The potential interaction of environmental pollutants and circadian rhythm regulations that may cause leukemia

Figures & data

Figure 1. Distribution of the different types of leukemias. The percentages of the main types of leukemia are shown according to their acute or chronic character (A), the predominant cell type (B), their classification (C) and according to the ages at which they occur (D). The graphs are based on data taken from Elert (2013).

Figure 2. Mammalian circadian clock controls transcription and circadian oscillations of blood cell components. A) The mammalian circadian clock mechanism is a time-delayed transcription-translation feedback loop (TTFL). BMAL1-CLOCK constitute the positive arm and cryptochrome (CRY1 and CRY2) - period (PER1 and PER2) constitute the repressive arm. REV-ERB inhibitor and RORA activator form a secondary feedback loop that consolidates the primary loop. It also shows which phases occur in the day (sun) and night (moon). B) Circadian oscillations of different cell types present in the blood and bone marrow. The graphs are based on data taken from Haus et al. (1983), Oh et al. (2019) and Paatela et al. (2019). CCG: Clock controlled gene, WBC: White blood cell, HSPC: Hematopoietic stem and progenitor cells, CT: Circadian time.

Table 1. Expression of core clock genes in patients with different types of leukemia.

Leukemia	CLOCK	BMAL1	PER1	PER2	PER3	CRY1	CRY2	Reference
AML	↓	↓	↓	↓	↓	↓	↓	(M.-Y. Yang et al., 2015) (Rahman et al., 2017)
ALL	↓	↓	---	↓	↓	↓	↓	(M.-Y. Yang et al., 2015) (Tomita et al., 2017) (Rahman et al., 2017) (N. Wang et al., 2020)
CML	↓	↓	---	↓	---	↓	=	(Rana et al., 2014) (Rahman et al., 2017)
CLL	↑	↓	↓	↓	---	↓	=	(Y. Yang et al., 2019b) (Rahman et al., 2017)

↑: Increased expression, ↓: Decreased expression, =: Without changes, –-: Undetermined.

Table 2. Changes in the expression of circadian clock genes after exposure to chemical environmental pollutants.

Environmental Pollutant	Model and Dose used	CLOCK	BMAL1	PER1	PER2	PER3	CRY1	CRY2	NR1D1	NR1D2	RORA	Reference
Benzene	9-week-old male BALB/c mice 1 μL/100 g body weight	↓	↓	---	↑	↑	↑	---	---	---	---	(Park et al., 2008)
Cigarette smoke	12-week-old male C57BL/6 mice 125 mg/m^3 TSP, 6 h/day for 18 days	↓	↓	↓	↑	=	↑	=	↓	---	=	(Vasu et al., 2009)
	8-week-old C57BL/6 mice 100 mg/m^3 TSP, 25 h/week for 10 days	↓	↓	↓	↓	---	↓	↓	↑	↓	=	(Hwang et al., 2014)
	11-week-old male C57BL/6 mice 1 h/day for 12 weeks	---	↓	---	↑	↑	---	---	↑	↑	---	(Tsutsumi et al., 2020)
Thifluzamide	1-h postfertilization AB zebrafish embryos 1.9 mg/L for 4 days	↑	↑	↑	↑	↑	↑	=	---	---	---	(Y. Yang et al., 2019a)
Flutolanil	1-h postfertilization AB zebrafish embryos 0.125 mg/L for 4 days	↓	↓	↓	↓	↓	↓	---	---	---	---	(Y. Yang et al., 2019b)
TCDD	8-week-old male C57BL/6 mice 30 μg/Kg every 4 days for 35 days	↓	↓	↓	↓	↓	↓	↓	↓	↓	=	(Fader et al., 2019)
	5-week-old female C57BL/6 mice Single dose 10 μg/Kg	---	↓	↓	↓	---	---	---	---	---	---	(Garrett & Gasiewicz, 2006)
PCB153	4-h postfertilization TL zebrafish embryos 1 μM for 5 days	---	---	↑	↑	↑	↑	---	↑	---	---	(Aluru et al., 2020)
BPA	Mice POMC neurons 100 μM	---	↑	---	↓	---	---	---	---	↑	---	(Loganathan et al., 2019)
DEHP	10-week-old male B6C3F1 mice 1150 mg/Kg for 3 days	↑	---	---	↓	↓	↑	---	↑	---	---	(Currie et al., 2005)

↑: Increased expression, ↓: Decreased expression, =: Without changes, –-: Undetermined, TCDD: 2,3,7,8-tetrachlorodibenzo-p-dioxin, PCB153: 2,2’,4,4’,5,5’-hexachlorobiphenyl, BPA: Bisphenol A, DEHP: Di(2-ethylhexyl) phthalate, TSP: Total suspended particles, POMC: pro-opiomelanocortin.

Figure 3. Impact of aryl hydrocarbon receptor (AhR) activation on circadian rhythms and hematopoiesis. A) The inactive AhR is localized in the cytosol in complex with 90 KDa heat shock protein (HSP90), AhR-interacting protein (AIP), 23 KDa prostaglandin (p23) and cellular-SRC (c-SRC). This can be activated by both endogenous and exogenous (xenobiotic) ligands or agonists. Upon interaction with an agonist, the conformational changes result in the translocation of the complex to the nucleus and the interaction of AhR with BMAL1 after dissociation of the cytoplasmic complex. AhR can compete with CLOCK to form heterodimers with BMAL1 and unlike the CLOCK/BMAL1 dimer that acts as an activator in the promoter E boxes, the AhR/BMAL1 dimer acts as a repressor. B) This causes proteins such as PER1, PER2, CRY1 and CRY2 to not be expressed and, therefore, the amplitude of the circadian oscillations decreases. C) Deregulated AhR signaling in hematopoietic stem and progenitor cells (HSPCs) can cause hematological diseases through a mechanism that is not yet fully understood. AhR overactivation alters bone marrow microenvironment signaling and disrupts quiescence in hematopoietic stem cells (HSCs). Cell proliferation is promoted, and differentiation is altered, favoring mainly the myeloid lineage at the expense of cells of the lymphoid lineage, although AhR overactivation has also been reported in some lymphoid leukemias. LT-HSC: Long-term hematopoietic stem cell, ST-HSC: Short-term hematopoietic stem cell, CMP: Common myeloid progenitor, CLP: Common lymphoid progenitor cell.

Figure 4. Schematic presentation of possible future experimental developments. We consider four levels: determining pollutants and drug intake, their metabolism/transformation, their arrival at the target organs and tissues, and the eventual development/treatment of leukemia in relation to alterations in circadian cycles.

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