impede their efficacy. Such a disparity in surface charge may have
resulted in the different toxicity between poly-L-lysine QDs Vs. alanine
and glycine QDs. Qu et al. (2011) suggested that negative surface
charged QDs had lower toxicity to development of C. elegans larvae
relative to positively charged QDs.
In summary, when QDs with heavy metals as nuclei are used, they
should be wrapped without compromising its performance to reduce the
release of heavy metal ions, and then modified with non-toxic negatively
charged ligands to enhance their water solubility and reduce their
toxicity. Of course, the best way is to use non-metallic core QDs as an
alternative.
In addition to size and surface chemistry, Chousidis et al. (2020)
found developmental toxicity is also associated with doping different
heteroatoms in QDs.
N, S-doped carbon QDs were the most toxic to zebrafish embryos, as
evidenced by the most significant alterations to larval morphology and
behavior, these were followed by N-doped carbon QDs and non-doped
carbon QDs. Therefore, researchers are advised to pay attention to pu­
rity when designing and producing QDs.
5. Perspectives
Given the increasing application of QDs, it is extremely important to
study and solve the problems associated with its large-scale use. How­
ever, due to the unique physical and chemical properties of QDs, their
exposure pathways, biological activities and target organs are different
from those of ordinary substances, thus exhibiting a spectrum of
reproductive and developmental toxic effects of varying magnitude.
Therefore, we hope to find low toxicity QDs or find a breakthrough in
reducing the toxicity of QDs through toxicity evaluation on the basis of
maintaining the excellent photoelectric properties.
The establishment of risk assessment tools requires data from large
databases. Therefore, the scope of research should also cover all aspects
of testing, from cellular level to organism level, from parental repro­
ductive organs, endocrine organs, gametes to multi-generation effect.
For mammals, some in vitro tests should be carried out to reveal the
mechanism of reproductive and development toxicity. For aquatic or­
ganisms, future research should focus on reproductive and endocrine
functions, and the relationship between them, to understand the toxicity
of QDs more comprehensively. In addition, it is very important to choose
an ideal model animal, just like C. elegans. Although the physiological
Y. Yao et al.
complexity of C. elegans is not as good as that of rodents, C. elegans
provides a physiological environment that is not available in vitro
models. In addition, the physiological control of germline development
of C. elegans and mammals share many molecular and biological simi­
larities, such as the AMPK, Insulin/IGF, TGFβ, and TOR-S6K signaling
pathways, data obtained in C. elegans can be extrapolated to a certain
extent to humans. C. elegans therefore bridges the gap between in vitro
tests and mammalian experiments. Also, C. elegans can reveal the eco­
toxicological effects of QDs.
Given that there are many types of QDs each with different physical
and chemical properties, the reproduction and development effect of
each type of QDs should to be assessed separately, which is exhausted. It
is therefore important to assess dose, time and multiple physicochemical
features of the QDs and to determine whether there is a structure-
activity relationship for QDs. For example, researchers should investi­
gate the kind of QDs that easily pass through the placenta to reach the
offspring, especially for emerging QDs. Apart from QDs, organisms in
aqueous environment face a more complicated environment. The
reproductive and developmental toxicity of QDs is not only affected by
QDs, instead, other elements such as Cu2+ synergize with QDs should be
considered (Zhang et al., 2012, 2013). Aggregated QDs and ions in the
aquatic environment make the results of toxicity evaluation of single QD
inaccurate. Therefore, understanding the transfer, transformation of
QDs, and how they interact with other substances is necessary.
Studies have shown that for pregnant couples, several factors such as
age, time, sex, frequency, and pathways of exposure, affect QDs toxicity.
For example, the QDs-modified nano-tracer showed differential distri­
bution pattern in the offspring, uterine, and placenta after injection into
pregnant rats in the early, middle, and late pregnancy (Kim et al., 2020).
Injection of QDs two weeks before mating did not produce any preg­
nancy complications and adverse pregnancy outcomes in the treated
animals, F1, and F2 offspring (Liu et al., 2017). Elsewhere, it was re­
ported that reproductive toxicity of QDs in marine mussel Mytilus gal­
loprovincialis and silkworm were sex-dependent, probably due to
difference in structures and size of gonad (Gonçalves et al., 2020; Yan
et al., 2016). Therefore, future studies should investigate the repro­
ductive and developmental-specific toxicity induced by QDs. The
observed changes in individual survivorship were then extrapolated to
population or community. We believe, through precise design and
reasonable and effective use, QDs can play their greatest role in the
future.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgement
This work was supported by National Natural Science Foundation of
China (No. 82173545, 21876026, and 31671034), the Natural Science
Foundation of Jiangsu Province (BK20180371).
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